User Panel
Originally Posted By exponentialpi: There is and anyone disputing that is not credible. The question is how many would have been prevented if early action therapeutics were pushed instead of the full court press for vaccines. Some should head to the gallows for that. View Quote View All Quotes View All Quotes Originally Posted By exponentialpi: Originally Posted By exDefensorMilitas: Originally Posted By planemaker: Originally Posted By exDefensorMilitas: Originally Posted By exponentialpi: Originally Posted By exDefensorMilitas: Originally Posted By lorazepam: Originally Posted By 79CJ7: Millions more died last year and so far this year. Look up the excess mortality stats. The facts do not support your opinion. Lol, excess mortality. Even though I've been a Flubro since the beginning, there is indeed an increase over the yearly projected deaths in most of the demographic groups. That can't really be disputed. There has been. The question is did it shift timing (were a majority on the end of the mortality table already) or a real impact. We won’t know for a few years. I think the biggest confounding variable to evaluating the impact of the frontloading will be to adequately factor in the migration of people that move from one age demographic to the next. Theoretically, a glut or deficit in the raw number of people moving from a younger to an older demo, could either mask or exacerbate the "apparent" impact, while the underlying statistics tell the opposite story. Hopefully that makes sense. The other thing about 2020 that was discussed previously was that as lockdowns, shutdowns, etc were implemented, people of all age groups simply stopped engaging in the types of activities that they used to do. Some of those were activities that carried risk, eg. driving - more work from home = less driving. It would be interesting to look at a time history to see as people got back to work, lockdowns/shutdowns etc. went away that those risks started increasing again. Bottom line to me is that I'm not convinced "excess mortality" stats are going to tell the whole story. The number is pulled in both directions, but there is excess mortality at the end of the day, due to SARS-CoV-2 There is and anyone disputing that is not credible. The question is how many would have been prevented if early action therapeutics were pushed instead of the full court press for vaccines. Some should head to the gallows for that. To be fair, Operation Warp Speed and the media both shortchanged monoclonal antibodies and fixated heavily on vaccines. Even if mcab's were pushed heavily, I'm not entirely sure if the necessary manufacturing capacity could have been spun up fast enough to make a difference early on. |
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Shit like this is why you don't give typewriters to monkeys. - L_JE
Colonialism, bringing ethnic diversity to a continent near you. - My Father |
bump to turn stuck page
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Let us never forget, government has no resources of its own. Government can only give to us what it has previously taken from us.
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Originally Posted By 79CJ7: 740,000 Americans might disagree with you. If they were still around. View Quote View All Quotes View All Quotes Originally Posted By 79CJ7: Originally Posted By Gunner226: Unless I really take a turn for the worse, I'd put my personal experience in the "moderate cold" catagory, so far. I realize some aren't so lucky, but forcing a vaccine for this is BS. Especially a vaccine that is showing less and less efficacy - if it ever had any efficacy to begin with. This is certainly not the zombie apocalypse virus some of us thought it might turn out to be last January. 740,000 Americans might disagree with you. If they were still around. You still disinfect your mail, don’t you? |
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Originally Posted By fl-ar-fan: You still disinfect your mail, don’t you? View Quote View All Quotes View All Quotes Originally Posted By fl-ar-fan: Originally Posted By 79CJ7: Originally Posted By Gunner226: Unless I really take a turn for the worse, I'd put my personal experience in the "moderate cold" catagory, so far. I realize some aren't so lucky, but forcing a vaccine for this is BS. Especially a vaccine that is showing less and less efficacy - if it ever had any efficacy to begin with. This is certainly not the zombie apocalypse virus some of us thought it might turn out to be last January. 740,000 Americans might disagree with you. If they were still around. You still disinfect your mail, don’t you? A lot of them were riding motorcycles when they died of covid. |
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Let us never forget, government has no resources of its own. Government can only give to us what it has previously taken from us.
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Originally Posted By FlashMan-7k: Ok, now THIS is attention getting: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1023849/Vaccine_surveillance_report_-_week_40.pdf From page 13 (numbered 12 on the pdf) ... Column labelled "Rates among persons vaccinated with 2 doses (per 100,000)" Negative efficacy vs catching the CCP crud, depending on your age group. Yep... think I'm gonna be watching next month's report to see if this isn't a blip... ----- Ok, I give up, the stupid forum upload a jpg thing isn't working and won't tell me why. Managed a reverse search and found a copy on the net: https://westernrifleshooters.us/wp-content/uploads/2021/10/oops-uk-1024x555.png View Quote https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1027511/Vaccine-surveillance-report-week-42.pdf Interpretation of data These data should be considered in the context of vaccination status of the population groups shown in the rest of this report. The vaccination status of cases, inpatients and deaths is not the most appropriate method to assess vaccine effectiveness and there is a high risk of misinterpretation. Vaccine effectiveness has been formally estimated from a number of different sources and is described earlier in this report. In the context of very high vaccine coverage in the population, even with a highly effective vaccine, it is expected that a large proportion of cases, hospitalisations and deaths would occur in vaccinated individuals, simply because a larger proportion of the population are vaccinated than unvaccinated and no vaccine is 100% effective. This is especially true because vaccination has been prioritised in individuals who are more susceptible or more at risk of severe disease. Individuals in risk groups may also be more at risk of hospitalisation or death due to non- COVID-19 causes, and thus may be hospitalised or die with COVID-19 rather than because of COVID-19. The case rates in the vaccinated and unvaccinated populations are crude rates that do not take into account underlying statistical biases in the data. There are likely to be systematic differences in who chooses to be tested and the COVID risk of people who are vaccinated. These biases become more evident as more people are vaccinated and the differences between the vaccinated and unvaccinated population become systematically different in ways that are not accounted for without undertaken formal analysis of vaccine effectiveness as is made clear. NIMS is used as a denominator because it is a database of named individuals eligible for vaccination in which there is a record of each individual’s vaccination status. Attached File It stuck around for the next week. |
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Hnm
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Carry it, shoot it. (repeat forever)
4:1 |
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Originally Posted By exponentialpi: Welcome to 2021 gents. It keeps giving 2020 a run for it's money. https://www.ar15.com/media/mediaFiles/200878/RoundandRound_JPG-2142317.JPG View Quote 2021 has comprehensively kicked 2020's ass. And there's still 2 months to go ... |
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Originally Posted By fl-ar-fan: You still disinfect your mail, don't you? View Quote View All Quotes View All Quotes Originally Posted By fl-ar-fan: Originally Posted By 79CJ7: Originally Posted By Gunner226: Unless I really take a turn for the worse, I'd put my personal experience in the "moderate cold" catagory, so far. I realize some aren't so lucky, but forcing a vaccine for this is BS. Especially a vaccine that is showing less and less efficacy - if it ever had any efficacy to begin with. This is certainly not the zombie apocalypse virus some of us thought it might turn out to be last January. 740,000 Americans might disagree with you. If they were still around. You still disinfect your mail, don't you? A study from several years ago (long before the chinese virus) found feces on nearly 3/4 shopping carts. Look at the people in wally world next to you....they are wiping, picking, and licking all kinds of things....the fat hairy weirdo in line ahead of you is picking his nose, swiping his greasy hair back, farts and then reaches down to scratch his ass....then goes tap, tap, tap on the payment terminal....maybe sneezes in your direction...he was rummaging through all those bags of chips just before you picked out a bag. So his nasty crotch snot is smeared across the top of your chip bag....now you've got the munchies, and open the bag of chips, rubbing your hands through that guys snot, and then you grab a handful of chips and snarf them down....infected snot and all! What about those delicious apples you enjoy? Ever drive by an apple orchard during picking season? Of course, they're all illegals - but anyway, notice where the porta-potty units are - at the edge of the field...no hand washing stations to be seen....last night was chalupa night at Dos Gringos....makes Taco Bell look like quality...the guys in the field just went there last night for cheap beer and chalupas, now they have feel a power growler coming on right before picking shift. It's a mess in there! Unfortunately no hand washing stations...so just wipe hands on pants, and start picking fresh apples for the rich gringos. Now at the store, the apples are all coated with....something...something you're going to eat - because cleaning foods before eating is for pussy doomers! You're so brave! |
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Something to keep an eye out for:
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Originally Posted By FlashMan-7k: Something to keep an eye out for:
View Quote Thanks for sharing. The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. Also, I like that guy's pinned tweet:
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Originally Posted By Obelix45: The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. View Quote The CDC is returning to it's glory days of producing junk studies on gun control and similar issues, with the data carefully selected and massaged to support the predetermined conclusion. |
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Earthsheltered house - a reinforced bunker that even the treehuggers consider to be socially acceptable.
Earthbag house - like an earthsheltered house, but cheaper and easier to DIY. |
Originally Posted By Obelix45: Thanks for sharing. The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. Also, I like that guy's pinned tweet:
View Quote View All Quotes View All Quotes Originally Posted By Obelix45: Originally Posted By FlashMan-7k: Something to keep an eye out for:
Thanks for sharing. The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. Also, I like that guy's pinned tweet:
Maybe they already know the answer because they funded the research into this bioweapon |
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Mach
Nobody is coming to save us. . |
Originally Posted By JPN: The CDC is returning to it's glory days of producing junk studies on gun control and similar issues, with the data carefully selected and massaged to support the predetermined conclusion. View Quote View All Quotes View All Quotes Originally Posted By JPN: Originally Posted By Obelix45: The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. The CDC is returning to it's glory days of producing junk studies on gun control and similar issues, with the data carefully selected and massaged to support the predetermined conclusion. Middle of the worse world health crisis since 1918 and the CDC ( and congress ) is concerned about 'gun violence 'studies makes you wonder what is really going on. |
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Mach
Nobody is coming to save us. . |
Originally Posted By Obelix45: Thanks for sharing. The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. Also, I like that guy's pinned tweet:
View Quote View All Quotes View All Quotes Originally Posted By Obelix45: Originally Posted By FlashMan-7k: Something to keep an eye out for:
Thanks for sharing. The CDC is beyond worthless. They are intentionally undermining public health and scientific knowledge. The fact that the public doesn't notice or care is disheartening to say the least. Also, I like that guy's pinned tweet:
https://technofog.substack.com/p/cdc-emails-our-definition-of-vaccine CDC Emails: Our Definition of Vaccine is "Problematic" CDC: Problematic Vaccine? No, Problematic Definition of Vaccine. Techno Fog 3 hr ago 72 32 Pic unrelated :) The CDC caused an uproar in early September 2021, after it changed its definitions of "vaccination" and "vaccine." For years, the CDC had set definitions for vaccination/vaccine that discussed immunity. This all changed on September 1, 2021. The prior CDC Definitions of Vaccine and Vaccination (August 26, 2021):
Twitter avatar for @RepThomasMassieThomas Massie @RepThomasMassie To many observers, it appeared the CDC changed the definitions because of the waning effectiveness of the COVID-19 vaccines. The effectiveness of the Pfizer vaccine falls over time, with an Israeli study reported in August 2021 as showing the vaccine being "only 16% effective against symptomatic infection for those individuals who had two doses of the shot back in January." The CDC recognizes their waning effectiveness, thus explaining their promotion of booster shots. Of course, the usual suspects defended the CDC. The Washington Post, for example, cast doubt that the CDC changed the definition because of issues with the COVID-19 vaccines. The CDC tried to downplay the change, stating "slight changes in wording over time haven't impacted the overall definition." Internal CDC E-Mails CDC emails we obtained via the Freedom of Information Act reveal CDC concerns with how the COVID-19 vaccines didn't match the CDC's own definition of "vaccine"/"vaccination". It was the CDC's Ministry of Truth hard at work in the face of legitimate public questions. In one August 2021 e-mail, a CDC employee cited to complaints that "Right-wing covid-19 deniers are using your 'vaccine' definition to argue that mRNA vaccines are not vaccines" After taking some suggestions, the CDC's Lead Health Communication Specialist went up the food chain to propose changes to the definitions: "I need to update this page Immunization Basics | CDC since these definitions are outdated and being used by some to say COVID-19 vaccines are not vaccines per CDC's own definition." Getting no response, there was a follow-up e-mail a week later: "The definition of vaccine we have posted is problematic and people are using it to claim the COVID-19 vaccine is not a vaccine based on our own definition." The change of the "vaccination" definition was eventually approved on August 31. The next day, on September 1, they approved the change to the "vaccine" definition from discussing immunity to protection (seen below). There you have it. Affirmative action for the multinational corporations. Why have them improve their vaccines when you can just change the definition of vaccine to fit their ineffective vaccines? Congrats to all the skeptics out there you raised enough concerns that the the CDC went and tried to change reality. |
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We have a new paper to digest:
https://www.mdpi.com/1999-4915/13/10/2056/htm From the journal Viruses. Synopsis - in vitro experiments have confirmed that spike proteins 1) concentrate around the nucleus in a cell 2) interfere with BRCA1 and other natural DNA repair mechanisms including 3) V(D)J recombination which is is an essential part of B and T cell development and building adaptive immunity (https://en.wikipedia.org/wiki/V) This gives a putative mechanism for two anecdotal claims that have been circulating, mainly that T cells (CD4+ and CD8 in particular) get incredibly low for some people after the second and subsequent doses, and that cancer cell activity is heightened because of the lack of immune response. In this case it isn't just the response of immune cells that is being moderated but the intracellular action to repair DNA. In case you didn't know, you all have cancer inside of you, pretty much guaranteed at any given time. Cells proliferate and encounter DNA replication errors when they split, leading to cancer eventually. Our bodies employ mechanisms to repair nicked or miscopied DNA at an intracellular level constantly. Showing that T cells can be affected is one thing, but the disruption of such a fundamental biochemical repair process is alarming when you consider we are instructing cells to churn out the spike protein itself. The authors make this point in their conclusions and propose it as a putative mechanism for some of the shot-related side effects being observed. Are we going to see a lot more cancer and AIDS-like symptoms? Hopefully not in most cases, but some people are going to get unlucky and have this effect them chronically, especially if we enter a regime where regular boosters become the norm. |
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"Nil desperandum, -- Never Despair. That is a motto for you and me. All are not dead; and where there is a spark of patriotic fire, we will rekindle it." - Samuel Adams
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Originally Posted By HighDesert6920: Yes, and groceries. Not necessarily for the virus so much anymore - the fomite transmission has pretty much been shown to be minimal - but for the virus and everything else. A study from several years ago (long before the chinese virus) found feces on nearly 3/4 shopping carts. Look at the people in wally world next to you....they are wiping, picking, and licking all kinds of things....the fat hairy weirdo in line ahead of you is picking his nose, swiping his greasy hair back, farts and then reaches down to scratch his ass....then goes tap, tap, tap on the payment terminal....maybe sneezes in your direction...he was rummaging through all those bags of chips just before you picked out a bag. So his nasty crotch snot is smeared across the top of your chip bag....now you've got the munchies, and open the bag of chips, rubbing your hands through that guys snot, and then you grab a handful of chips and snarf them down....infected snot and all! What about those delicious apples you enjoy? Ever drive by an apple orchard during picking season? Of course, they're all illegals - but anyway, notice where the porta-potty units are - at the edge of the field...no hand washing stations to be seen....last night was chalupa night at Dos Gringos....makes Taco Bell look like quality...the guys in the field just went there last night for cheap beer and chalupas, now they have feel a power growler coming on right before picking shift. It's a mess in there! Unfortunately no hand washing stations...so just wipe hands on pants, and start picking fresh apples for the rich gringos. Now at the store, the apples are all coated with....something...something you're going to eat - because cleaning foods before eating is for pussy doomers! You're so brave! View Quote View All Quotes View All Quotes Originally Posted By HighDesert6920: Originally Posted By fl-ar-fan: Originally Posted By 79CJ7: Originally Posted By Gunner226: Unless I really take a turn for the worse, I'd put my personal experience in the "moderate cold" catagory, so far. I realize some aren't so lucky, but forcing a vaccine for this is BS. Especially a vaccine that is showing less and less efficacy - if it ever had any efficacy to begin with. This is certainly not the zombie apocalypse virus some of us thought it might turn out to be last January. 740,000 Americans might disagree with you. If they were still around. You still disinfect your mail, don't you? A study from several years ago (long before the chinese virus) found feces on nearly 3/4 shopping carts. Look at the people in wally world next to you....they are wiping, picking, and licking all kinds of things....the fat hairy weirdo in line ahead of you is picking his nose, swiping his greasy hair back, farts and then reaches down to scratch his ass....then goes tap, tap, tap on the payment terminal....maybe sneezes in your direction...he was rummaging through all those bags of chips just before you picked out a bag. So his nasty crotch snot is smeared across the top of your chip bag....now you've got the munchies, and open the bag of chips, rubbing your hands through that guys snot, and then you grab a handful of chips and snarf them down....infected snot and all! What about those delicious apples you enjoy? Ever drive by an apple orchard during picking season? Of course, they're all illegals - but anyway, notice where the porta-potty units are - at the edge of the field...no hand washing stations to be seen....last night was chalupa night at Dos Gringos....makes Taco Bell look like quality...the guys in the field just went there last night for cheap beer and chalupas, now they have feel a power growler coming on right before picking shift. It's a mess in there! Unfortunately no hand washing stations...so just wipe hands on pants, and start picking fresh apples for the rich gringos. Now at the store, the apples are all coated with....something...something you're going to eat - because cleaning foods before eating is for pussy doomers! You're so brave! I think you got a bug, because you certainly have diarrhea of the mouth. I don't eat my mail, so I don't understand your dissertation and how disinfecting mail relates to washing food off before you eat it. But, I don't understand a lot of what you doomers do either. |
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Originally Posted By BlackTuono: We have a new paper to digest: https://www.mdpi.com/1999-4915/13/10/2056/htm From the journal Viruses. Synopsis - in vitro experiments have confirmed that spike proteins 1) concentrate around the nucleus in a cell 2) interfere with BRCA1 and other natural DNA repair mechanisms including 3) V(D)J recombination which is is an essential part of B and T cell development and building adaptive immunity (https://en.wikipedia.org/wiki/V) This gives a putative mechanism for two anecdotal claims that have been circulating, mainly that T cells (CD4+ and CD8 in particular) get incredibly low for some people after the second and subsequent doses, and that cancer cell activity is heightened because of the lack of immune response. In this case it isn't just the response of immune cells that is being moderated but the intracellular action to repair DNA. In case you didn't know, you all have cancer inside of you, pretty much guaranteed at any given time. Cells proliferate and encounter DNA replication errors when they split, leading to cancer eventually. Our bodies employ mechanisms to repair nicked or miscopied DNA at an intracellular level constantly. Showing that T cells can be affected is one thing, but the disruption of such a fundamental biochemical repair process is alarming when you consider we are instructing cells to churn out the spike protein itself. The authors make this point in their conclusions and propose it as a putative mechanism for some of the shot-related side effects being observed. e Are we going to see a lot more cancer and AIDS-like symptoms? Hopefully not in most cases, but some people are going to get unlucky and have this effect them chronically, especially if we enter a regime where regular boosters become the norm. View Quote |
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Originally Posted By BlackTuono: We have a new paper to digest: https://www.mdpi.com/1999-4915/13/10/2056/htm From the journal Viruses. Synopsis - in vitro experiments have confirmed that spike proteins 1) concentrate around the nucleus in a cell 2) interfere with BRCA1 and other natural DNA repair mechanisms including 3) V(D)J recombination which is is an essential part of B and T cell development and building adaptive immunity (https://en.wikipedia.org/wiki/V) This gives a putative mechanism for two anecdotal claims that have been circulating, mainly that T cells (CD4+ and CD8 in particular) get incredibly low for some people after the second and subsequent doses, and that cancer cell activity is heightened because of the lack of immune response. In this case it isn't just the response of immune cells that is being moderated but the intracellular action to repair DNA. In case you didn't know, you all have cancer inside of you, pretty much guaranteed at any given time. Cells proliferate and encounter DNA replication errors when they split, leading to cancer eventually. Our bodies employ mechanisms to repair nicked or miscopied DNA at an intracellular level constantly. Showing that T cells can be affected is one thing, but the disruption of such a fundamental biochemical repair process is alarming when you consider we are instructing cells to churn out the spike protein itself. The authors make this point in their conclusions and propose it as a putative mechanism for some of the shot-related side effects being observed. Are we going to see a lot more cancer and AIDS-like symptoms? Hopefully not in most cases, but some people are going to get unlucky and have this effect them chronically, especially if we enter a regime where regular boosters become the norm. View Quote The vaccine causes cancer and aids now lmao |
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... this stuff is the crud that keeps on giving.
https://elifesciences.org/articles/69314 https://elifesciences.org/download/aHR0cHM6Ly9jZG4uZWxpZmVzY2llbmNlcy5vcmcvYXJ0aWNsZXMvNjkzMTQvZWxpZmUtNjkzMTQtdjEucGRmP2Nhbm9uaWNhbFVyaT1odHRwczovL2VsaWZlc2NpZW5jZXMub3JnL2FydGljbGVzLzY5MzE0/elife-69314-v1.pdf?_hash=EmvRHSELeW1%2B6TaCi5lceBOonxLdiPrMYzpcuPgcMEE%3D Effect of SARS-CoV-2 proteins on vascular permeability Rossana Rauti, Meishar Shahoha, Yael Leichtmann-Bardoogo, Rami Nasser, Eyal Paz, Rina Tamir, Victoria Miller, Tal Babich, Kfir Shaked Department of Biomedical Engineering, Tel Aviv University, Israel; School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel; Sagol School of Neuroscience, Tel Aviv University, Israel; Blavatnik School of Computer Science, Tel Aviv University, Israel; Grass Center for Bioengineering, The Hebrew University of Jerusalem, Israel; The Center for Nanoscience and Nanotechnology, Tel Aviv University, Israel Research Article Oct 25, 2021 Cited 0 Views 1,400 Cite as: eLife 2021;10:e69314 doi: 10.7554/eLife.69314 Abstract Severe acute respiratory syndrome (SARS)-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19. Introduction Coronavirus disease (COVID-19) caused by the 2019 novel coronavirus (2019-nCoV/SARS-CoV-2) led to a global pandemic in 2020. By late September 2021, coronavirus had infected more than 220 million people worldwide, causing over 4.5 million deaths. After the initial phase of the viral infection, ~ 30% of patients hospitalized with COVID-19 develop severe disease with progressive lung damage, known as severe acute respiratory syndrome (SARS), and a severe immune response. Interestingly, additional pathologies have been observed, such as hypoxemia and cytokine storm which, in some cases, lead to heart and kidney failure, and neurological symptoms. Recent observations suggest that these pathologies are mainly due to increased coagulation and vascular dysfunction (Lee et al., 2021; Libby and Lüscher, 2020; Siddiqi et al., 2020). It is currently believed that in addition to being a respiratory disease, COVID-19 might also be a ‘vascular disease’ (Lee et al., 2021), as it may result in a leaky vascular barrier and increased expression of von Willebrand factor (VWF) (Siddiqi et al., 2020), responsible for increased coagulation, cytokine release, and inflammation (Siddiqi et al., 2020; Teuwen et al., 2020; Aid et al., 2020; Potus et al., 2020; Wazny et al., 2020; Pum et al., 2021; Barbosa et al., 2021; Lin et al., 2020; Matarese et al., 2020; Xiao et al., 2020). Recent studies suggest that the main mechanism disrupting the endothelial barrier occurs in several stages: First, a direct effect on the endothelial cells that causes an immune response of the vascular endothelium (endotheliitis) and endothelial dysfunction. Second, lysis and death of the endothelial cells Teuwen et al., 2020; Xiao et al., 2020 followed by sequestering of human angiotensin I-converting enzyme 2 (hACE2) by viral spike proteins that activate the kallikrein–bradykinin and renin–angiotensin pathways, increasing vascular permeability (Teuwen et al., 2020; Varga et al., 2020). Last, overreaction of the immune system, during which a combination of neutrophils and immune cells producing reactive oxygen species, inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor), and vasoactive molecules (e.g., thrombin, histamine, thromboxane A2, and vascular endothelial growth factor), and the deposition of hyaluronic acid lead to disruption of endothelial junctions, increased vascular permeability, and leakage and coagulation (Libby and Lüscher, 2020; Teuwen et al., 2020; Varga et al., 2020). Of great interest is the effect on the brain’s vascular system. Cerebrovascular effects have been suggested to be among the long-lasting effects of COVID-19. Indeed, the susceptibility of brain endothelial cells to direct SARS-CoV-2 infection was found to increase due to increased expression of hACE2 in a blood flow-dependent manner, leading to a unique gene expression process that might contribute to the cerebrovascular effects of the virus (Pober and Sessa, 2007). While many studies point out the importance of the vascular system in COVID-19 (Kaneko et al., 2021; Jung et al., 2020b; Nägele et al., 2020), only a few Pons et al., 2020; Chioh et al., 2020; Nascimento Conde et al., 2020; Buzhdygan et al., 2020 have looked at the direct vascular response to the virus. Most of those reports stem from either clinical observations, or in vitro studies or in vivo studies in which animals/cells were transfected with the SARS-CoV-2 virus and their systemic cellular response assessed, without pinpointing the specific viral protein(s) causing the observed changes. SARS-CoV-2 is an enveloped virus with a positive-sense, single-stranded RNA genome of ∼30 kb, encoding 29 proteins (Figure 1). These proteins can be classified as: structural proteins: S (spike proteins), E (envelope proteins), M (membrane proteins), N (nucleocapsid protein and viral RNA); nonstructural proteins: nsp1–16; open reading frame accessory proteins: orf3–10 (Kim et al., 2020; Hu et al., 2021). Table 1 summarizes the known effects of specific SARS-CoV-2 proteins (Gordon et al., 2020; Peng et al., 2020b; Procko, 2020; Cornillez-Ty et al., 2009; Romano et al., 2020; Hillen et al., 2020; Chi et al., 2003). The functionality of some of these is still unknown. Moreover, a considerable knowledge gap still exists regarding molecular mechanisms, especially the protein–protein interaction (PPI) pathways (Cowen et al., 2017), leading to tissue dysfunction. Figure 1 Effect of severe acute respiratory syndrome (SARS)-CoV-2 proteins on endothelial cells. (a) Sketch representing the main organs affected by SARS-CoV-2; (b) structure and gene composition of SARS-CoV-2. Table 1 Severe acute respiratory syndrome (SARS)-CoV-2 proteins. SARS-CoV-2 proteinsGeneral impact Structural proteins S (spike)Spike protein, mediates binding to ACE2, fusion with host membrane Surface glycoprotein, needs to be processed by cellular protease TMPRSS2 (Gordon et al., 2020) M (membrane)Membrane glycoprotein, the predominant component of the envelope A major driver for virus assembly and budding (Gordon et al., 2020) E (envelope)Envelope protein, involved in virus morphogenesis and assembly Coexpression of M and E is sufficient for virus-like particle formation and release (Gordon et al., 2020) N (nucleocapsid)Nucleocapsid phosphoprotein binds to RNA genome (Gordon et al., 2020) Nonstructural proteins nsp1Leader sequence, suppresses host antiviral response Antagonizes interferon induction to suppress host antiviral response (Gordon et al., 2020) nsp2Interferes with host cell signaling, including cell cycle, cell-death pathways, and cell differentiation May serve as an adaptor for nsp3 Not essential for virus replication, but deletion of nsp2 diminishes viral growth and RNA synthesis (Gordon et al., 2020; Procko, 2020) nsp3nsp3–nsp4–nsp6 complex involved in viral replication Functions as papain-like protease (Gordon et al., 2020) nsp4nsp3–nsp4–nsp6 complex involved in viral replication (Gordon et al., 2020) The complex is predicted to nucleate and anchor viral replication complexes on double-membrane vesicles in the cytoplasm (mitochondria) nsp5Inhibits interferon I signaling processes by intervening in the NF-κB process and breaking down STAT one transcription factor Functions as 3-chymotrypsin-like protease, cleaves the viral polyprotein (Gordon et al., 2020) nsp5_c145aCatalytic dead mutant of nsp5 (Gordon et al., 2020) nsp6nsp3–nsp4–nsp6 complex involved in viral replication Limits autophagosome expansion Components of the mitochondrial complex V (the complex regenerates ATP from ADP) copurify with nsp6 (Gordon et al., 2020) nsp7Cofactor of nsp12 nsp7–nsp8 complex in part of RNA polymerase (nsp7, 8, 12 – replication complex)Affects electron transport, GPCR signaling, and membrane trafficking (Gordon et al., 2020; Peng et al., 2020b; Romano et al., 2020; Hillen et al., 2020) nsp8Cofactor of nsp12 nsp7–nsp8 complex in part of RNA polymerase. Affects the signal recognition particle and mitochondrial ribosome (Gordon et al., 2020; Peng et al., 2020b; Romano et al., 2020; Chi et al., 2003) nsp9ssRNA binding protein (can bind both DNA and RNA, but prefers ssRNA) Interacts with the replication complex (nsp7, 8, 12) (Cornillez-Ty et al., 2009) nsp10Cofactor of nsp16 and nsp14 (Romano et al., 2020) Essential for nsp16 methyltransferase activity (stimulator of nsp16) Zinc finger protein essential for replication (Gordon et al., 2020; Peng et al., 2020b) nsp11Unknown function nsp12Functions as an RNA-direct RNA polymerase, the catalytic subunitAffects the spliceosome (Gordon et al., 2020; Peng et al., 2020b; Romano et al., 2020; Hillen et al., 2020) nsp13Has helicase and 5’ triphosphatase activity Initiates the first step in viral mRNA capping nsp13,14,16 installs the cap structure onto viral mRNA in the cytoplasm instead of in the nucleus, where the host mRNA is capped (Gordon et al., 2020; Peng et al., 2020b; Romano et al., 2020; Ivanov et al., 2004) nsp14In addition to the capping function of the methyltransferase, nsp14 is also an endonuclease (3’–5’ exoribonuclease) that corrects mutations during genome replication (Gordon et al., 2020; Peng et al., 2020b; Romano et al., 2020) nsp15Endoribonuclease has uridine-specific endonuclease activity, essential for viral RNA synthesis (Gordon et al., 2020; Romano et al., 2020) nsp16May involve complexation with nsp10 and nsp14, for stabilization of homoenzyme, for capping the mRNA (Gordon et al., 2020; Peng et al., 2020b; Romano et al., 2020) Open reading frame (accessory factors) orf3aPackaging into virions Mediates trafficking of spike protein by providing ER/golgi retention signals Induces IL-6b, activates NF-κB, activates the NLRP3 inflammasome (Gordon et al., 2020) orf3bInterferon antagonist and involved in pathogenesis (Gordon et al., 2020) orf6Type I interferon antagonist, suppresses the induction of interferon, and interferon signaling pathways (Gordon et al., 2020) orf7aMay be related to viral-induced apoptosis (Gordon et al., 2020) orf7bUnknown function orf8Recombination hotspot Induces ER stress and activates NLRP3 inflammasomes Low similarity to SAR-CoV (Gordon et al., 2020) orf9bSuppresses host antiviral response Targets the mitochondrion-associated adaptor molecules MAVS and limits host cell interferon responses (Gordon et al., 2020) orf9cNo evidence that this protein is expressed during SARS-CoV-2 infection (Gordon et al., 2020) orf10No evidence that this protein is expressed during SARS-CoV-2 infection (Gordon et al., 2020) To tackle these challenges, we cultured human umbilical vein endothelial cells (HUVECs) and systematically transduced them with lentiviral particles encoding 26 out of the 29 viral proteins, separately. The three remaining genes were not included in this study purely for technical reasons. We then examined their effects on HUVEC monolayer permeability and the expression of factors involved in vascular permeability and coagulation. The results were analyzed in the context of virus–host and host–host PPI networks. By combining the insights from the experimental and computational results, we generated a model that explains how each of the 26 proteins of SARS-CoV-2, including a mutated form of nsp5, the catalytic dead mutant termed nsp5_c145a, affects the protein network regulating vascular functionality. Moreover, once the PPI model was validated with our experimental data, we applied it to more than 250 proteins that have been identified in the literature as affected by the SARS-CoV-2 proteins. This enabled us to pinpoint the more dominant SARS-CoV-2 proteins and chart their effects. Overall, this work shows how each of the SARS-CoV-2 proteins differentially affects vascular functionality; moreover, once the model was validated, we applied it to identify how SARS-CoV-2 proteins interact with proteins that have been significantly correlated with changes in cell functionality. Results SARS-CoV-2 proteins impair barrier properties affecting cell-junction proteins Increasing numbers of studies indicate a significant role for the vasculature in the physiological response to SARS-CoV-2. However, neither the exact molecular mechanism that leads to these effects nor the individual contribution of any of the SARS-CoV-2 proteins is known. Plasmids encoding SARS-CoV-2 proteins were cloned into lentivirus vectors, with eGFP-encoding vector used as a negative control. To shed light on the vascular response to the virus, HUVECs were cultured on different platforms, transduced with these lentiviral particles, and assessed for the effects of the virus proteins on different functionalities. Culturing HUVEC on Transwells or glass coverslips (Figure 2a) allowed us to identify how the specific proteins affect endothelial functionality. To ensure proper infection, the control vector included a GFP label, which enabled us to estimate infection efficiency at around 70 % (Figure 2a). Since the most basic function of the endothelium is to serve as a barrier, we sought to identify the changes in endothelium permeability in response to the SARS-CoV-2 proteins, and to pinpoint which of these proteins have the most significant effect. Barrier functions and properties were measured via trans-epithelial-endothelial electrical resistance (TEER), a standard method that identifies changes in impedance values, reflecting the integrity and permeability of the cell monolayer (Srinivasan et al., 2015). The GFP control and nine SARS-CoV-2 proteins did not show any significant change in TEER values (compared to the untreated condition), whereas 18 of the SARS-CoV-2 proteins caused significant changes in value (see plot in Figure 2b). The most dominant permeability changes were observed with nsp5_c145a, nsp13, nsp7, orf7a, and nsp2, with a 20–28% decrease in TEER values (Figure 2—figure supplement 1, and Figure 2c), in which the different SARS-CoV-2 proteins are listed and the gradual color change from red to violet represents the progressive reduction in TEER values. Figure 2—figure supplement 1 shows the comparison in TEER values before the infection and 3 and 4 days after the infection, showing that the permeability changes in the cells exposed to the viral proteins are maintained. Figure 2 with 1 supplement Effect of severe acute respiratory syndrome (SARS)-CoV-2 proteins on human umbilical vein endothelial cell (HUVEC) at day 3. (a) Bright-field and fluorescent image of infected eGFP HUVEC, scale bar: 50 µm; (b) changes in barrier functions as a result of SARS-CoV-2 proteins were assessed by trans-epithelial-endothelial … Next, we analyzed some of the proteins that exhibited the most significant (nsp2, nsp5_c145a, and nsp7) or least significant (S) changes in TEER value for changes in expression of the cell-junction proteins such as CD31 (Figure 2d and e), cadherin 1–5, occludin, and ZO 1–3 (presented later), indicating altered barrier functions. Analysis of the immunocytochemistry (ICC) (Figure 2d and e) showed, as expected, that nsp2, nsp5_c145a, and nsp7 significantly reduce the expression levels of CD31 compared to the untreated, eGFP, and S conditions, suggesting a deterioration in barrier function. Hence, these data show a differential effect of SARS-CoV-2 proteins on endothelial functionality and provide a mechanistic explanation for the reduction in endothelial integrity. Increased endothelial inflammatory response caused by SARS-CoV-2 proteins It is known that SARS-CoV-2 can cause a severe cytokine storm (Pum et al., 2021; Wang et al., 2020a) and a significant increase in coagulation-related pathologies. As we were interested in identifying the role of the vasculature in these observations, we stained and analyzed the expression level of VWF (Figure 3a and b), which is highly correlated with coagulation (Rietveld et al., 2019). Similar to the CD31 staining, we characterized only those proteins that resulted in a significant decrease in TEER values (nsp2, nsp5_c145a, and nsp7). As shown in Figure 3a and b, the control samples did not exhibit marked expression of VWF, whereas the cells transfected with nsp2, nsp5_c145a, and nsp7 showed a significant change in VWF expression. Moreover, as VWF is also associated with increased inflammation (Kawecki et al., 2017), we monitored changes in cytokine expression due to the different SARS-CoV-2 proteins (Figure 3c). We were particularly interested in IL-6, which has been identified as one of the most dominant cytokines expressed due to SARS-CoV-2 infection (Wang et al., 2020a; Akbari and Rezaie, 2020; Peruzzi et al., 2020; Liao et al., 2020b; Liao et al., 2020a). We observed that 13 out of the 26 proteins caused an increase in IL-6 secretion, 3 of which had resulted in a decrease in barrier function and increased VWF expression. Figure 3 Human umbilical vein endothelial cell (HUVEC) response to specific proteins. (a) Confocal reconstructions of HUVEC stained for von Willebrand factor (VWF) (green) and Hoechst (blue) for three conditions: control (untreated), eGFP, and nsp5_c145a, scale bar: 20 µm; (b) … Correlation between vascular permeability impairment and viral proteins We then investigated how SARS-CoV-2 causes the observed changes in HUVECs permeability. We collected sets of proteins responsible for specific functionalities of endothelial cells. We also constructed an integrated viral–host and host–host PPI network. For each viral protein and each prior functional set, we measured the network proximity between the viral protein and the human functional set using a network propagation algorithm. We scored the significance of these propagation calculations by comparing them to those obtained on random PPI networks with the same node degrees. Proteins receiving high and significant scores were most likely to interact with the specific SARS-CoV-2 protein and thus might cause the observed functional changes. When comparing the overall effects of the 26 SARS-CoV-2 proteins on endothelial TJ proteins (e.g., cadherin 1–5, occludin, and ZO 1–3), we found a correlation between the effects of the SARS-CoV-2 proteins and TEER values (Figure 4a). Moreover, some of the proteins that significantly affected the TEER parameters (Figure 2c) were also observed to be significantly proximal to the permeability-related set. These included nsp2, nsp7, and nsp13 (Figure 4a). Our algorithm identified cadherin-2, α-catenin, β-catenin, δ-catenin, and ZO 1 and 2 as the most susceptible proteins to SARS-CoV-2 infection (Figure 4b). Figure 4 Correlation between viral protein effect on permeability and proximity to permeability-related proteins in a protein–protein interaction (PPI) network. (a) Correlation of adjusted p-value versus permeability (Pearson = 0.295); (b) proximity between vascular proteins and the viral proteins. To validate our PPI network model, we performed immunostaining of some TJ proteins (β-catenin, cadherin-5, ZO-1, and occludin) of HUVEC transfected with viral proteins and to compare it to the model prediction. Similar to the CD31 staining, we characterized only those proteins that significantly decreased TEER values (nsp2, nsp5_c145a, and nsp7) compared to the eGFP and untreated condition (Figure 5). As shown in Figure 5a–c, the cells transfected with nsp2, nsp5_c145a, and nsp7 showed a significant reduction in the β-catenin, cadherin-5, and ZO-1 intensity, confirming the ability of the SARS-CoV-2 proteins to impair endothelial permeability. Figure 5 Tight-junctions impairment by severe acute respiratory syndrome (SARS)-CoV-2 proteins. Immunocytochemistry (ICC) for (a) β-catenin (green), (b) cadherin-5 (green), (c) ZO-1 (green), (d) occludin (green), and Hoechst (blue) for five specified conditions: untreated, eGFP, nsp2, … Once the model was validated, we used it to identify how the individual SARS-Cov-2 proteins affect nine other different vascular endothelial cells. As a starting point, we created a table (Table 2) (based on the literature) where we compared the expression of 12 different TJ proteins across nine different types of endothelial cells. We then applied the network-based model to identify which endothelial cells are more susceptible to the different SARS-Cov-2 proteins. As can be seen in Figure 6, there are significant differences in the response of various viral proteins on different types of vascular endothelial cells. For example,, the viral proteins nsp13, nsp11, orf6, and S seem to have a significant effect on the different types of vascular endothelial cells, according to the network score detected. However, the proteins m, E, n, nsp12, and nsp8 are the less interactive with the vascular cells. Table 2 Comparison of tight junction (TJ) proteins expression among different types of vascular endothelial cells. Endothelial cells typeTJ proteins Cadherin-2Cadherin-3Cadherin-4Cadherin-5δ-1-Cateninβ-Cateninα-CateninOccludinClaudin-5ZO-1ZO-2ZO-3 Human pulmonary artery endothelial cells (HPAECs) (Nakato et al., 2019; Chi et al., 2003; Ivanov et al., 2004; Ferreri et al., 2008; DiStefano et al., 2014; Zebda et al., 2013; Yuan et al., 2012; Wang et al., 2011)+−−++++++++− Human umbilical vein endothelial cells (HUVECs) (Nakato et al., 2019; Chi et al., 2003; Ferreri et al., 2008; Wu et al., 2008; Dean et al., 2009; Polus et al., 2006; DeBusk et al., 2010; Wessells et al., 2009)++++++++++++ Human umbilical artery endothelial cells (HUAECs) (Nakato et al., 2019; Chi et al., 2003; Davis et al., 2003; Ikuno et al., 2017; Kevil et al., 1998; Kluger et al., 2013)−+−+++−+++++ Human great saphenous vein endothelial cells (HGSVECs) (Nakato et al., 2019; Chi et al., 2003; Latif et al., 2006; Murakami et al., 2008)−−−++−++++++ Human common carotid artery endothelial cells (HCCaECs) (Nakato et al., 2019; Chi et al., 2003)+−+−−+−+++++ Human aortic endothelial cells (HAoECs) (Nakato et al., 2019; Chi et al., 2003; Wu et al., 2017; Sandig et al., 1999; DeMaio et al., 2006)−−−−−+++++++ Human coronary artery endothelial cells (HCAECs) (Nakato et al., 2019; Chi et al., 2003; Wessells et al., 2009; Wu et al., 2004; Pinto et al., 2018)−−++++++++++ Human endocardial cells (HENDCs) (Nakato et al., 2019; Chi et al., 2003; Vestweber et al., 2009; Bao et al., 2017)+−−+−+++++−− Human renal artery endothelial cells (HRAECs) (Nakato et al., 2019; Chi et al., 2003; Maciel et al., 2018)−−++−+−+++−− Figure 6 Correlation between viral proteins and different types of vascular endothelial cells. Correlation of adjusted p-value between vascular proteins identified in vascular endothelial cells and the viral proteins. As our network propagation model is highly correlated with our experimental results, we applied it to other physiological systems that are known to be affected by SARS-CoV-2. We created a list of all proteins that are known to be affected by the SARS-CoV-2 proteins according to the literature (Supplementary file 1A, white columns). The table was composed of both proteins identified experimentally via western blot, proteomics, and immunohistochemistry (marked in blue) and those identified clinically as being highly correlated with loss of specific functionality in specific tissues (marked in red). We then applied the network-based model to identify which proteins in Supplementary file 1A are most susceptible to the different SARS-CoV-2 proteins. As can be seen in Figure 7—figure supplements 2–7, Supplementary file 1A and B, specific SARS-CoV-2 proteins were identified as affecting specific proteins in specific tissues. As expected, most of the SARS-CoV-2 proteins affected more than one protein, the most salient being nsp11, nsp4, and nsp7 (Figure 7b), each of which was predicted to affect more than 40 different proteins. An additional parameter that should be considered is the protein’s ‘distance’ from the viral proteins. This value represents the number of hops in the PPI network from a given protein to the viral proteins, where a value of 1 represents a direct viral–host connection. We hypothesized that the closer the distance between the viral proteins and the given protein, the more significant the viral effect. Supplementary file 1A (gray columns) and Figure 7c present the calculated distances. Most of the identified proteins in Supplementary file 1A were classified with a distance of 1 or 2 from the virus, suggesting more severe putative effects. A very clear example, are the T cells, macrophages, lung epithelial and cardiomyocytes which show that the most significant effect was by the viral proteins which present a close connection with the relative cell proteins reported. This suggest a potential effect on the related functional or metabolic pathway (Supplementary file 1A). Figure 7 with 7 supplements Protein identification using protein–protein interaction (PPI). (a) PPI results for the severe acute respiratory syndrome (SARS)-CoV-2 proteins that have a significant effect on the proteins presented in SI Table 1 for each system; (b) number of proteins … Discussion Due to the impact of SARS-CoV-2, many studies have looked at the physiological responses to the virus (Lee et al., 2021; Libby and Lüscher, 2020; Siddiqi et al., 2020; Teuwen et al., 2020; Chioh et al., 2020). In this work, we sought to identify how specific SARS-CoV-2 proteins affect the vasculature by assessing the effect of individual SARS-CoV-2 proteins on endothelial cells (HUVEC). This approach has significant advantages: it enables pinpointing and isolating how each of the SARS-CoV-2 proteins independently affects the endothelial response, and directly measuring endothelial functionality. The HUVEC model, derived from the umbilical cord, is physiologically representative of the human vascular endothelium, allowing the study of the physiological and pathological conditions as well as the effects of novel drugs on human endothelium (Bouïs et al., 2001; Medina-Leyte et al., 2020). Among technical advantages, cultured HUVECs are a simple in vitro vascular endothelial model, particularly suitable for studying endothelial properties and dynamics as well as the putative role of adhesion molecules, the synthesis of extracellular proteins and blood vessel maturation (Vailhé et al., 2001). The current study showed that almost 70 % (18 out of 26) of the SARS-CoV-2 proteins affect endothelial barrier integrity; however, the most significant proteins were nsp2, nsp5_c145a, and nsp7, which also induced upregulated expression of the coagulation factor VWF and cytokine release. These critical facts can shed light on the multiple pathologies observed in SARS-CoV-2 infection, including cytokine storm, increased coagulation and related diseases (e.g., heart attack and stroke) (Lee et al., 2021; Aid et al., 2020), increased cardiovascular disease, and increased neurological symptoms. The results presented here showed an effect of in vitro cultured endothelial cells, which may lead to vasculature leakiness, consequently causing exotoxicity (i.e., the penetration of toxic reagents from the blood into the brain). While there are many parameters associated with functional changes, the use of advanced tools, including network-based analysis, enabled us to elucidate the specific proteins and the specific interactions that are predicted to cause these changes. The PPI network enabled us to predict that the changes observed in barrier function are possibly due to interactions between host proteins such as cadherin 2, α-catenin, β-catenin, δ-catenin, and ZO 1 and 2, and at least with the viral proteins nsp2, nsp5_c145a, and nsp7. Moreover, we validated our PPI model performing further immunostaining analysis demonstrating not only the ability of the viral proteins to strongly impair TJ expression, but also to confirm the data predicted by our model in which some TJ proteins can be more affected than others. PPI analysis revealed a highly correlated effect of nsp7 and nsp13 on β-catenin in endothelial cells (Figure 4b; Jung et al., 2020a; Lengfeld et al., 2017). Interestingly, neither nsp2 nor nsp5_c145a affected a high number of proteins (Figure 7b), whereas nsp7 did, as identified by the network. Analyzing the repertoire of SARS-CoV-2 proteins, we see almost no effect of the structural proteins; rather, mostly nonstructural and open reading frame proteins affected HUVEC functionality, manifested as decreased barrier function and increased cytokine secretion (Figures 2 and 3). While the nonstructural proteins are mainly responsible for replicating viral RNA, the open reading frame proteins are related to counteraction with the host immune system; some of these are localized to the mitochondria and have been shown to alter the mitochondrial antiviral signaling pathway (Miller et al., 2021). We found that the proteins most affecting barrier function (decreased TEER and decreased CD31, β-catenin, cadherin-5, and ZO-1 expression) and cytokine response (IL-6 secretion and VWF expression) were nsp2, nsp5_c145a, and nsp7 (Figure 2; Figure 3; Figure 6); nsp7 forms a replication complex with nsp8 and nsp12 that is essential for viral replication and transcription (Cowen et al., 2017; Peng et al., 2020a). Peng et al., 2020b suggested that in the core polymerase complex nsp7–nsp8–nsp12, nsp12 is the catalytic subunit, and nsp7 and nsp8 function as cofactors. They further suggested that the mechanism of activation mainly involves the cofactors rather than the catalytic subunit (Peng et al., 2020b). This might explain why we saw mainly an effect of the cofactor proteins on endothelial cells and almost no effect of the catalytic subunit. Network interactions Díaz, 2020 have shown that nsp7 has the most interactions with the host, suggesting a potential target for the treatment of COVID-19. Moreover, no mutations were found in nsp7 compared to nsp2 or nsp5_c145a (Kaushal et al., 2020), suggesting a conserved protein with a vital function in virus survival. The nsp13 protein has both helicase activity and 5’ triphosphatase activity, which play an important role in mRNA capping. We saw a significant effect of nsp13 on barrier function, but hardly any effect on cytokine secretion. Chen et al., 2020, suggested functional complexation between nsp8 and nsp12, the RdRp (RNA-dependent RNA polymerase) replication complex, and nsp13. Given the fact that we observed a substantial effect of nsp7 – one of the proteins of the replication complex – and an effect of nsp13 on HUVEC barrier function, complexation of nsp13 with the replication complex might indicate an important role for this complex in the impaired functionality of the HUVECs, and therefore in the propagation of the disease, and the known vascular damage seen in COVID-19 patients. As suggested by our model, nsp13 seems to have a strong effect also on other types of vascular endothelial cells (Figure 6) as well as on all cell types (Figure 7a), positioning nsp13 as one of the main targets for disease treatment. It is important to note that the comparison between the different endothelial cell types revealed exciting differences in the TJ protein expression, which correlate to the different properties of the different cell types (Nakato et al., 2019). One of the major differences was that some endothelial cell lines do not have cadherin at all (e.g., HAoEC), or very limited amount of cadherin (e.g., HPAEC, HUAEC, HGSVEC). Our model suggests that some endothelial types (e.g., HUVEC, HUAEC, HGSVEC, HCAEC) are more susceptible to the SARS-Cov-2 virus. It, therefore, suggests that the treatment of one type of endothelial cell might be different from another type but offers the PPI model as a tool for initial prediction. Overall, the combination of identifying the differences in the TJ protein expression between the different endothelial cells and the use of the PPI model enabled us to pinpoint the differences in susceptibility to the disease and to identify which specific proteins have the most significant effect. Many studies have looked at the SARS-CoV-2 interaction with nonpulmonary/nonvascular tissues (e.g., neurons, hepatocytes, immune components such as lymphocytes, macrophages, etc.) (Lee et al., 2021), as pathological studies identified a viral effect on these tissues, despite their very limited amount, or lack of ACE2 receptors. To better understand how SARS-CoV-2 interacts with and affects other tissues, we consolidated all of the proteins currently known to be affected by the virus into Supplementary file 1A. It is interesting to note that the most dominant SARS-CoV-2 proteins are nsp4, nsp11, and nsp7. Davies et al., 2020, identified the interaction of nsp2 with nsp4, both involved in endoplasmic reticulum (ER) calcium signaling and mitochondrial biogenesis. This suggests a new functional role in the host ER and mitochondrial organelle contact process and calcium homeostasis. By now it is clear that vasculature plays a significant role in the physiological response to the virus. However, it is still unclear how the virus affects the vasculature, and if it can be found in the blood. This is a critical question, as it has significant consequences on the extent of the virus’s ability to affect the vasculature. Current studies demonstrate that the pulmonary vasculature is significantly affected and is one of the dominant triggers for the pathologies mentioned above. However, involvement with the rest of the vasculature is still unclear, as is whether the virus can be found in an active form in the blood circulation (Peng et al., 2020a; Chang et al., 2020; Orologas-Stavrou et al., 2020; Andersson et al., 2020; Escribano et al., 2020; Wang et al., 2020b). Some studies suggest that even if there are traces of SARS-CoV-2 in the blood, it is not in an active form and cannot cause disease or a systemic response (Andersson et al., 2020). On the other hand, some studies suggest that SARS-CoV-2 can be found in the blood, and can induce the disease and cause both cellular and systemic dysfunction (Peng et al., 2020a; Chang et al., 2020; Escribano et al., 2020). While this question is beyond the scope of this work, it is important to note that if future studies do identify the active form of SARS-CoV-2 in human blood, then the implications of our findings will apply to this systemic response as well (Ahmed et al., 2020; Park et al., 2020). As already noted, the pathology is probably a combination of multiple conditions and pathways activated by the different proteins. However, our findings might open new avenues for future therapeutics. Moreover, most of the proteins that were identified as affected by SARS-CoV-2 had a distance factor of at most three to the human and viral proteins. This coincides with the current dogma, whereby proteins that have a shorter distance between them are more likely to be affected. While beneficial, our approach has two major limitations: (a) our inability to identify the effect of multiple proteins and (b) our neglect of the effect of the coronavirus structure and binding on the cellular response. The former point can be overcome by expressing combinations of different SARS-CoV-2 proteins. However, since the SARS-CoV-2 expresses 29 proteins, there are about ~9 × 1030 possible protein combinations. Therefore, we decided to focus on individual proteins and allow further studies to pursue any combinations of interest. Regarding the latter limitation, we did not include the coronavirus structure (including the ACE2 receptors) in this study, because many studies have already demonstrated the cellular response to this structure (Chioh et al., 2020; Yang et al., 2020; Procko, 2020), and how tissues that do not have significant ACE2 expression (neurons, immune components such as B and T lymphocytes, and macrophages) are affected by the virus remains an open question. Conclusions Accumulating clinical evidence suggests that COVID-19 is a disease with vascular aspects. However, only a few studies have identified the specific role of each of the SARS-CoV-2 proteins in the cellular response leading to vascular dysfunctions. In this work, we characterized the endothelial response to each of 26 SARS-CoV-2 proteins and identified those that have the most significant effect on the barrier function. In addition, we used PPI network-based analysis to predict which of the endothelial proteins is most affected by the virus and to identify the specific role of each of the SARS-CoV-2 proteins in the observed changes in systemic protein expression. Overall, this work identified which of the SARS-CoV-2 proteins are most dominant in their effect on the physiological response to the virus. We believe that the data presented in this work will give us better insight into the mechanism by which the vasculature and the system respond to the virus, and will enable us to expedite drug development for the virus by targeting the identified dominant proteins. Materials and methods Generation of lentiviral SARS-CoV-2 plasmids Request a detailed protocol Plasmids encoding the SARS-CoV-2 open reading frames proteins and eGFP control were a kind gift of Nevan Krogan (Addgene plasmid #141367–141395). Plasmids were acquired as bacterial LB–agar stabs and used per the provider’s instructions. Briefly, each stab was first seeded in LB agar (Bacto Agar; BD Biosciences, San Jose, CA) in 10 cm plates. Then, single colonies were inoculated into flasks containing LB (BD Difco LB Broth, Lennox) and 100 µg/ml penicillin (Biological Industries, Beit HaEmek, Israel). Transfection-grade plasmid DNA was isolated from each flask using the ZymoPURE II Plasmid Maxiprep Kit (Zymo Research, Irvine, CA) according to the manufacturer’s instructions. Lentivirus preparation Request a detailed protocol HEK293T cells (ATCC, Manassas, VA) were seeded in 10 cm cell culture plates at a density of 4 × 106 cells/plate. The cells were maintained in 293T medium composed of DMEM high glucose (4.5 g/l; Merck, Rahway, NJ) supplemented with 10 % fetal bovine serum (FBS; Biological Industries), 1× NEAA (Biological Industries), and 2 mM L-alanine–L-glutamine (Biological Industries, Israel). Lentiviral stocks, pseudo-typed with VSV-G, were produced in HEK293T cells as previously described (Kutner et al., 2009). Briefly, each of the pLVX plasmids containing the SARS-CoV-2 genes or EGFP for control were cotransfected with third-generation lentivirus helper plasmids at equimolar ratio; 48 hr later, the lentivirus-containing medium was collected and supernatant was clarified by centrifugation (500 g, 5 min) and filtration (0.45 µm, Millex-HV, Merck Millipore, Burlington, MA). All virus stocks were aliquoted and stored at –80 °C until thawed for subsequent use. Endothelial cell culture Request a detailed protocol HUVECs (C-12200, PromoCell GmbH, Heidelberg, Germany, tested negative for mycoplasma contamination) were used to test each viral protein’s impact on vascular properties. After thawing, the HUVECs were expanded in low-serum endothelial cell growth medium (PromoCell) at 37°C with 5% CO2 in a humidifying incubator, and used at passage p4–p6. Cells were grown to 80–90% confluence before being transferred to transparent polyethylene terephthalate Transwell supports (0.4 µm pore size, Greiner Bio-One, Austria) or a glass-bottom well plate (Cellvis, Mountain View, CA). Before seeding, the uncoated substrates were treated with Entactin-Collagen IV-Laminin (ECL) Cell Attachment Matrix (Merck) diluted in DMEM (10 µg/cm2) for 1 hr in the incubator. Then, the HUVECs were harvested using a DetachKit (PromoCell), were seeded inside the culture platforms at a density of 250,000 cells/cm2, and grown for 3 days. Then viral infection with the different plasmids was performed and its impact on cell behavior was tested 3 days later. TEER measurement Request a detailed protocol The barrier properties of the endothelial monolayer were evaluated by TEER measurements, 3 and 4 days after viral infection. TEER was measured with the Millicell ERS-2 Voltohmmeter (Merck Millipore). TEER values (Ω cm2) were calculated and compared to those obtained in a Transwell insert without cells, considered as a blank, in three different individual experiments, with two inserts used for each viral protein. Immunofluorescence Request a detailed protocol HUVEC plated on glass-bottom plates were rinsed in phosphate buffered saline (PBS) and fixed in 4 % paraformaldehyde (Sigma-Aldrich, Rehovot, Israel) for 20 min at RT, 5 days after viral infection. ICC was carried out after permeabilization with 0.1 % Triton X-100 (Sigma-Aldrich, Rehovot, Israel) in PBS for 10 min at RT and blocking for 30 min with 5 % FBS in PBS. The following primary antibodies were applied overnight in PBS at 4°C: rabbit anti-VWF (Abcam, Cambridge, UK), rabbit anti-CD31 (Abcam) against platelet endothelial cell adhesion molecule 1 (PECAM1), rabbit anti-β-catenin (Cell Signaling Technology, Danvers, MA), rabbit anti-cadherin-5 (Cell Signaling Technology, Danvers, MA), rabbit anti ZO-1 (Cell Signaling Technology, Danvers, MA), rabbit anti-occludin (Cell Signaling Technology, Danvers, MA). Cells were then washed three times in PBS and stained with the secondary antibody, anti-rabbit Alexa Fluor 488 (Invitrogen, Carlsbad, CA), for 1 hr at RT. After four washes with PBS, cells were incubated with Hoechst in PBS for 10 min at RT to stain the nuclei. After two washes with PBS, imaging was carried out using an inverted confocal microscope (Olympus FV3000-IX83) with suitable filter cubes and equipped with 20× (0.8 NA), 40× (0.95 NA), and 60× (1.42 NA) objectives. Image reconstruction and analysis were done using open-source ImageJ software (Schindelin et al., 2012). Network analysis Request a detailed protocol We scored the effect of each viral protein on selected human proteins using network propagation (Cowen et al., 2017). Specifically, a viral protein was represented by the set of its human interactors (Hu et al., 2021); each of these received a prior score, equal to 1 /n, where n is the size of the interactor set; these scores were propagated in a network of PPI (Almozlino et al., 2017). To assess the statistical significance of the obtained scores, we compared them to those computed on 1000 randomized networks that preserve node degrees. The PPI score was then compared versus the other random networks (this is empirical p-value). p-Values were adjusted for multiple testing using Benjamini–Hochberg FDR approach. For display purposes, the plotted p-value is the negative log of the p-value, which means numbers are non-negative and the higher is the more significant. Quantitative ELISA for IL-6 Request a detailed protocol ELISA was performed on conditioned medium of infected HUVEC 3 days postinfection, according to the manufacturer’s recommendations (PeproTech Rehovot, Israel). Statistical analysis Request a detailed protocol The results are presented as mean ± SD, unless otherwise indicated. Statistically significant differences among multiple groups were evaluated by F-statistic with two-way ANOVA, followed by the Holm–Sidak test for multiple comparisons (GraphPad Prism 8.4.3). The difference between the two data sets was assessed and p < 0.05 was considered statistically significant. Data availability All data generated or analysed during this study are included in the manuscript and supporting files. The custom scripts available in GitHub: https://github.com/raminass/covid_networks, (copy archived at https://archive.softwareheritage.org/swh:1:rev:b239ae7e0e72b722beb6d694436068541ea28dbb). 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Acceptance summary: In their manuscript, Rauti, Shahoha et al., sought to identify the effect of SARS-CoV2 proteins on endothelial functions. They systematically transduced HUVECs cultured on a transwell with various SARS-CoV2 proteins from three classes including non-structural and accessory proteins. They have assessed the effect of separate overexpression of each of 26 proteins, and tested their effect on 26 of the 29 proteins in the SARS-CoV2 genome. The authors found that overexpression of some proteins had stronger effect on the barrier functions on HUVECs compared to other proteins. Using a PPI network analysis, they predicted endothelial proteins that may be affected by the viral protein, which may potentially mediate this effect. The findings add to the understanding how SARS-CoV2 may negatively affect endothelial cell homeostasis, which may contribute to vascular and thrombotic complications associated with a severe course of the disease in patients diagnosed with COVID-19. Decision letter after peer review: Thank you for submitting your article "Effect of SARS-CoV-2 proteins on vascular permeability" for consideration by eLife. Your article has been reviewed by 2 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Matthias Barton as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Francesco Pasqualini (Reviewer #1); Gad Vatine (Reviewer #2). The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission. Essential revisions: 1) The authors provide putative virus-host protein-protein interaction networks that could be very valuable for future translational efforts. However, it would be best to validate at least one of those on the HUVECS/TEER assay. Would it be possible to rescue endothelial dysfunction acting (pharmacologically or genetically) on any of the identified host proteins downstream of the viral protein? 2) The authors provide virus-host protein interaction networks for endothelial cells of various organs. This, again, could be a very valuable target identification exercise for future pharmacological work but it would need to be validated. Can the rescue experiment discussed above be replicated using the TEER assay, organ-specific endothelial cells, and pharmacological or genetic means to normalize the expression of host proteins downstream of the viral protein in the organ-specific PPI network? 3) More validation data will help but it might be worth revising the discussion as well, especially as the new validation data may make parts of the current Discussion redundant. 4) Page 4, line 98 – "Permeability was measured via trans-epithelial-endothelial 99 electrical resistance (TEER), a standard method that identifies changes in impedance values". TEER is a method for assessing barrier functions, and it is related to permeability, but permeability should be measured by fluorescent paracellular assays. These should be separated. 5) While significant, the changes in TEER are very small. The authors should specify in the figure legend, which statistical tests have been applied, and should specify that they have accounted for multiple comparison tests. Also, changes in TEER over time should be showed. 6) In order to avoid conclusions that may be linked to direct regulation on CD31, changes in protein expression should be made on additional proteins that are related to tight junctions such as ZO1. 7) Overall, all experiments were performed on a single source of in vitro human endothelial cells. The authors should discuss possibilities for additional endothelial cell models that could potentially be used for future studies, and discuss the advantages and disadvantages of HUVECs. 8) The authors develop a mathematic model to identify interactions of the SARS-CoV2 proteins with tissue targets. While this represents a novel an important approach, authors should show a validation of the model to prove its validity. If this cannot be applied in the HUVECs system, the authors should explain its limitations and at least discuss what possible models could be used to validate it in the future. 9) Since the authors identify WNT signaling as a key pathway, the authors cold consider manipulating the WNT pathway in HUVECs cells as a possible treatment for rescuing this effect.Reviewer #1: The hypothesis of the authors is that non-spike SARS-CoV-2 proteins are responsible for the increased vascular permeability observed in COVID-19 patients during the primary infection and, possibly, long after it is resolved. To identify which protein(s) might be responsible, they used lentiviruses to express 26/29 SARS-CoV-2 proteins in human endothelial cells (HUVECS) using trans-epithelial-endothelial electrical resistance (TEER), a standard assessment of vascular permeability. Among the viral proteins that directly increased vascular permeability, the authors identified a subset (nsp2,29 nsp5_c145a (catalytic dead mutant of nsp5) and nsp7) capable of inducing broader endothelial dysfunction (downregulated CD31 and upregulated VWF and IL-6). Finally, they used protein-protein interaction analysis to semi-quantitatively speculate how these viral proteins may lead to endothelial dysfunction and increased vascular permeability in various human organs. Strengths The use of a library of LV to test each individual SARS-CoV-2 protein is interesting. While hard to use combinatorially, being able to isolate the influence of each protein will be important in understanding the secondary effect of COVID-19 infections (e.g., long COVID). The combination of imaging and TEER to screen how each viral protein changes endothelial structure, function, or both. The use of bio-informatics to relate the raw findings from the cellular assay with broader translational implications, namely through which pathways may viral protein end up affecting vascular permeability and endothelial dysfunction. Weaknesses I feel like the paper is missing two key additional validations. First, the authors provide putative virus-host protein-protein interaction networks that could be very valuable for future translational efforts. However, it would be best to validate at least one of those on the HUVECS/TEER assay. Would it be possible to rescue endothelial dysfunction acting (pharmacologically or genetically) on any of the identified host proteins downstream of the viral protein? Second, the authors provide virus-host protein interaction networks for endothelial cells of various organs. This, again, could be a very valuable target identification exercise for future pharmacological work but it would need to be validated. Can the rescue experiment discussed above be replicated using the TEER assay, organ-specific endothelial cells, and pharmacological or genetic means to normalize the expression of host proteins downstream of the viral protein in the organ-specific PPI network?Reviewer #2: In their manuscript, Rauti, Shahoha et al., sought to identify the effect of SARS-CoV2 proteins on endothelial functions. They systematically transduced HUVECs cultured on a transwell with various SARS-CoV2 proteins from three classes including non-structural and accessory proteins. They have assessed the effect of separate overexpression of each of 26 proteins, and tested their effect on 26 of the 29 proteins in the SARS-CoV2 genome. The authors found that overexpression of some proteins had stronger effect on the barrier functions on HUVECs compared to other proteins. Using a PPI network analysis, they predicted endothelial proteins that may be affected by the viral protein, which may potentially mediate this effect. The novelty of the study is in directly testing the response of endothelial cells to the virus. Previous reports focused on the phenotype in patients, or using animal models without specifying the exact proteins involved in the dysfunction. Gaining knowledge on the molecular mechanisms, especially the protein-protein interaction pathways that lead to tissue dysfunction, may help understanding the pandemic a potentially help develop treatments. https://doi.org/10.7554/eLife.69314.sa1 Author response Essential revisions: 1) The authors provide putative virus-host protein-protein interaction networks that could be very valuable for future translational efforts. However, it would be best to validate at least one of those on the HUVECS/TEER assay. Would it be possible to rescue endothelial dysfunction acting (pharmacologically or genetically) on any of the identified host proteins downstream of the viral protein? We would like to thank the referee for his suggestion. We agree that it is important to show the validity of the model before using it on other proteins. Following the referee’s suggestion, we have performed a series of experiments to validate the model (new Figure 5). Our new data present high correlation between the PPI prediction and the experimental data. 2) The authors provide virus-host protein interaction networks for endothelial cells of various organs. This, again, could be a very valuable target identification exercise for future pharmacological work but it would need to be validated. Can the rescue experiment discussed above be replicated using the TEER assay, organ-specific endothelial cells, and pharmacological or genetic means to normalize the expression of host proteins downstream of the viral protein in the organ-specific PPI network? Following the referee’s suggestion to examine different organ-specific endothelial cells, we have made a unique comparison of the expression level of the different endothelial proteins in 9 different vascular endothelial cell types (see new Table 2). Although we assumed that most proteins will be detected in these lines, we were surprised to learn that in some cell lines, like the HAoEC, all cadherin proteins (Cadherin 2-5) do not express while in others Catenin d is not expressed while in other most ZO proteins are missing. We were surprised to learn that such a comparison was never published, making this publication also unique in that way. After we validated the PPI network, we used it to examine how the specific SARS-Cov-2 proteins affect the organ-specific endothelial cells (for 9 organ-specific vascular endothelial cells). Our results presented in new Figure 6 predict that not only the HUVEC permeability properties are impaired by the SARSCov-2 proteins, but other vascular endothelial cells are strongly affected as well. Interestingly, we see that different endothelial cells response differently to SARS-Cov-2, mainly due to the different expression of the tight junctions proteins. 3) More validation data will help but it might be worth revising the discussion as well, especially as the new validation data may make parts of the current Discussion redundant. The discussion was revised according to the new validation. 4) Page 4, line 98 – "Permeability was measured via trans-epithelial-endothelial 99 electrical resistance (TEER), a standard method that identifies changes in impedance values". TEER is a method for assessing barrier functions, and it is related to permeability, but permeability should be measured by fluorescent paracellular assays. These should be separated. We thank the author for this comment. The text was revised to better clarify this point. 5) While significant, the changes in TEER are very small. The authors should specify in the figure legend, which statistical tests have been applied, and should specify that they have accounted for multiple comparison tests. Also, changes in TEER over time should be showed. In this work we used ANOVA-multiple comparison test to account for the multiple comparison among different groups. This was described in the method section and per the reviewer request, it was also added to the figure legend. The TEER dynamic is highly dependent on the cell density, age, and condition. Per the reviewer request, we added the TEER values of the cells in multiple time points (before the infection, 3 and 4 days after the infection (new Figure S1)). 6) In order to avoid conclusions that may be linked to direct regulation on CD31, changes in protein expression should be made on additional proteins that are related to tight junctions such as ZO1. We would like to thank the referee for this comment. We have performed additional set of experiments examining also the effect on ZO1 (and other 3 proteins, B-Catenin, Cadherine 5 and Occludin). The new data, now in new Figure 5, show that the viral proteins that showed a significant decrease in the TEER values as well as in the CD31 intensity, significant affect the expression of these other tight-junctions proteins. 7) Overall, all experiments were performed on a single source of in vitro human endothelial cells. The authors should discuss possibilities for additional endothelial cell models that could potentially be used for future studies, and discuss the advantages and disadvantages of HUVECs. As we discussed in “point 2”, we created a table which compares 9 organ-specific endothelial cells. We added the results as Table 2 and new Figure 6. We also revised the text accordingly. 8) The authors develop a mathematic model to identify interactions of the SARS-CoV2 proteins with tissue targets. While this represents a novel an important approach, authors should show a validation of the model to prove its validity. If this cannot be applied in the HUVECs system, the authors should explain its limitations and at least discuss what possible models could be used to validate it in the future. As we discussed in “point 2”, we created a table which compares 9 organ-specific endothelial cells. We added the results as Table 2 and new Figure 6. We also revised the text accordingly. 9) Since the authors identify WNT signaling as a key pathway, the authors cold consider manipulating the WNT pathway in HUVECs cells as a possible treatment for rescuing this effect. WNT was suggested as a relevant pathway due to its known contribution to BBB impairment in multiple sclerosis and other pathologies (Jung, Y., et al. ACS Infect. Dis. (2020); Lengfeld, J. E.,et al. Proc Natl Acad Sci (2017)). In addition, the ßcatenin is part of the WNT signaling, and we showed the validation of its effect by the SARS-Cov-2, i.e. decrease in expression caused by the virus infection. But since it is not the main claim of the paper, (the contribution of the WNT to the BBB impairment due to the SARS-Cov-2) we removed this point from the discussion. Manipulation of the WNT signaling pathway is beyond the scope of this paper. https://doi.org/10.7554/eLife.69314.sa2 Article and author information Author details Rossana Rauti Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel Contribution Conceptualization, Formal analysis, Methodology, Project administration, Writing – original draft Contributed equally with Meishar Shahoha and Yael Leichtmann-Bardoogo Competing interests No competing interests declared ORCID icon 0000-0001-8569-0810 Meishar Shahoha School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel Contribution Conceptualization, Data curation, Investigation, Methodology, Visualization Contributed equally with Rossana Rauti and Yael Leichtmann-Bardoogo Competing interests No competing interests declared ORCID icon 0000-0001-5947-484X Yael Leichtmann-Bardoogo Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel Contribution Conceptualization, Data curation, Investigation, Methodology, Visualization, Writing – original draft Contributed equally with Rossana Rauti and Meishar Shahoha Competing interests No competing interests declared Rami Nasser Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel Contribution Formal analysis, Software Competing interests No competing interests declared Eyal Paz School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel Contribution Methodology, Writing - review and editing Competing interests No competing interests declared Rina Tamir Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel Contribution Formal analysis, Investigation Competing interests No competing interests declared Victoria Miller Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel Contribution Formal analysis, Investigation Competing interests No competing interests declared Tal Babich Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Contribution Formal analysis, Investigation Competing interests No competing interests declared Kfir Shaked Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Contribution Formal analysis, Investigation Competing interests No competing interests declared Avner Ehrlich Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, Israel Contribution Methodology, Resources Competing interests No competing interests declared Konstantinos Ioannidis Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, Israel Contribution Methodology, Resources Competing interests No competing interests declared Yaakov Nahmias Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, Israel Contribution Methodology, Resources Competing interests No competing interests declared Roded Sharan Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel Contribution Formal analysis, Software Competing interests No competing interests declared Uri Ashery School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel The Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel Contribution Funding acquisition, Investigation, Supervision, Writing – original draft Competing interests No competing interests declared ORCID icon 0000-0001-6338-7888 Ben Meir Maoz Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel The Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel Contribution Conceptualization, Funding acquisition, Project administration, Supervision, Visualization, Writing – original draft For correspondence [email protected] Competing interests No competing interests declared ORCID icon 0000-0002-3823-7682 Funding Israel Science Foundation (2248/19) Rossana Rauti Yael Leichtmann-Bardoogo Rina Tamir Victoria Miller Tal Babich Kfir Shaked Ben Meir Maoz Azrieli Foundation Rossana Rauti Yael Leichtmann-Bardoogo Ben Meir Maoz Horizon 2020 (SweetBrain 851765) Rossana Rauti Yael Leichtmann-Bardoogo Ben Meir Maoz Aufzien Family Center for the Prevention and Treatment of Parkinson's Disease Rossana Rauti Meishar Shahoha Yael Leichtmann-Bardoogo Eyal Paz Rina Tamir Victoria Miller Tal Babich Kfir Shaked Uri Ashery Ben Meir Maoz Deutsche Forschungsgemeinschaft (207/10-1) Rami Nasser Avner Ehrlich Konstantinos Ioannidis Yaakov Nahmias Roded Sharan Teva Pharmaceutical Industries Yael Leichtmann-Bardoogo Ben Meir Maoz Zimin Yael Leichtmann-Bardoogo Ben Meir Maoz Ministry of Science and Technology, Israel (3-17351) Rossana Rauti Yael Leichtmann-Bardoogo Ben Meir Maoz TCCP Uri Ashery Ben Meir Maoz Israel Science Foundation (953/16) Rina Tamir Victoria Miller Tal Babich Kfir Shaked Ben Meir Maoz The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Acknowledgements BMM was supported by the Azrieli Foundation, Israel Science Foundation (ISF grant: 2248/19), ERC SweetBrain 851765, TEVA, The Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease at Tel Aviv University, Zimin, Israel Ministry of Science and Technology (Grant No. 3–17351), and TCCP. UA was supported by the Israel Science Foundation (ISF grant 953/16), TEVA, The Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease at Tel Aviv University, the German Research Foundation (DFG) (NA: 207/10–1) and the Taube/Koret Global Collaboration in Neurodegenerative Diseases. RS was supported by the Israel Science Foundation (ISF grant 2417/20), within the Israel Precision Medicine Partership program. The work of YN, AE, and KI was supported by European Research Council Consolidator Grant OCLD (project no. 681870). Senior Editor Matthias Barton, University of Zurich, Switzerland Reviewing Editor Arduino A Mangoni, Flinders Medical Centre, Australia Reviewers Francesco Pasqualini Gad Vatine, Ben Gurion University Publication history Preprint posted: March 1, 2021 (view preprint) Received: April 12, 2021 Accepted: October 9, 2021 Version of Record published: October 25, 2021 (version 1) Copyright © 2021, Rauti et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Metrics 1,400 Page views 140 Downloads 0 Citations Daily Monthly Daily Monthly Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus. Categories and tags Research Article Microbiology and Infectious Disease SARS-COV-2 vasculature endothelium protein interactions Research organism Human View Quote The current study showed that almost 70 % (18 out of 26) of the SARS-CoV-2 proteins affect endothelial barrier integrity; however, the most significant proteins were nsp2, nsp5_c145a, and nsp7, which also induced upregulated expression of the coagulation factor VWF and cytokine release. These critical facts can shed light on the multiple pathologies observed in SARS-CoV-2 infection, including cytokine storm, increased coagulation and related diseases (e.g., heart attack and stroke) (Lee et al., 2021; Aid et al., 2020), increased cardiovascular disease, and increased neurological symptoms. The results presented here showed an effect of in vitro cultured endothelial cells, which may lead to vasculature leakiness, consequently causing exotoxicity (i.e., the penetration of toxic reagents from the blood into the brain). While there are many parameters associated with functional changes, the use of advanced tools, including network-based analysis, enabled us to elucidate the specific proteins and the specific interactions that are predicted to cause these changes. The PPI network enabled us to predict that the changes observed in barrier function are possibly due to interactions between host proteins such as cadherin 2, α-catenin, β-catenin, δ-catenin, and ZO 1 and 2, and at least with the viral proteins nsp2, nsp5_c145a, and nsp7. Moreover, we validated our PPI model performing further immunostaining analysis demonstrating not only the ability of the viral proteins to strongly impair TJ expression, but also to confirm the data predicted by our model in which some TJ proteins can be more affected than others. Coagulation AND leaky blood vessels?!?!?!?! Why haven't certain people been tried in court and hung? While beneficial, our approach has two major limitations: (a) our inability to identify the effect of multiple proteins and (b) our neglect of the effect of the coronavirus structure and binding on the cellular response. The former point can be overcome by expressing combinations of different SARS-CoV-2 proteins. However, since the SARS-CoV-2 expresses 29 proteins, there are about ~9 × 1030 possible protein combinations. Therefore, we decided to focus on individual proteins and allow further studies to pursue any combinations of interest. Regarding the latter limitation, we did not include the coronavirus structure (including the ACE2 receptors) in this study, because many studies have already demonstrated the cellular response to this structure (Chioh et al., 2020; Yang et al., 2020; Procko, 2020), and how tissues that do not have significant ACE2 expression (neurons, immune components such as B and T lymphocytes, and macrophages) are affected by the virus remains an open question. ... I'm gonna have to print this one off and read it really slow. It's not an easy read. |
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Below are the two papers from the video.
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00648-4/fulltext https://www.thelancet.com/action/showPdf?pii=S1473-3099%2821%2900648-4 Click To View Spoiler Summary Background The SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community. Methods Between Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status. Findings The SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for uninfected individuals (64 days [32–97], p=0·001). SAR among household contacts exposed to fully vaccinated index cases was similar to household contacts exposed to unvaccinated index cases (25% [95% CI 15–35] for vaccinated vs 23% [15–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological analysis in three index case–contact pairs. Although peak viral load did not differ by vaccination status or variant type, it increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak log10 viral load per mL between those aged 10 years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load decline (0·95 log10 copies per mL per day) than did unvaccinated individuals with pre-alpha (0·69), alpha (0·82), or delta (0·79) variant infections. Within individuals, faster viral load growth was correlated with higher peak viral load (correlation 0·42 [95% credible interval 0·13 to 0·65]) and slower decline (–0·44 [–0·67 to –0·18]). Interpretation Vaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory. Funding National Institute for Health Research. • View related content for this article Introduction While the primary aim of vaccination is to protect individuals against severe COVID-19 disease and its consequences, the extent to which vaccines reduce onward transmission of SARS-CoV-2 is key to containing the pandemic. This outcome depends on the ability of vaccines to protect against infection and the extent to which vaccination reduces the infectiousness of breakthrough infections. Research in context Evidence before this study The SARS-CoV-2 delta variant is spreading globally, including in populations with high vaccination coverage. While vaccination remains highly effective at attenuating disease severity and preventing death, vaccine effectiveness against infection is reduced for delta. Determining the extent of transmission from vaccinated delta-infected individuals to their vaccinated contacts is a public health priority. Comparing the upper respiratory tract (URT) viral load kinetics of delta infections with those of other variants gives insight into potential mechanisms for its increased transmissibility. We searched PubMed and medRxiv for articles published between database inception and Sept 20, 2021, using search terms describing "SARS-CoV-2, delta variant, viral load, and transmission". Two studies longitudinally sampled the URT in vaccinated and unvaccinated delta variant-infected individuals to compare viral load kinetics. In a retrospective study of a cohort of hospitalised patients in Singapore, more rapid viral load decline was found in vaccinated individuals than unvaccinated cases. However, the unvaccinated cases in this study had moderate-to-severe infection, which is known to be associated with prolonged shedding. The second study longitudinally sampled professional USA sports players. Again, clearance of delta viral RNA in vaccinated cases was faster than in unvaccinated cases, but only 8% of unvaccinated cases had delta variant infection, complicating interpretation. Lastly, a report of a single-source nosocomial outbreak of a distinct delta sub-lineage in Vietnamese health-care workers plotted viral load kinetics (without comparison with unvaccinated delta infections) and demonstrated transmission between fully vaccinated health-care workers in the nosocomial setting. The findings might therefore not be generalisable beyond the particular setting and distinct viral sub-lineage investigated. Added value of this study The majority of SARS-CoV-2 transmission occurs in households, but transmission between fully vaccinated individuals in this setting has not been shown to date. To ascertain secondary transmission with high sensitivity, we longitudinally followed index cases and their contacts (regardless of symptoms) in the community early after exposure to the delta variant of SARS-CoV-2, performing daily quantitative RT-PCR on URT samples for 14–20 days. We found that the secondary attack rate in fully vaccinated household contacts was high at 25%, but this value was lower than that of unvaccinated contacts (38%). Risk of infection increased with time in the 2–3 months since the second dose of vaccine. The proportion of infected contacts was similar regardless of the index cases’ vaccination status. We observed transmission of the delta variant between fully vaccinated index cases and their fully vaccinated contacts in several households, confirmed by whole-genome sequencing. Peak viral load did not differ by vaccination status or variant type but did increase modestly with age. Vaccinated delta cases experienced faster viral load decline than did unvaccinated alpha or delta cases. Across study participants, faster viral load growth was correlated with higher peak viral load and slower decline, suggesting that host–virus interactions early in infection shape the entire viral trajectory. Since our findings are derived from community household contacts in a real-life setting, they are probably generalisable to the general population. Implications of all the available evidence Although vaccines remain highly effective at preventing severe disease and deaths from COVID-19, our findings suggest that vaccination is not sufficient to prevent transmission of the delta variant in household settings with prolonged exposures. Our findings highlight the importance of community studies to characterise the epidemiological phenotype of new SARS-CoV-2 variants in increasingly highly vaccinated populations. Continued public health and social measures to curb transmission of the delta variant remain important, even in vaccinated individuals. Vaccination was found to be effective in reducing household transmission of the alpha variant (B.1.1.7) by 40–50%,1 and infected, vaccinated individuals had lower viral load in the upper respiratory tract (URT) than infections in unvaccinated individuals,2 which is indicative of reduced infectiousness.3 , 4 However, the delta variant (B.1.617.2), which is more transmissible than the alpha variant,5 , 6 is now the dominant strain worldwide. After a large outbreak in India, the UK was one of the first countries to report a sharp rise in delta variant infection. Current vaccines remain highly effective at preventing admission to hospital and death from delta infection.7 However, vaccine effectiveness against infection is reduced for delta, compared with alpha,8 , 9 and the delta variant continues to cause a high burden of cases even in countries with high vaccination coverage. Data are scarce on the risk of community transmission of delta from vaccinated individuals with mild infections. Here, we report data from a UK community-based study, the Assessment of Transmission and Contagiousness of COVID-19 in Contacts (ATACCC) study, in which ambulatory close contacts of confirmed COVID-19 cases underwent daily, longitudinal URT sampling, with collection of associated clinical and epidemiological data. We aimed to quantify household transmission of the delta variant and assess the effect of vaccination status on contacts’ risk of infection and index cases’ infectiousness, including (1) households with unvaccinated contacts and index cases and (2) households with fully vaccinated contacts and fully vaccinated index cases. We also compared sequentially sampled URT viral RNA trajectories from individuals with non-severe delta, alpha, and pre-alpha SARS-CoV-2 infections to infer the effects of SARS-CoV-2 variant status—and, for delta infections, vaccination status—on transmission potential. Methods Study design and participants ATACCC is an observational longitudinal cohort study of community contacts of SARS-CoV-2 cases. Contacts of symptomatic PCR-confirmed index cases notified to the UK contact-tracing system (National Health Service Test and Trace) were asked if they would be willing to be contacted by Public Health England to discuss participation in the study. All contacts notified within 5 days of index case symptom onset were selected to be contacted within our recruitment capacity. Household and non-household contacts aged 5 years or older were eligible for recruitment if they could provide written informed consent and agree to self-swabbing of the URT. Further details on URT sampling are given in the appendix (p 13). The ATACCC study is separated into two study arms, ATACCC1 and ATACCC2, which were designed to capture different waves of the SARS-CoV-2 pandemic. In ATACCC1, which investigated alpha variant and pre-alpha cases in Greater London, only contacts were recruited between Sept 13, 2020, and March 13, 2021. ATACCC1 included a pre-alpha wave (September to November, 2020) and an alpha wave (December, 2020, to March, 2021). In ATACCC2, the study was relaunched specifically to investigate delta variant cases in Greater London and Bolton, and both index cases and contacts were recruited between May 25, and Sept 15, 2021. Early recruitment was focused in West London and Bolton because UK incidence of the delta variant was highest in these areas.10 Based on national and regional surveillance data, community transmission was moderate-to-high throughout most of our recruitment period. This study was approved by the Health Research Authority. Written informed consent was obtained from all participants before enrolment. Parents and caregivers gave consent for children. Data collection Demographic information was collected by the study team on enrolment. The date of exposure for non-household contacts was obtained from Public Health England. COVID-19 vaccination history was determined from the UK National Immunisation Management System, general practitioner records, and self-reporting by study participants. We defined a participant as unvaccinated if they had not received a single dose of a COVID-19 vaccine at least 7 days before enrolment, partially vaccinated if they had received one vaccine dose at least 7 days before study enrolment, and fully vaccinated if they had received two doses of a COVID-19 vaccine at least 7 days before study enrolment. Previous literature was used to determine the 7-day threshold for defining vaccination status.11 , 12 , 13 We also did sensitivity analyses using a 14-day threshold. The time interval between vaccination and study recruitment was calculated. We used WHO criteria14 to define symptomatic status up to the day of study recruitment. Symptomatic status for incident cases—participants who were PCR-negative at enrolment and subsequently tested positive—was defined from the day of the first PCR-positive result. Laboratory procedures SARS-CoV-2 quantitative RT-PCR, conversion of ORF1ab and envelope (E-gene) cycle threshold values to viral genome copies, whole-genome sequencing, and lineage assignments are described in the appendix (pp 13–14). Outcomes Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants infected with pre-alpha versus alpha versus delta variants and between unvaccinated delta-infected participants and vaccinated delta-infected participants. We assessed vaccine effectiveness and susceptibility to SARS-CoV-2 infection stratified by time elapsed since receipt of second vaccination as exploratory analyses. Statistical analysis To model viral kinetics, we used a simple phenomenological model of viral titre15 during disease pathogenesis. Viral kinetic parameters were estimated on a participant-specific basis using a Bayesian hierarchical model to fit this model to the entire dataset of sequential cycle threshold values measured for all participants. For the 19 participants who were non-household contacts of index cases and had a unique date of exposure, the cycle threshold data were supplemented by a pseudo-absence data point (ie, undetectable virus) on the date of exposure. Test accuracy and model misspecification were modelled with a mixture model by assuming there was a probability p of a test giving an observation drawn from a (normal) error distribution and probability 1 – p of it being drawn from the true distribution. The hierarchical structure was represented by grouping participants based on the infecting variant and their vaccination status. A single-group model was fitted, which implicitly assumes that viral kinetic parameters vary by individual but not by variant or vaccination status. A four-group model was also explored, where groups 1, 2, 3, and 4 represent pre-alpha, alpha, unvaccinated delta, and fully vaccinated delta, respectively. We fitted a correlation matrix between participant-specific kinetic parameters to allow us to examine whether there is within-group correlation between peak viral titre, viral growth rate, and viral decline rate. Our initial model selection, using leave-one-out cross-validation, selected a four-group hierarchical model with fitted correlation coefficients between individual-level parameters determining peak viral load and viral load growth and decline rates (appendix p 5). However, resulting participant-specific estimates of peak viral load (but not growth and decline rates) showed a marked and significant correlation with age in the exploratory analysis, which motivated examination of models where mean peak viral load could vary with age. The most predictive model overall allowed mean viral load growth and decline rates to vary across the four groups, with mean peak viral load common to all groups but assumed to vary linearly with the logarithm of age (appendix p 5). We present peak viral loads for the reference age of 50 years with 95% credible intervals (95% CrIs). 50 years was chosen as the reference age as it is typical of the ages of the cases in the whole dataset and the choice of reference age made no difference in the model fits or judgment of differences between the groups. We computed group-level population means and within-sample group means of log peak viral titre, viral growth rate, and viral decline rate. Since posterior estimates of each of these variables are correlated across groups, overlap in the credible intervals of an estimate for one group with that for another group does not necessarily indicate no significant difference between those groups. We, therefore, computed posterior probabilities, pp, that these variables were larger for one group than another. For our model, Bayes factors can be computed as pp/(1–pp). We only report population (group-level) posterior probabilities greater than 0·75 (corresponding to Bayes factors >3) as indicating at least moderate evidence of a difference. For vaccine effectiveness, we defined the estimated effectiveness at preventing infection, regardless of symptoms, with delta in the household setting as 1 – SAR (fully vaccinated) / SAR (unvaccinated). Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Results Between Sept 13, 2020, and Sept 15, 2021, 621 community-based participants (602 contacts and 19 index cases) from 471 index notifications were prospectively enrolled in the ATACCC1 and ATACCC2 studies, and contributed 8145 URT samples. Of these, ATACCC1 enrolled 369 contacts (arising from 308 index notifications), and ATACCC2 enrolled 233 contacts (arising from 163 index notifications) and 19 index cases. SARS-CoV-2 RNA was detected in 163 (26%) of the 621 participants. Whole-genome sequencing of PCR-positive cases confirmed that 71 participants had delta variant infection (18 index cases and 53 contacts), 42 had alpha variant infection (one index case and 41 contacts), and 50 had pre-alpha variant infection (all contacts; figure 1A). Figure thumbnail gr1 Figure 1Recruitment, SARS-CoV-2 infection, variant status, and vaccination history for ATACCC study participants Show full caption View Large Image Figure ViewerDownload Hi-res image Download (PPT) Of 163 PCR-positive participants, 89 (55%) were female and 133 (82%) were White. Median age was 36 years (IQR 26–50). Sex, age, ethnicity, body-mass index (BMI) distribution, and the frequency of comorbidities were similar among those with delta, alpha, and pre-alpha infection, and for vaccinated and unvaccinated delta-infected participants, except for age and sex (appendix pp 2–3). There were fewer unvaccinated females than males (p=0·04) and, as expected from the age-prioritisation of the UK vaccine roll-out, unvaccinated participants infected with the delta variant were significantly younger (p<0·001; appendix p 3). Median time between exposure to the index case and study enrolment was 4 days (IQR 4–5). All participants had non-severe ambulatory illness or were asymptomatic. The proportion of asymptomatic cases did not differ among fully vaccinated, partially vaccinated, and unvaccinated delta groups (appendix p 3). No pre-alpha-infected and only one alpha-infected participant had received a COVID-19 vaccine before study enrolment. Of 71 delta-infected participants (of whom 18 were index cases), 23 (32%) were unvaccinated, ten (14%) were partially vaccinated, and 38 (54%) were fully vaccinated (figure 1A; appendix p 3). Of the 38 fully vaccinated delta-infected participants, 14 had received the BNT162b2 mRNA vaccine (Pfizer–BioNTech), 23 the ChAdOx1 nCoV-19 adenovirus vector vaccine (Oxford–AstraZeneca), and one the CoronaVac inactivated whole-virion vaccine (Sinovac). It is highly probable that all but one of the 233 ATACCC2 contacts were exposed to the delta variant because they were recruited when the regional prevalence of delta was at least 90%, and mostly 95–99% (figure 1B).10 Of these, 206 (89%) were household contacts (in 127 households), and 26 (11%) were non-household contacts. Distributions of age, ethnicity, BMI, smoking status, and comorbidities were similar between PCR-positive and PCR-negative contacts (appendix p 4). The median time between second vaccine dose and study recruitment in fully vaccinated contacts with delta variant infection was 74 days (IQR 35–105; range 16–201), and this was significantly longer in PCR-positive contacts than in PCR-negative contacts (101 days [IQR 74–120] vs 64 days [32–97], respectively, p=0·001; appendix p 4). All 53 PCR-positive contacts were exposed in household settings and the SAR for all delta variant-exposed household contacts was 26% (95% CI 20–32). SAR was not significantly higher in unvaccinated (38%, 95% CI 24–53) than fully vaccinated (25%, 18–33) household contacts (table 1). We estimated vaccine effectiveness at preventing infection (regardless of symptoms) with delta in the household setting to be 34% (bootstrap 95% CI –15 to 60). Sensitivity analyses using a 14 day threshold for time since second vaccination to study recruitment to denote fully vaccinated did not materially affect our estimates of vaccine effectiveness or SAR (data not shown). Although precision is restricted by the small sample size, this estimate is broadly consistent with vaccine effectiveness estimates for delta variant infection based on larger datasets.9 , 16 , 17 Table 1SAR in contacts of delta-exposed index cases recruited to the ATACCC2 study TotalPCR positivePCR negativeSAR (95% CI)p value Contacts All2315317823 (18–29)NA Fully vaccinated1403110922 (16–30)0·16 Unvaccinated44152934 (22–49).. Partially vaccinated4774015 (7–28)NA Household contacts All2055315226 (20–32)NA Fully vaccinated126319525 (18–33)0·17 Unvaccinated40152538 (24–53).. Partially vaccinated3973218 (9–33)NA χ2 test was performed to calculate p values for differences in SAR between fully vaccinated and unvaccinated cases. One PCR-negative contact who withdrew from the study without vaccination status information was excluded. NA=not applicable. SAR=secondary attack rate. Open table in a new tab The vaccination status of 138 epidemiologically linked index cases of 204 delta variant-exposed household contacts was available (figure 1B, table 2). The SAR in household contacts exposed to fully vaccinated index cases was 25% (95% CI 15–35; 17 of 69), which is similar to the SAR in household contacts exposed to unvaccinated index cases (23% [15–31]; 23 of 100; table 2). The 53 PCR-positive contacts arose from household exposure to 39 PCR-positive index cases. Of these index cases who gave rise to secondary transmission, the proportion who were fully vaccinated (15 [38%] of 39) was similar to the proportion who were unvaccinated (16 [41%] of 39). The median number of days from the index cases’ second vaccination to the day of recruitment for their respective contacts was 73 days (IQR 38–116). Time interval did not differ between index cases who transmitted infection to their contacts and those who did not (94 days [IQR 62–112] and 63 days [35–117], respectively; p=0·43). Table 2Comparison of vaccination status of the 138 epidemiologically linked PCR-positive index cases for 204 delta variant-exposed household contacts All household contacts (n=204)* Fully vaccinated contacts (n=125)Partially vaccinated contacts (n=39)Unvaccinated contacts (n=40) PCR positive (n=31)PCR negative (n=94)PCR positive (n=7)PCR negative (n=32)PCR positive (n=15)PCR negative (n=25) Fully vaccinated index cases (n=50)69123118413 Partially vaccinated index cases (n=25)3571231030 Unvaccinated index cases (n=63)1001251314812 Non-household exposed contacts (n=24, all PCR negative) were excluded. One PCR-negative household contact who withdrew from the study without vaccination status information was excluded. One PCR-negative household contact who could not be linked to their index case was also excluded. * The rows below show the number of contacts exposed to each category of index case. Open table in a new tab 18 of the 163 delta variant-infected index cases that led to contact enrolment were themselves recruited to ATACCC2 and serial URT samples were collected from them, allowing for more detailed virology and genome analyses. For 15 of these, their contacts were also recruited (13 household contacts and two non-household contacts). A corresponding PCR-positive household contact was identified for four of these 15 index cases (figure 1B). Genomic analysis showed that index–contact pairs were infected with the same delta variant sub-lineage in these instances, with one exception (figure 2A). In one household (number 4), an unvaccinated index case transmitted the delta variant to an unvaccinated contact, while another partially vaccinated contact was infected with a different delta sub-lineage (which was probably acquired outside the household). In the other three households (numbers 1–3), fully vaccinated index cases transmitted the delta variant to fully vaccinated household contacts, with high viral load in all cases, and temporal relationships between the viral load kinetics that were consistent with transmission from the index cases to their respective contacts (figure 2B). Figure thumbnail gr2 Figure 2Virological, epidemiological, and genomic evidence for transmission of the SARS-CoV-2 delta variant (B.1.617.2) in households Show full caption View Large Image Figure ViewerDownload Hi-res image Download (PPT) Inclusion criteria for the modelling analysis selected 133 participant's viral load RNA trajectories from 163 PCR-positive participants (49 with the pre-alpha variant, 39 alpha, and 45 delta; appendix p 14). Of the 45 delta cases, 29 were fully vaccinated and 16 were unvaccinated; partially vaccinated cases were excluded. Of the 133 included cases, 29 (22%) were incident (ie, PCR negative at enrolment converting to PCR positive subsequently) and 104 (78%) were prevalent (ie, already PCR positive at enrolment). 15 of the prevalent cases had a clearly resolvable peak viral load. Figure 3 shows modelled viral RNA (ORF1ab) trajectories together with the viral RNA copy numbers measured for individual participants. The E-gene equivalent is shown in the appendix (p 2). Estimates derived from E-gene cycle threshold value data (appendix pp 5, 7, 9, 11) were similar to those for ORF1ab. Figure thumbnail gr3a Figure 3ORF1ab viral load trajectories from 14 days before to 28 days after peak for 133 participants infected with pre-alpha or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants Show full caption View Large Image Figure ViewerDownload Hi-res image Download (PPT) Figure thumbnail gr3b Figure 3ORF1ab viral load trajectories from 14 days before to 28 days after peak for 133 participants infected with pre-alpha or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants Show full caption View Large Image Figure ViewerDownload Hi-res image Download (PPT) Although viral kinetics appear visually similar for all four groups of cases, we found quantitative differences in estimated viral growth rates and decline rates (Table 3, Table 4). Population (group-level) estimates of mean viral load decline rates based on ORF1ab cycle threshold value data varied in the range of 0·69–0·95 log10 units per mL per daxes 4; appendix p 10), indicating that a typical 10-day period was required for viral load to decline from peak to undetectable. A faster decline was seen in the alpha (pp=0·93), unvaccinated delta (pp=0·79), and fully vaccinated delta (pp=0·99) groups than in the pre-alpha group. The mean viral load decline rate of the fully vaccinated delta group was also faster than those of the alpha group (pp=0·84) and the unvaccinated delta group (pp=0·85). The differences in decline rates translate into a difference of about 3 days in the mean duration of the decline phase between the pre-alpha and delta vaccinated groups. Table 3Estimates of VL growth rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data VL growth rate (95% CrI), log10 units per dayPosterior probability estimate is less than pre-alphaPosterior probability estimate is less than alphaPosterior probability estimate is less than delta (unvaccinated)Posterior probability estimate is less than delta (fully vaccinated) Pre-alpha (n=49)3·24 (1·78–6·14)..0·440·270·21 Alpha (n=39)3·13 (1·76–5·94)0·56..0·320·25 Delta, unvaccinated (n=16)2·81 (1·47–5·47)0·730·68..0·44 Delta, fully vaccinated (n=29)2·69 (1·51–5·17)0·790·750·56.. VL growth rates are shown as within-sample posterior mean estimates. Remaining columns show population (group-level) posterior probabilities that the estimate on that row is less than an estimate for a different group. Posterior probabilities are derived from 20 000 posterior samples and have sampling errors of <0·01. VL=viral load. CrI=credible interval. Open table in a new tab Table 4Estimates of VL decline rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data VL decline rate (95% CrI), log10 units per dayPosterior probability estimate is larger than pre-alphaPosterior probability estimate is larger than alphaPosterior probability estimate is larger than delta (unvaccinated)Posterior probability estimate is larger than delta (fully vaccinated) Pre-alpha (n=49)0·69 (0·58–0·81)..0·070·210·01 Alpha (n=39)0·82 (0·67–1·01)0·93..0·600·16 Delta, unvaccinated (n=16)0·79 (0·59–1·04)0·790·40..0·15 Delta, fully vaccinated (n=29)0·95 (0·76–1·18)0·990·840·85.. VL decline rates are shown as within-sample posterior mean estimates. Remaining columns show population (group-level) posterior probabilities that the estimate on that row is less than an estimate for a different group. Posterior probabilities are derived from 20 000 posterior samples and have sampling errors of <0·01. VL=viral load. CrI=credible interval. Open table in a new tab Viral load growth rates were substantially faster than decline rates, varying in the range of 2·69–3·24 log10 units per mL per day between groups, indicating that a typical 3-day period was required for viral load to grow from undetectable to peak. Our power to infer differences in growth rates between groups was more restricted than for viral decline, but there was moderate evidence (pp=0·79) that growth rates were lower for those in the vaccinated delta group than in the pre-alpha group. We estimated mean peak viral load for 50-year-old adults to be 8·14 (95% CrI 7·95 to 8·32) log10 copies per mL, but peak viral load did not differ by variant or vaccination status. However, we estimated that peak viral load increases with age (pp=0·96 that the slope of peak viral load with log[age] was >0), with an estimated slope of 0·24 (95% CrI –0·02 to 0·49) log10 copies per mL per unit change in log(age). This estimate translates to a difference of 0·39 (–0·03 to 0·79) in mean peak log10 copies per mL between those aged 10 years and 50 years. Within-group individual participant estimates of viral load growth rate were positively correlated with peak viral load, with a correlation coefficient estimate of 0·42 (95% CrI 0·13 to 0·65; appendix p 8). Hence, individuals with faster viral load growth tend to have higher peak viral load. The decline rate of viral load was also negatively correlated with viral load growth rate, with a correlation coefficient estimate of –0·44 (95% CrI –0·67 to –0·18), illustrating that individuals with faster viral load growth tend to experience slower viral load decline. Discussion Households are the site of most SARS-CoV-2 transmission globally.19 In our cohort of densely sampled household contacts exposed to the delta variant, SAR was 38% in unvaccinated contacts and 25% in fully vaccinated contacts. This finding is consistent with the known protective effect of COVID-19 vaccination against infection.8 , 9 Notwithstanding, these findings indicate continued risk of infection in household contacts despite vaccination. Our estimate of SAR is higher than that reported in fully vaccinated household contacts exposed before the emergence of the delta variant.1 , 20 , 21 The time interval between vaccination and study recruitment was significantly higher in fully vaccinated PCR-positive contacts than fully vaccinated PCR-negative contacts, suggesting that susceptibility to infection increases with time as soon as 2–3 months after vaccination—consistent with waning protective immunity. This potentially important observation is consistent with recent large-scale data and requires further investigation.17 Household SAR for delta infection, regardless of vaccination status, was 26% (95% CI 20–32), which is higher than estimates of UK national surveillance data (10·8% [10·7–10·9]).10 However, we sampled contacts daily, regardless of symptomatology, to actively identify infection with high sensitivity. By contrast, symptom-based, single-timepoint surveillance testing probably underestimates the true SAR, and potentially also overestimates vaccine effectiveness against infection. We identified similar SAR (25%) in household contacts exposed to fully vaccinated index cases as in those exposed to unvaccinated index cases (23%). This finding indicates that breakthrough infections in fully vaccinated people can efficiently transmit infection in the household setting. We identified 12 household transmission events between fully vaccinated index case–contact pairs; for three of these, genomic sequencing confirmed that the index case and contact were infected by the same delta variant sub-lineage, thus substantiating epidemiological data and temporal relationships of viral load kinetics to provide definitive evidence for secondary transmission. To our knowledge, one other study has reported that transmission of the delta variant between fully vaccinated people was a point-source nosocomial outbreak—a single health-care worker with a particular delta variant sub-lineage in Vietnam.22 Daily longitudinal sampling of cases from early (median 4 days) after exposure for up to 20 days allowed us to generate high-resolution trajectories of URT viral load over the course of infection. To date, two studies have sequentially sampled community cases of mild SARS-CoV-2 infection, and these were from highly specific population groups identified through asymptomatic screening programmes (eg, for university staff and students23 and for professional athletes24 ). Our most predictive model of viral load kinetics estimated mean peak log10 viral load per mL of 8·14 (95% CrI 7·95–8·32) for adults aged 50 years, which is very similar to the estimate from a 2021 study using routine surveillance data.25 We found no evidence of variation in peak viral load by variant or vaccination status, but we report some evidence of modest but significant (pp=0·95) increases in peak viral load with age. Previous studies of viral load in children and adults4 , 25 , 26 have not used such dense sequential sampling of viral load and have, therefore, been restricted in their power to resolve age-related differences; the largest such study25 reported a similar difference between children and adults to the one we estimated. We found the rate of viral load decline was faster for vaccinated individuals with delta infection than all other groups, and was faster for individuals in the alpha and unvaccinated delta groups than those with pre-alpha infection. For all variant vaccination groups, the variation between participants seen in viral load kinetic parameter estimates was substantially larger than the variation in mean parameters estimated between groups. The modest scale of differences in viral kinetics between fully vaccinated and unvaccinated individuals with delta infection might explain the relatively high rates of transmission seen from vaccinated delta index cases in our study. We found no evidence of lower SARs from fully vaccinated delta index cases than from unvaccinated ones. However, given that index cases were identified through routine symptomatic surveillance, there might have been a selection bias towards identifying untypically symptomatic vaccine breakthrough index cases. The differences in viral kinetics we found between the pre-alpha, alpha, and delta variant groups suggest some incremental, but potentially adaptive, changes in viral dynamics associated with the evolution of SARS-CoV-2 towards more rapid viral clearance. Our study provides the first evidence that, within each variant or vaccination group, viral growth rate is positively correlated with peak viral load, but is negatively correlated with viral decline rate. This finding suggests that individual infections during which viral replication is initially fastest generate the highest peak viral load and see the slowest viral clearance, with the latter not just being due to the higher peak. Mechanistically, these data suggest that the host and viral factors determining the initial growth rate of SARS-CoV-2 have a fundamental effect on the trajectory throughout infection, with faster replication being more difficult (in terms of both peak viral load and the subsequent decline of viral load) for the immune response to control. Analysis of sequentially sampled immune markers during infection might give insight into the immune correlates of these early differences in infection kinetics. It is also possible that individuals with the fastest viral load growth and highest peaks contribute disproportionately to community transmission, a hypothesis that should be tested in future studies. Several population-level, single-timepoint sampling studies using routinely available data have found no major differences in cycle threshold values between vaccinated and unvaccinated individuals with delta variant infection.10 , 27 , 28 However, as the timepoint of sampling in the viral trajectory is unknown, this restricts the interpretation of such results. Two other studies longitudinally sampled vaccinated and unvaccinated individuals with delta variant infection.23 , 29 A retrospective cohort of hospitalised patients in Singapore29 also described a faster rate of viral decline in vaccinated versus unvaccinated individuals with delta variant, reporting somewhat larger differences in decline rates than we estimated here. However, this disparity might be accounted for by the higher severity of illness in unvaccinated individuals in the Singaporean study (almost two-thirds having pneumonia, one-third requiring COVID-19 treatment, and a fifth needing oxygen) than in our study, given that longer viral shedding has been reported in patients with more severe illness.30 A longitudinal sampling study in the USA reported that pre-alpha, alpha, and delta variant infections had similar viral trajectories.24 The study also compared trajectories in vaccinated and unvaccinated individuals, reporting similar proliferation phases and peak cycle threshold values, but more rapid clearance of virus in vaccinated individuals. However, this study in the USA stratified by vaccination status and variant separately, rather than jointly, meaning vaccinated individuals with delta infection were being compared with, predominantly, unvaccinated individuals with pre-alpha and alpha infection. Moreover, sampling was done as part of a professional sports player occupational health screening programme, making the results not necessarily representative of typical community infections. Our study has limitations. First, we recruited only contacts of symptomatic index cases as our study recruitment is derived from routine contact-tracing notifications. Second, index cases were defined as the first household member to have a PCR-positive swab, but we cannot exclude the possibility that another household member might already have been infected and transmitted to the index case. Third, recording of viral load trajectories is subject to left censoring, where the growth phase in prevalent contacts (already PCR-positive at enrolment) was missed for a proportion of participants. However, we captured 29 incident cases and 15 additional cases on the upslope of the viral trajectory, providing valuable, informative data on viral growth rates and peak viral load in a subset of participants. Fourth, owing to the age-stratified rollout of the UK vaccination programme, the age of the unvaccinated, delta variant-infected participants was lower than that of vaccinated participants. Thus, age might be a confounding factor in our results and, as discussed, peak viral load was associated with age. However, it is unlikely that the higher SAR observed in the unvaccinated contacts would have been driven by younger age rather than the absence of vaccination and, to our knowledge, there is no published evidence showing increased susceptibility to SARS-CoV-2 infection with decreasing age.31 Finally, although we did not perform viral culture here—which is a better proxy for infectiousness than RT-PCR—two other studies27 , 32 have shown cultivable virus from around two-thirds of vaccinated individuals infected with the delta variant, consistent with our conclusions that vaccinated individuals still have the potential to infect others, particularly early after infection when viral loads are high and most transmission is thought to occur.30 Our findings help to explain how and why the delta variant is being transmitted so effectively in populations with high vaccine coverage. Although current vaccines remain effective at preventing severe disease and deaths from COVID-19, our findings suggest that vaccination alone is not sufficient to prevent all transmission of the delta variant in the household setting, where exposure is close and prolonged. Increasing population immunity via booster programmes and vaccination of teenagers will help to increase the currently limited effect of vaccination on transmission, but our analysis suggests that direct protection of individuals at risk of severe outcomes, via vaccination and non-pharmacological interventions, will remain central to containing the burden of disease caused by the delta variant. This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on November 2, 2021 Contributors AS, JD, MZ, NMF, WB, and ALal conceptualised the study. AS, SH, JD, KJM, AK, JLB, MGW, ND-F, RV, RK, JF, CT, AVK, JC, VQ, EC, JSN, SH, EM, TP, HH, CL, JS, SB, JP, CA, SA, and NMF were responsible for data curation and investigation. AS, SH, KJM, JLB, AC, NMF, and ALal did the formal data analysis. MAC, AB, DJ, SM, JE, PSF, SD, and ALac did the laboratory work. RV, RK, JF, CT, AVK, JC, VQ, EC, JSN, SH, EM, and SE oversaw the project. AS, SH, JD, KJM, JLB, NMF, and ALal accessed and verified the data. JD, MZ, and ALal acquired funding. NMF sourced and oversaw the software. AS and ALal wrote the initial draft of the manuscript. AS, JD, GPT, MZ, NMF, SH, and ALal reviewed and edited the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The ATACCC Study Investigators Anjna Badhan, Simon Dustan, Chitra Tejpal, Anjeli V Ketkar, Janakan Sam Narean, Sarah Hammett, Eimear McDermott, Timesh Pillay, Hamish Houston, Constanta Luca, Jada Samuel, Samuel Bremang, Samuel Evetts, John Poh, Charlotte Anderson, David Jackson, Shahjahan Miah, Joanna Ellis, and Angie Lackenby. Data sharing An anonymised, de-identified version of the dataset can be made available upon request to allow all results to be reproduced. Modelling code will also be made publicly available on the GitHub repository. Declaration of interests NMF reports grants from UK Medical Research Council, UK National Institute of Health Research, UK Research and Innovation, Community Jameel, Janssen Pharmaceuticals, the Bill & Melinda Gates Foundation, and Gavi, the Vaccine Alliance; consulting fees from the World Bank; payment or honoraria from the Wellcome Trust; travel expenses from WHO; advisory board participation for Takeda; and is a senior editor of the eLife journal. All other authors declare no competing interests. Acknowledgments This work is supported by the National Institute for Health Research (NIHR200927), a Department of Health and Social Care COVID-19 Fighting Fund award, and the NIHR Health Protection Research Units (HPRUs) in Respiratory Infections and in Modelling and Health Economics. NMF acknowledges funding from the MRC Centre for Global Infectious Disease Analysis and the Jameel Institute. PSF and MAC are supported by the UK Dementia Research Institute. JD is supported by the NIHR HPRU in Emerging and Zoonotic Infections. MGW is supported by the NIHR HPRU in Healthcare Associated Infections and Antimicrobial Resistance. GPT is supported by the Imperial NIHR Biomedical Research Centre. We thank all the participants who were involved in the study, Public Health England staff for facilitating recruitment into the study, the staff of the Virus Reference Department for performing PCR and sequencing assays, and the Immunisations Department for assisting with analysis of vaccination data. We also thank Kristel Timcang, Mohammed Essoussi, Holly Grey, Guilia Miserocchi, Harriet Catchpole, Charlotte Williams, Niamh Nichols, Jessica Russell, Sean Nevin, Lulu Wang, Berenice Di Biase, Alice Panes, Esther Barrow, and Lauren Edmunds for their involvement in logistics, conducting data entry, or quality control; and the Molecular Diagnostics Unit at Imperial College London, in particular Lucy Mosscrop, Carolina Rosadas de Oliveira, and Patricia Watber, for performing RNA extraction, quantitative RT-PCR, and preparing samples for sequencing. Supplementary Material Download .pdf (1.01 MB) Help with pdf files Supplementary appendix References 1. Harris RJ Hall JA Zaidi A Andrews NJ Dunbar JK Dabrera G Effect of vaccination on household transmission of SARS-CoV-2 in England. N Engl J Med. 2021; 385: 759-760 View in Article Scopus (15) PubMed Crossref Google Scholar 2. Levine-Tiefenbrun M Yelin I Katz R et al. 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(preprint). https://doi.org/10.1101/2021.07.31.21261387 View in Article Google Scholar 28. Brown CM Vostok J Johnson H et al. Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings–Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. 2021; 70: 1059-1062 View in Article PubMed Crossref Google Scholar 29. Chia PY Ong S Chiew CJ et al. Virological and serological kinetics of SARS-CoV-2 delta variant vaccine-breakthrough infections: a multi-center cohort study. medRxiv. 2021; (published online July 31.) (preprint). https://doi.org/10.1101/2021.07.28.21261295 View in Article Google Scholar 30. Cevik M Tate M Lloyd O Maraolo AE Schafers J Ho A SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe. 2021; 2: e13-e22 View in Article PubMed Summary Full Text Full Text PDF Google Scholar 31. Viner RM Mytton OT Bonell C et al. Susceptibility to SARS-CoV-2 infection among children and adolescents compared with adults: a systematic review and meta-analysis. JAMA Pediatr. 2021; 175: 143-156 View in Article Scopus (60) PubMed Crossref Google Scholar 32. Shamier MC Tostmann A Bogers S et al. Virological characteristics of SARS-CoV-2 vaccine breakthrough infections in health care workers. medRxiv. 2021; (published online Aug 21.) (preprint). https://doi.org/10.1101/2021.08.20.21262158 View in Article Google Scholar Article Info Publication History Published: October 29, 2021 Identification DOI: https://doi.org/10.1016/S1473-3099(21)00648-4 Copyright © 2021 The Author(s). Published by Elsevier Ltd. User License Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse Information Icon ScienceDirect Access this article on ScienceDirect Figures Figure thumbnail gr1 Figure 1Recruitment, SARS-CoV-2 infection, variant status, and vaccination history for ATACCC study participants Figure thumbnail gr2 Figure 2Virological, epidemiological, and genomic evidence for transmission of the SARS-CoV-2 delta variant (B.1.617.2) in households Figure thumbnail gr3a Figure 3ORF1ab viral load trajectories from 14 days before to 28 days after peak for 133 participants infected with pre-alpha or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants Figure thumbnail gr3b Figure 3ORF1ab viral load trajectories from 14 days before to 28 days after peak for 133 participants infected with pre-alpha or alpha variants (uncaccinated), or the delta variant (vaccinated and unvaccinated) variants Tables Table 1SAR in contacts of delta-exposed index cases recruited to the ATACCC2 study Table 2Comparison of vaccination status of the 138 epidemiologically linked PCR-positive index cases for 204 delta variant-exposed household contacts Table 3Estimates of VL growth rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data Table 4Estimates of VL decline rates for pre-alpha, alpha, and delta (unvaccinated and fully vaccinated) cases, derived from ORF1ab cycle threshold data https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3949410 https://papers.ssrn.com/sol3/Delivery.cfm/SSRN_ID3949410_code2488747.pdf?abstractid=3949410&mirid=1 Click To View Spoiler Manuscript Click here to view linked References Effectiveness of Covid-19 vaccination against risk of symptomatic infection, hospitalization, and death up to 9 months: a Swedish total-population cohort study Peter Nordström, MD, PhD, Marcel Ballin, MSc., Anna Nordström, MD, PhD Department of Community Medicine and Rehabilitation, Unit of Geriatric Medicine, Umeå University, Umeå, Sweden (Peter Nordström and Marcel Ballin) Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden (Marcel Ballin and Anna Nordström) School of Sport Sciences, UiT the Arctic University of Norway, Tromsø, Norway (Anna Nordström) Abstract word count: 299 Main text word count: 3467 Corresponding author: Peter Nordström, Professor Unit of Geriatric Medicine Department of Community Medicine and Rehabilitation Umeå University 90187 Umeå Sweden Phone: +4670 899 65 99 E-mail: [email protected] This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 Abstract Background: Whether vaccine effectiveness against Coronavirus disease 2019 (Covid-19) lasts longer than 6 months is unclear. Methods: A retrospective cohort study was conducted using Swedish nationwide registries. The cohort comprised 842,974 pairs (N=1,684,958), including individuals vaccinated with 2 doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals. Cases of symptomatic infection and severe Covid-19 (hospitalization or 30-day mortality after confirmed infection) were collected from 12 January to 4 October 2021. Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, P<0·001) at day 15-30 to 47% (95% CI, 39-55, P<0·001) at day 121180, and from day 211 and onwards no effectiveness could be detected (23%; 95% CI, -2-41, P=0·07). The effectiveness waned slightly slower for mRNA-1273, being estimated to 59% (95% CI, 18-79) from day 181 and onwards. In contrast, effectiveness of ChAdOx1 nCoV-19 was generally lower and waned faster, with no effectiveness detected from day 121 and onwards (-19%, 95% CI, -97-28), whereas effectiveness from heterologous ChAdOx1 nCoV19 / mRNA was maintained from 121 days and onwards (66%; 95% CI, 41-80). Overall, vaccine effectiveness was lower and waned faster among men and older individuals. For the outcome severe Covid-19, effectiveness waned from 89% (95% CI, 82-93, P<0·001) at day 15-30 to 42% (95% CI, -35-75, P=0·21) from day 181 and onwards, with sensitivity analyses showing notable waning among men, older frail individuals, and individuals with comorbidities. Interpretation: Vaccine effectiveness against symptomatic Covid-19 infection wanes progressively over time across all subgroups, but at different rate according to type of vaccine, and faster for men and older frail individuals. The effectiveness against severe illness seems to remain high through 9 months, although not for men, older frail individuals, and This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 individuals with comorbidities. This strengthens the evidence-based rationale for administration of a third booster dose. Research in context Evidence before this study Clinical trials have demonstrated high efficacy of Coronavirus disease 2019 (Covid-19) vaccines against the risk of infection and severe illness. However, reports on breakthrough infections and waning immunity have raised concerns regarding the duration of vaccine protection, and whether additional doses are warranted. Currently, there is some evidence to suggest waning vaccine effectiveness against infection up to 6 months after vaccination, with protection against severe illness appearing to be better maintained. Yet, the evidence is limited and consistent, in part due to evaluations of vaccines that may have different long- lasting effects, a low proportion of old participants, and varying and relatively short follow-up times. Specifically, whether vaccine effectiveness persist beyond 6 months is unknown. Added value of this study In this study, vaccine effectiveness of BNT162b2 against symptomatic infection waned progressively from 92% during the first month, to 47% by month 4-6 and from 7 months and onwards no effectiveness was detected. Effectiveness waned slightly slower for mRNA-1273, whereas effectiveness of ChAdOx1 nCoV-19 was generally lower. Overall, effectiveness was lower and waned faster among men and older individuals. For the outcome of hospitalization or death, effectiveness (any vaccine) waned from 89% during the first month to 42% from month 6 and onwards in the total population. There was notable waning among especially men, older frail individuals, and individuals with comorbidities. Implications of all the available evidence This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 Vaccine effectiveness against symptomatic Covid-19 infection wanes progressively over time across all subgroups, but at different rate according to type of vaccine, and faster for older frail individuals. The effectiveness against hospitalization or death seems to remain high through 9 months, but not for men, older frail individuals, and individuals with comorbidities. This strengthens the evidence-based rationale for administration of a third booster dose. Introduction Initial clinical trials showed a high efficacy of the BNT162b2 (Pfizer-BioNTech)1, mRNA1273 (Moderna)2, and ChAdOx1 nCoV-19 (Oxford/AstraZeneca) Coronavirus disease 2019 (Covid-19) vaccines3 4, and observational studies have estimated a high real-world effectiveness5-8 . However, reports on breakthrough infections9 and waning immunity10-14 have raised concerns regarding the duration of protection. With respect to severe Covid-19 such as hospitalization or death, follow-ups of clinical trials showed about 84% and 92% efficacy of BNT162b2 and mRNA-1273 after 4 months15 16, with similar results reported by the CDC, although slightly lower maintained protection of BNT162b217. Also, studies from US and Qatar showed that the effectiveness of BNT162b2 against hospitalization and death persisted through 6 months18 19, whereas preliminary data from UK indicate a slight waning, most notably for older adults and for ChAdOx1 nCoV-19 compared to BNT162b220. Altogether, although current evidence suggests that vaccine effectiveness against severe Covid-19 is relatively well maintained, the data are inconsistent. Similarly, also the duration of protection against less severe infection is unclear. After 4-5 months of follow-up, the effectiveness of BNT162b2 has been estimated to above 80%15, 50%19,20 , down to about 20%18 in a study from Qatar. For the ChAdOx1 nCoV-19, This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 preliminary data from UK suggest about 50% remaining effectiveness after 5 months of follow-up20. The different results in recent studies may relate to several factors, such as the evaluations of vaccines that may have different long-lasting effects16 18-20 , a low proportion of old participants18, varying and relatively short follow-up times15 16 21 . Collectively, there is insufficient evidence to determine vaccine effectiveness beyond 6 months. In this study, we investigate the effectiveness of Covid-19 vaccination, against the risk of symptomatic infection, hospitalization, and death through the first 9 months for the total population of Sweden. Methods Study design and cohort This study was approved by the Swedish Ethical Review Authority (number 495/2021), who waived the requirement of obtaining informed consent given the retrospective study design. The individuals considered for inclusion were all individuals (N=3,640,421) vaccinated with at least one dose of any Covid-19 vaccine (ChAdOx1 nCoV-19, BNT162b2, or mRNA-1273) in Sweden until 26 May 2021, and all individuals with a confirmed infection until 24 May 2021 (N=1,331,989). To these individuals, Statistics Sweden (the national agency for statistics, www.scb.se) randomly sampled one individual from the total population of Sweden, matched on birth year, sex and municipality. These matched individuals had neither been vaccinated nor infected with Covid-19 on the date of first vaccination dose or infection in the vaccinated individual. The total population consisted of 5,833,003 unique individuals that was considered for inclusion in this study. This population was updated with respect to vaccination status and Covid-19 infections until 4 October, 2021 (Figure 1). From this cohort, This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 the main study cohort was formed. Specifically, from the total cohort, each fully vaccinated (2 doses) individual was matched 1:1 to one randomly sampled unvaccinated individual on birth year, and sex, with baseline set to the date of the second dose of vaccine, in both vaccinated and matched unvaccinated individuals. Matched unvaccinated individuals were excluded if they received a first dose of vaccine or died within 14 days of baseline, and a new individual was searched from the remaining total cohort. This procedure was repeated 5 times. The final study cohort comprised 842,974 matched pairs of vaccinated/unvaccinated individuals (N=1,684,958). Data on individuals vaccinated or diagnosed with Covid-19 were collected from the Swedish Vaccination Register and SmiNet register, respectively, both of which are managed by the Public Health Agency of Sweden22 23 . All health care providers in Sweden are obliged to report to these registers according to Swedish law, with a 100% coverage of the total population. We also formed a second cohort to be used in a forthcoming sensitivity analysis. This cohort was formed using less strict matching criteria to increase the size of the cohort. In this data set, each vaccinated individual was matched to the rest of the cohort on age only, with an allowance of a 5-year difference in age within each pair. This process was repeated 10 times and one unvaccinated individual could be paired with several vaccinated individuals. This resulted in a cohort of 1,983,315 pairs (N=3,966,630). Exposure, outcome, and baseline date for the analyses In the analyses, the exposure variables were vaccination status (vaccinated with 2 doses/unvaccinated). Vaccination status was defined according to each specific vaccine schedule, as well as a composite variable (any vaccine). There were two outcomes of the study. The first was symptomatic infection until 4 October, 2021 latest. In 94·4% of cases, This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 symptomatic infection was confirmed using polymerase chain reaction and in 4·8% by sequencing, according to the SmiNet registry23. The term “symptomatic” was defined on the basis that in Sweden, health authorities have urged citizens to take a test if they experience any symptoms of Covid-19. The second outcome was a composite endpoint of severe disease until 28 September 2021 latest, defined as inpatient hospitalization with Covid-19 as main diagnosis, or all-cause mortality within 30 days after confirmed infection. Hospitalized cases were collected from the Swedish National Inpatient Register using the International Classification of Disease (ICD, version 10) code U071 and Statistics Sweden provided data on mortality. All outcomes were collected from >14 days after baseline. Covariates From Statistics Sweden, we obtained information on whether individuals were born in Sweden or not, birth year, birth month, and sex for all individuals24. From Statistics Sweden, we also obtained individual-level data on highest education during year 2019. Individual-level data regarding diagnoses, prescription medications, country of birth, and homemaker service were obtained from national registries managed by the Swedish National Board of Health and Welfare (www.socialstyrelsen.se). Homemaker services includes domestic services provided to individuals (primarily older individuals) who live at home but need help with shopping, cleaning, meal preparation, and similar tasks. Local governments are responsible for determining eligibility for these services. From the Swedish National Inpatient Register and National Outpatient Register for specialist care, diagnoses from 1998 and 2001 and later, respectively, were obtained, based on ICD-10 codes. Prescription medications from 2018 and later were obtained from the Prescribed Drug Register using Anatomic Therapeutic Chemical classification system codes. These three registers are complete for all specialist care and medications prescribed in Sweden for the years selected. The diagnoses and medications This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 selected as covariates for this study were based on the results from a previous nationwide study25. See Supplemental Table 1 for definitions. Statistical analysis Time-to-event for the outcomes (symptomatic infection/severe disease) based on vaccination status (vaccinated/unvaccinated) was illustrated using proportional hazards models with 95% confidence intervals (CI), and restricted cubic splines with four knots in default positions. To compare the risk of the outcomes based on the level of exposure (vaccinated/unvaccinated), Cox regression was used to calculate hazard ratios (HR). To adjust for the matched samples, 95% CIs were estimated using robust standard errors by the VCE procedure and ROBUST option in Stata. To formally test whether the associations were time-dependent, Schoenfeld’s residuals were evaluated using estat phtest command (Stata software). Given that the test indicated that the proportional hazard assumption was violated (χ2 = 3184·25; P<0·001) in the main analyses, the associations were evaluated in time intervals. The first model was adjusted for age and baseline date (date of second dose of vaccine) to adjust for variations in infection pressure during follow-up. The second model included the additional covariates sex, homemaker service (yes/no), education (six categories), whether the individual was born in Sweden or not, and eight diagnoses at baseline (yes/no). The adjusted HR was used to calculate vaccine effectiveness using the following formula: vaccine effectiveness = (1adjusted HR) x 100%. To investigate whether effectiveness was influenced by the covariates as listed in Table 1, interaction analyses were performed, using product terms created by multiplying the variable coding for vaccination status at baseline (vaccinated/unvaccinated) by each respective covariate, which were added to the fully adjusted Cox model. Given that the interaction terms were highly significant (P<0·001) for age, sex, homemaker service and all diagnoses at baseline except asthma, effectiveness was also estimated for subgroups This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 according to these covariates. Follow-up time in days was counted until date of confirmed outcome (symptomatic infection or severe Covid-19), date of first vaccination after baseline among unvaccinated individuals, death, or end of possible follow-up time (described earlier), whichever occurred first. All analyses were performed in SPSS v27·0 for Mac (IBM Corp, Armonk, NY, USA), and Stata v16·1 for Mac (Statcorp, College Station, Texas, USA). A two-sided P-value <0·05 or HR with 95% CIs not crossing one were considered significant. Role of the funding source The present study was not funded. Results Study cohort Between 28 December 2020 and 4 October 2021, 842,974 individuals were fully vaccinated (2 doses), and were matched 1:1 to an equal number of unvaccinated individuals. Thus, the total study cohort comprised 842,974 pairs (N=1,684,958). The mean date for the second dose of vaccine in the vaccinated group according to each vaccine schedule are shown in Table 1. Outcomes were collected between 12 January to 4 October, 2021. Baseline characteristics for the study cohort are presented in Table 1. Compared to unvaccinated individuals, vaccinated individuals more often had homemaker service, were more often born in Sweden, had more medical diagnoses, and had a higher level of education at baseline (P<0·001 for all, Table 1). Similar differences were evident when comparing different vaccines schedules. Vaccine effectiveness against symptomatic infection During a mean (range) follow-up of 116 (15-280) days, a symptomatic infection was confirmed in a total of 27,918 individuals, of which 6,147 were vaccinated individuals This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 (incidence rate [IR], 4·9/100,000 person-days) and 21,771 were unvaccinated individuals (IR, 31·6/100,000 person-days). As shown in Figure 2 and Table 2, there was a progressive waning in vaccine effectiveness (2 doses of any vaccine) against symptomatic infection over time. Effectiveness peaked at day 15-30 (92%; 95% CI, 91-93, P<0·001) and declined marginally at day 31-60 (89%; 95% CI, 88-89, P<0·001). From thereon, the waning became more pronounced, and from day 211 days onwards, there was no remaining detectable effectiveness (23%; 95% CI, -2-41, P=0·07). Vaccine effectiveness was influenced significantly by type of vaccine, age, sex, home maker service and all diagnoses at baseline (Pinteraction <0·001 for all), but asthma (Pinteraction =0·86). At day 61-120, effectiveness declined to 50% (95% CI, 30-64, P<0·001) among individuals aged >80 years, and to 70% (95% CI, 59-79, P<0·001) among individuals with home maker service (Table 3). With respect to sex, there was no detectable effectiveness in men (17%; 95% CI, -13-40, P=0·23) from day 181 and onwards, whereas it remained in women (34%; 95% CI, 22-45, P<0·001). With respect to vaccine type, there was a waning in effectiveness for all vaccines during follow-up (Table 2). Effectiveness of BNT162b2 waned to 47% (95% CI, 39-55, P<0·001) at day 121-180, and no effectiveness was detected from day 211 and onwards (23%; 95% CI, -2-41, P=0·07). Waning was slightly slower for mRNA-1273, with a remaining effectiveness of 59% (95% CI, 18-79, P<0·001) after more than 180 days of follow up, and for heterologous ChAdOx1 nCoV-19 / mRNA schedules (66%; 95% CI, 41-80, P14 days after the second dose) according to sex, age and for individuals with homemaker service and with any comorbidity at baseline Vaccinated Unvaccinated Vaccine effectiveness, % (95% CI) No. of IR/100000 No. of IR/100000 Adjusted for age Fully adjusteda Total (2 doses of any vaccine) events person-days events person-days and baseline date 15-30 days (N=1,684,958) Men (N=685,354) 133 1·3 1,687 17·1 93 (91-94) 93 (91-94) Women (N=1,000,594) 264 1·8 3,032 21·1 92 (91-93) 92 (91-93) 14 days after the second dose) in the second matched cohort (N=3,966,630) according to age and for individuals with homemaker service and with any comorbidity at baseline Vaccinated Unvaccinated Vaccine effectiveness, % (95% CI) No. of IR/100000 No. of IR/100000 Adjusted for age Fully events person-days events person-days and baseline date adjusted* Total (2 doses of any vaccine) 15-30 days (N=3,966,630) Men (N=1,824,056) Women N=2,142,574) <50 years (N=1,129,195) 50-64 years (N=1,306,783) 65-79 years (N=1,072,599) ≥80 years (N=458,053) Any diagnosis at baseline (N=1,700,258) Homemaker service (N=264,778) 31-60 days (N=3,667,937) Men (N=1,683,085) Women (N=1,984,852) <50 years (N=1,044,921) 50-64 years (N=1,237,496) 65-79 years (N=997,293) ≥80 years (N=388,227) Any diagnosis at baseline (N=1,561,378) Homemaker service (N=244,561) 61-120 days (N=3,353,855) Men (N=1,533,402) Women (N=1,820,453) <50 years (N=936,779) 50-64 years (N=1,163,704) 65-79 years (N=919,304) ≥80 years (N=334,068) Any diagnosis at baseline (N=1,429,158) Homemaker service (N=228,320) 121-180 days (1,428,433) Men (N=582,945) Women (N=855,488) <50 years (N=320,382) 235 420 255 186 83 131 326 136 681 1,383 913 646 254 251 835 284 1,417 2,672 1,939 1,226 541 383 1,685 437 420 771 536 0·9 1·3 1·5 1·0 0·5 1·9 1·1 2·7 1·3 2·1 2·7 1·7 0·8 1·8 1·5 2·9 1·5 2·2 3·4 1·8 0·9 1·4 1·6 2·3 0·7 0·8 1·6 3,502 3,411 4,600 1,370 499 444 1,692 207 6,400 6,589 8,780 3,165 663 381 2,813 208 6,259 6,639 8,100 3,606 1,011 181 2,911 194 363 461 367 12·6 11·6 28·2 7·1 3·3 7·2 7·9 7·5 13·6 13·3 31·9 9·2 2·5 4·5 8·1 4·7 9·0 9·1 21·8 6·9 2·4 1·5 5·7 2·7 1·2 1·3 2·5 89 (88-91) 90 (88-91) 94 (93-95) 87 (85-89) 84 (79-87) 77 (72-81) 85 (83-86) 78 (72-83) 85 (84-87) 85 (84-86) 91 (90-91) 83 (81-84) 71 (66-75) 72 (68-76) 81 (80-83) 74 (67-79) 79 (78-80) 79 (78-80) 83 (82-84) 78 (76-79) 69 (65-72) 55 (47-62) 76 (74-77) 57 (48-64) 45 (36-53) 52 (46-58) 50 (43-57) 90 (89-91) 90 (89-91) 94 (93-95) 87 (85-89) 85 (81-88) 79 (74-82) 86 (84-87) 77 (71-82) 86 (85-88) 86 (85-86) 90 (90-91) 82 (80-84) 73 (68-77) 75 (71-79) 80 (80-83) 72 (65-78) 79 (78-80) 79 (78-80) 83 (82-83) 76 (74-78) 63 (59-67) 55 (45-63) 74 (72-75) 52 (41-61) 49 (40-56) 48 (40-54) 49 (41-56) This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 50-64 years (N=280,596) 243 0·8 91 0·8 45 (38-57) 33 (11-50) 65-79 years (N=533,415) 212 0·4 145 0·6 52 (39-62) 43 (27-56) ≥8-64 years (N=280,596) 243 0·8 91 0·8 45 (38-57) 33 (11-50) 65-79 years (N=533,415) 212 0·4 145 0·6 52 (39-62) 43 (27-56) ≥80 years (N=304,040) 200 0·5 221 1·6 65 (57-71) 60 (50-68) Any diagnosis at baseline (N=755,262) 524 0·6 345 1·2 60 (54-66) 56 (48-62) Home maker service (N=194,230) 145 0·5 125 1·9 69 (58-77) 64 (51-73) 181-210 days (N=504,501) Men (N=170,689) 259 0·9 107 1·7 33 (15-47) 29 (9-55) Women (N=333,812) 618 1·0 148 1·8 46 (35-56) 40 (37-51) 14 days after the second dose) Vaccinated Unvaccinated Vaccine effectiveness (95% CI) No. of IR/100000 No. of IR/100000 Adjusted for age Fully adjusted* events person-events person-and baseline date days days 15-30 days (N=3,966,630) 42 0·07 398 0·70 91 (88-94) 92 (89-94) Men (N=1,824,056) 25 0·10 199 0·70 88 (81-92) 90 (84-93) Women (N=2,142,574) 17 0·05 199 0·70 94 (89-96) 94 (90-97) <80 years (N=3,508,577) 22 0·04 213 0·42 91 (85-94) 92 (87-95) ≥80 years (N=458,053) 20 0·28 185 3·00 92 (87-95) 92 (88-95) Any diagnosis (1,700,258) 41 0·14 281 1·31 89 (85-92) 86 (84-87) Homemaker service (N=264,778) 23 0·46 101 3·64 92 (88-95) 92 (87-95) 31-60 days (N=3,675,040) 128 0·11 750 0·77 90 (88-91) 90 (88-91) Men (N=1,686,584) 66 0·13 368 0·78 86 (82-90) 88 (84-91) Women (N=1,988,456) 62 0·09 282 0·77 91 (89-93) 91 (88-93) <80 years (N=3,286,444) 53 0·05 487 0·55 92 (89-94) 92 (89-94) ≥80 years (N=388,596) 75 0·54 263 3·13 88 (84-91) 88 (84-91) Any diagnosis (N=1,563,063) 123 0·22 478 1·37 88 (85-90) 87 (85-90) Homemaker service (N=244,779) 76 0·76 120 2·69 89 (85-92) 89 (84-92) 61-120 days (N=3,282,190) 168 0·08 674 0·49 89 (87-91) 89 (87-90) Men (N=1,499,366) 98 0·11 357 0·53 87 (83-89) 88 (85-90) Women (N=1,782,824) 70 0·06 317 0·45 91 (89-93) 90 (86-92) <80years (N=2,947,640) 73 0·04 562 0·45 93 (91-959 92 (92-94) ≥80 years (N=334,550) 95 0·35 112 0·98 83 (78-87) 84 (79-89) Any diagnosis (N=1,421,723) 157 0·15 424 0·85 88 (86-90) 86 (83-89) Homemaker service (N=228,454) 112 0·58 82 1·15 82 (75-88) 81 (73-87) 121-180 days (N=1,194,976) 54 0·04 96 0·18 85 (80-89) 83 (75-88) Men (N=468,292) 28 0·06 33 0·14 77 (62-86) 75 (55-86) Women (N=726,684) 26 0·03 63 0·22 89 (83-93) 87 (79-92) 180 days (N=495,577) 87 0·10 22 0·14 66 (47-79) 75 (43-78) Men (N=167,494) 44 0·15 9 0·13 50 (1-75) 52 (0-77) Women (N=328,083) 43 0·07 13 0·15 75 (54-86) 73 (49-85) This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 <80 years (N=321,154) 25 0·04 10 0·10 82 (74-91) 83 (72-93) ≥80years (N=174,423) 62 0·20 12 0·22 56 (20-75) 51 (2-74) Any diagnosis (N=280,974) 79 0·15 14 0·23 62 (34-78) 58 (26-77) Homemaker service (N=143,534) 67 0·23 6 0·28 60 (10-82) 57 (7-80) s (N=321,154) 25 0·04 10 0·10 82 (74-91) 83 (72-93) ≥80years (N=174,423) 62 0·20 12 0·22 56 (20-75) 51 (2-74) Any diagnosis (N=280,974) 79 0·15 14 0·23 62 (34-78) 58 (26-77) Homemaker service (N=143,534) 67 0·23 6 0·28 60 (10-82) 57 (7-80) *Adjusted for age, baseline date, sex, home maker service, place of birth, education, and comorbidities according to Table 1. CI denotes confidence interval. IR denotes incidence rate. Legends to Figures Figure 1. Description of selection of the cohort. Figure 2. Adjusted vaccine effectiveness (any vaccine) against symptomatic Covid-19 infection among 842,974 vaccinated individuals matched to equally number of unvaccinated individuals through 9 months of follow-up. To model the association between vaccine effectiveness during follow-up, restricted cubic splines were used with 5 degrees of freedom. Supplemental Figure 1. Adjusted vaccine effectiveness (any vaccine) against Covid-19 hospitalization or death among 842,974 vaccinated individuals matched to equally number of unvaccinated individuals through 9 months of follow-up. To model the association between vaccine effectiveness during follow-up, restricted cubic splines were used with 5 degrees of freedom. This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 All individuals diagnosed with Covid-19 in Sweden until May 26, 2021 (N=1,331,989) All individuals vaccinated against Covid-19 in Sweden until May 26, 2021 (N=3,640,421) One matched individual to each individual diagnosed or vaccinated against Covid-19 (N=3,348,248) by Statistics Sweden Total cohort of 5,833,003 unique individuals The cohort was updated with individuals diagnosed with COVID- 19 and vaccinated against COVID-19 until 4 October, 2021 From this cohort, 4,034,787 individuals were identified that had two shots of vaccine no later than August 5. Baseline date was set to date of second dose of vaccine In total 842,974 matched pairs could be identified (N=1,684,958) Excluded 3,939 Died within 14 days of baseline 4,030,848 individuals was matched with the total cohort on birth year and sex. Matched individuals were excluded if death or a first dose of vaccine occurred within 14 days of baseline, and a new unvaccinated individual was searched from the remaining cohort. All individuals diagnosed with Covid-19 in Sweden until May 26, 2021 (N=1,331,989) All individuals vaccinated against Covid-19 in Sweden until May 26, 2021 (N=3,640,421) One matched individual to each individual diagnosed or vaccinated against Covid-19 (N=3,348,248) by Statistics Sweden Total cohort of 5,833,003 unique individuals The cohort was updated with individuals diagnosed with COVID- 19 and vaccinated against COVID-19 until 4 October, 2021 From this cohort, 4,034,787 individuals were identified that had two shots of vaccine no later than August 5. Baseline date was set to date of second dose of vaccine In total 842,974 matched pairs could be identified (N=1,684,958) Excluded 3,939 Died within 14 days of baseline 4,030,848 individuals was matched with the total cohort on birth year and sex. Matched individuals were excluded if death or a first dose of vaccine occurred within 14 days of baseline, and a new unvaccinated individual was searched from the remaining cohort. Figure 1 Figure 1 This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410 Figure 2 Click here to access/download;Figure;Figure 2 - Final.tif This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410Preprint not peer reviewed Figure S1 Click here to access/download;Figure;Figure S1 - Final.tif This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3949410Preprint not peer reviewed Video transcript in spoiler. Click To View Spoiler [Music] two of the strongest pillars for the vaccine mandates are that the vaccinated spread the disease less than the unvaccinated of course and that they experience lower rates of disease are those two things true come on we're gonna find out today [Music] hello everyone dr chris martinson here and it's uh just a lovely rainy day in new england and we're gonna talk about a couple of pieces of data that have come out very recently that just make the whole rationale for a vaccine and vaccine mandate a little bit more difficult to support from the logic and from the data so let's go through the data first let's start here um yeah the mandate rationale it just takes another blow maybe not a fatal blow but it's just it's getting trickier all the time to figure out who to trust and what to believe in and so these are the headlines that just came out recently first in the hill on the 29th of october we had vaccinated just as likely to spread delta variant within household as unvaccinated study we're going to go into that study i'll show you the data of course we always go to the data this is interesting they notice the word household in there and that's important because the household is actually the place where you get the highest rates of spreading of sars co v2 the reason for that is there are four d's that remember we talked about the four d's a long time ago that you want to minimize or optimize in order to avoid catching any viral born disease but in particular an airborne viral disease and those would be the density the density of the people around you how close is everybody right how many of them do you have who actually have the disease in a communicable form then you have draft hey more draft is better right you want to optimize that as well distance right how far away are you from everybody so if you have a lot of people who are sick at a really close distance with no draft obviously you get into all sorts of difficulties with that and then how diffuse is is this thing spread through the room so at any rate households are where this stuff tends to spread so the uk did a really cool study which again we're going to go into as you can see here as i get my drawing tool out uh this is obviously of a lot of interest thousands over you know five and a half thousand comments there on the hill as well here's a headline written slightly differently in bloomberg vaccined people also spread the delta variant year-long study shows so this is important information because of course you know one of the things we've heard is that the unvaccinated according to some on the vaccinated side are selfish because they're they're busy spreading this thing around there's another way we could look at it too though which is if this data is correct and the vax needed are spreading just as much as or nearly as much as unvaccinated then they should know that right because if you falsely believe that you are safe right because even the president of the united states what did he say he said that health care workers who are vaccinated cannot pass covet to their patients right that's the president of the united states spreading what turns out to be incorrect information so looking forward to a correction on that from jen saki or the president himself soon because that's really important distinction because if you falsely believe that you can't communicate a disease because you're vaccinated but you can well now you're putting yours you're putting people at risk potentially even somebody who is vaccinated even double vaccinated who's elderly or with co-morbidities they are still at risk and we're going to show you data around that as well that comes to us from sweden two really interesting papers that begin to crisp up what we know what we don't know about this disease here's the paper and the disease and how it spreads in the lancet i told you i put the lancet on double secret probation after uh the surgisphere fraud and the other fraudulent papers they ran it was just horrifying so i'm a little i don't like quoting the lancet much anymore but this is where it came out so let's go there i guess i can't throw every baby out with the bath bath water but uh the paper is community transmission and viral load kinetics that's how fast the the disease comes into a large amount in somebody's body and how rapidly that goes away again that's the kinetics viral load kinetics of the sars co v2 delta variant that's the very handily named b.1. the delta variant in vaccinated and unvaccinated individuals in the uk a prospective longitudinal cohort study a lot of authors on here i will tell you they did a really good job in this study it's very complete i read it all the way through didn't find a lot of places i was going to pick it apart methodologically so the methods look pretty good so let's start here with their discussion first in the first yellow part up top quote households are the site of most sarsko v2 transmission globally in our cohort of densely sampled household contacts exposed to the delta variant sar was 30 uh that's the sars attack rate sar was 38 in unvaccinated contacts and 25 percent in fully vaccinated contacts this finding is consistent with the known protective effect of covid19 vaccination against infection it is consistent we did see that more unvaccinated contacts had a higher attack rate 38 percent so in a household somebody comes in carrying sars cov2 38 of that household if they were unvaccinated would get infected whereas it would be 25 if they were vaccinated so 38 to 25 the issue is when you look at the numbers that's not a statistically significant difference so it didn't achieve significance i'll show you the data down below in green continuing quote notwithstanding these findings indicate continued risk of infection in household contacts despite vaccination so yes they say this is you know finding is consistent with known protective effects of cova-19 vaccination against infection but despite that people who have or fully vaccinated can still spread the infection throughout their household so there's that continuing all the way down here in yellow again quote it says suggesting that susceptibility to infection increases with time as soon as two to three months after vaccination that's a finding they came up with consistent with waning protective immunity now we've all known about this for a while we've heard about the boosters there's really no surprise here but they've got some good data on this in fact the whole paper is worth it i didn't put all the tables in here but they have a lot of samples of where they were looking at viral loads in people and they would do it over and over and over and over again not just one snapshot they would take a snapshot a day or every other day so they have a really complete record of how quickly and forcefully the virus is coming into a peak load in in people so at any rate they were able to detect within this data set that just two to three months after vaccination the vaccination's waning and they start to see a higher susceptibility to infection just within a couple of months continuing in green quote household sars tax rates for delta infection regardless of vaccination status was 26 regardless of vaccination status doesn't matter vaccinated unvaccinated the attack rate for delta was 26 percent so that's equal that's equal vaccinated or not same number which is higher than estimates of uk national surveillance data which suggests it's about 10.8 percent reason for that is that these people sampled everybody in their study regardless of whether they had symptoms or not so they have a much more complete record whereas the surveillance data from the uk those are people who are getting sampled because they have cause to be sampled they have symptoms or they are around somebody with a lot of symptoms but they sort of self-checked in to get to get tested here they're testing the whole household so whether you're vaccinated or not what they found was about 26 percent chance of coming down with a sars kov2 or covet infection if you live with somebody who has it and it doesn't matter if they're vaccinated or not or if you're vaccinated or not comes up with that number all right continuing down again in down there quote however we sampled contacts daily regardless of symptomology to actively identify infection with high sensitivity by contrast symptom-based single-time point surveillance testing probably underestimates the true sars attack rate and potentially also overestimates vaccine effectiveness against infection now this is a really important point because this is exactly what pfizer did in their first study when they said you know they took you know 42 000 people roughly half were vaccinated not but they didn't test everybody in that in that whole scene they just tested people who became symptomatic for or presumptively symptomatic for covet so again the only way you can really get good data is by testing everybody something i've been saying since the beginning this study did that they tested everybody and it's a whole year-long study now i know what some of you are thinking which is totally accurate which is well look the vaccinated may get an infection and they may pass it but they don't get symptoms and they don't go to the hospital so those are great points which is why this most recent paper which is a pre-print hasn't been through peer review yet that just came out of sweden good looking paper though uh it feels you know pretty solidly done and uh here's the title this paper effectiveness of covid19 vaccination against risk of symptomatic infection hospitalization and death up to nine months a swedish total population cohort study this is a big study they matched a lot of people against a lot of other people so this uh just came out very recently and this is really cool study because what did they do well let's talk about this um first up what they're looking for is what happens after like six months for these vaccines and they want to know about the the effectiveness against disease so the prior paper was just saying look with delta in play whether you're vaccinated or not you have about the same uh capability of of transmitting it or passing it on or infecting somebody else so this is asking the question well if somebody does get infected then what here they did a retrospective cohort study so they're looking back in time in their databases and they're asking the question who was vaccinated who wasn't what were their outcomes this was conducted using swedish nationwide registries the cohort comprised 842 000 pairs that's 1.684 million people total including individuals vaccinated with two doses of this vaccine right here the mrna one from moderna the pfizer so those three vaccines and matched to unvaccinated individuals so when you're matching what are you matching for age comorbidities gender things like that so so when you match them we could say well we have two guys one vaccinated one unvaccinated 40 years old both relatively fit now we can compare what happened to them so that's what they mean by matched here cases of symptomatic infection and severe covet 19 hospitalization or 30-day mortality after confirmed infection were collected from 12 january to the 4th of october so yeah we've got about 10 months of data in there that's pretty pretty big study so what did they come up with this is really cool findings here first quote in the yellow up top vaccine ineffectiveness of the physical vaccine against infection waned progressively from 92 percent at day 15 to 30 where people had max sort of antibodies mac protectiveness was it days 15 to 30 all the way down to 47 at day 121 today 180. so within six months this thing had gone from 92 percent effective this is just against an infection again to about under the 50 mark now why is that important because the 50 mark is the mark that you have to hit if you're a vaccine manufacturer to show that you have a protective benefit that that's the remember they always said that was the line and then where everybody's thrilled because pfizer hit 92 percent so these are very statistically significant um uh findings here and then they say from uh day to eleven onwards no effectiveness could be detected so it's like nothing's happened like we're back down to close to zero but this wasn't a significant finding um they couldn't differentiate whether it was uh went from the confidence interval here goes from -2 to 41 so it goes below zero so uh p .07 not not a strong finding that one continuing in green quote the effectiveness weighed slightly slower for mrna 1273 moderna being estimated to 59 from day 8 181 and onwards in contrast the chad aux 1 the oxford vaccine there was generally lower and waned faster with no effectiveness detected from day 121 and onwards continuing in yellow down here overall vaccine effectiveness was lower and waned faster among men and older individuals so we're starting to put a story here which is to say that if somebody is vaccinated if they're male or older or both then you're gonna want to understand that from about six months onward they they're they're still at risk they are back to being at risk again continuing in green at the bottom here quote for the outcome severe covet 19 that's the outcome they were tracking their severe covet 19 effectiveness weighing from 89 at day 15 to 30 to 42 percent from day 181 and onwards with sensitivity analyses showing notable waning among men older frail individuals and individuals with comorbidities so now we're just back to the people you would normally put into your critical category which is older frail individuals and individuals with comorbidities but we're also tucking men into this data set here so that's what they found here's what it looks like on a chart and in blue we have protectiveness the vaccine effectiveness the ve first against here which is just infection which could be symptomatic could be asymptomatic it's just infection and we see that that peaks out at about 92 percent crosses below that magic 50 barrier here at about half a year and plummets and heads right on down towards zero there here we see the vaccine effectiveness for severe covet infection so this means your your pretty strong symptomology if not in the hospital if not worse and the effect is a little higher and it tails off with about six months it crosses the 50 mark tails off to here this is where their study went to only went this long so they had to sort of guess what they think was going to happen looks like a fair guess there what that dotted line might suggest something like that so still it's 20 effective here closing in on three quarters of a year what this is really arguing for though is the idea that this vaccine effectiveness really does wane and this is why people talk about wanting to put boosters on and those boosters probably need to be at the six-month mark if not before but you'd have to decide where you draw on the line are you saying we want 80 infection protection levels then you would have to draw the mark here i mean sorry 60 if you want 80 percent you're going to need to draw the mark here which is barely 90 days in so if you wanted to say hey we want everybody to be 80 and uh protected against infection you're on a 90-day booster program according to this assuming the boosters behave the same as the earlier injections maybe they'll maybe they last longer maybe they last less long we don't know don't have that data yet obviously because here we are nearly two years into this and we're just getting this data now we should have had it before before now this is what a endless booster cycle might look like if you gave it at the half year mark something like that my crudely drawn little uh endless mountain range there that's what it might look like if it behaves the same it might be different than that we don't know but the point here is is contained in the word endless because these things are just going to continue on for a long time now why is that for whatever reason nature and coronaviruses and humans have worked out a deal where humans will retain very durable long lasting antibody protection more than that immunological protection against viruses and some bacteria some of them for the life time of that individual right if you get chicken pox it's a kind of a once it once a lifetime deal mumps kind of a once a lifetime deal things like that you get it once your body remembers it not allowed back in the door but coronaviruses they come and they go our body has just decided i'm not going to keep a keep a memory of that thing don't know why but that's why we typically would get colds over and over and over again even though you're being exposed to prince pretty much the same cold coronavirus the hku-9 something like that so that's just the deal so here we are the question would be does it make sense to try and fight a coronavirus with injections like this we'd have to argue about it and debate it because it may not make sense in a coronavirus environment where this is the pattern particularly since we do know that so far the data says particularly the israeli data that the natural immunity you might get looks very very different from this it's more durable and longer lasting the reason is pretty simple to explain the virus is a very complicated thing with lots of different pieces on the surface when you get the injection you're getting just one snippet one piece of information across the whole top of this outside of the virus your body makes antibodies against that one part when you get exposed to the whole virus you make antibodies against all these different parts different things like the e protein the n protein the s the spike and when you have a much more robust more poly heterogeneous sort of a response then this seems to last longer for whatever reason that's what the data says so far all right so as we look in this this is kind of interesting because a permanent vaccine schedule may thwart what we're actually after in this story which is what which is to have this virus just be out there we've struck some sort of a bargain with it over time it's become slightly less deadly we've become more immune to it including natural immunity or whatever we've we've come to some deal with it the issue here shows up to us in the week 42 covet 19 vaccine surveillance report out of the uk where they note where they were doing serial positivity tests for people so they're looking for both the s protein antibodies the spike protein antibodies which could come from a natural source or from a vaccine they were comparing those and looking for the n protein antibodies in there so these n proteins if you have those you didn't get in protein antibodies because of exposure to a vaccine you only could have gotten the end proteins from a natural immunity so they were looking at that and the interesting finding is down here in yellow number three quote recent observations from uk health security agency surveillance data that n antibodies appear to be lower in individuals who acquire infection following two doses of vaccination let me decode that so for an individual hasn't been exposed to covet gets two vaccinations and then he is in one of these households gets a covered infection turns out that when you measure their antibodies against the n protein they don't have the n-protein antibodies or they're lower in there so it means that two doses of vaccination is preventing or potentially blocking or thwarting that natural immunity response this is something that came up in our interview with gert vandenbosch he talked about it this falls under the term of something known as antigenic sin potentially antigenic sin is the process whereby your body received the vaccines it became primed to fight that thing and so when it is exposed to a sars cov2 in the future it doesn't spend time fighting that it says i know how to do this and it just spends time remaking the old antibodies that it made before it doesn't spend time trying to figure out a new method for fighting this invader once it sees it again hey that's nature being efficient that efficiency though seems to thwart natural immunity so to the extent to which we would want natural immunity to emerge so that we can avoid being on this treadmill forever this may be a complicating factor here this is why vaccines vaccines development and the whole prospect of vaccines in a public health setting is actually a very complicated subject and it needs to be talked about with a lot of rigor all right that's kind of an interesting finding there here is the bombshell for me that came out of the end of this swedish paper now here what they're talking about is the vaccine effectiveness here okay so and this is for symptomatic covid you can see here they've got a very tight range the black line and the the gray is a are the error bars in the story the error bars obviously get larger the further out you go but they note here that vaccine effectiveness comes all the way down and if their extrapolations are correct it not only comes down to zero but potentially goes below zero hey you know what this might be the correct line and it might do this it might end up over here and stay above zero the whole time or it might go below zero what does that mean how does vaccine effectiveness go below zero well it turns out that after a certain time people who've been exposed to the vaccines and then later to covet after a certain period of time here this might cross zero in in their particular extrapolation here at about day 240 it would mean from that day forward without another booster the people who are double vaccinated are actually more at risk of developing symptomatic kova than somebody who has not been vaccinated that's what the paper says it was kind of a surprising finding i didn't expect to see that wider error bars on this but this is uh us for severe covet which could include icu and death and stuff like that so again very wide error bars out here super wide this tends their model has this staying above zero which is very helpful but they can't preclude the possibility it goes below zero as well so we don't know we're just gonna have to track this over time as things develop but again this is why i argue for more data more data more data we just need more data and then we can make better informed decisions over time makes sense right all right um so yeah why do we need more more better data listen we need better data because if we want to make a logically sound set of conclusions we we want to we need a logical and sound set of data for that and then we would actually need to start comparing the vaccines and their long-term outcomes to natural immunity or early treatment now you know me i like to set things up and frame things a little bit so this is what an actual proper study would have looked like given all the billions and billions and billions of dollars thrown at this could we have spent 500 million designing a proper study please so we could have gotten this this is what it would look like we would have said oh we're going to design this study to test the effectiveness of any particular vaccine candidate so this is this is where the pfizer study started and stopped right here they just put it they vaccinated some people and they left some controls on unvaccinated so that's what happened but if we were doing it right we would care further we'd say well if we put it into a vaccinated person let's be sure we track those who had prior natural immunity so we can track things like the s protein the n protein other things like that does it boost downstream protected protective ve against infection sirius coveted stuff like that and then we'd also compare those to the naive people so they're vaccinated but they've never had cova before so we would be able to compare those two groups but once each of those people in those groups got coveted we would then want to compare what happens if we give these people early treatment versus no early treatment and the naive population they get covered early treatment versus no early treatment same thing in our control group we have unvaccinated but there are those who have prior natural immunity there are those who are naive same thing each of them comes down with covet again great let's compare early treatment to no early treatment all the way down once you do that now we have a complete data set where if you're a public health administrator or you're a parent with a child you get to look this data and make the decision for yourself hey what makes the most sense here how you know how would i go through this and where are the risks really lying the problem is we don't have any of this data out here nothing we have nothing out here in this part except we have clues nothing out here we have clues about this stuff based on the israeli data which gave us a little bit of information about prior natural immunity which was great but we don't have any data at all comparing this early treatment to no early treatment across these different cohorts so we oh sorry let me put that back see if you can slide it right into that window without any white edges and then just go back to that last line yep but what we don't have is we don't have any any data yet about the difference between early treatment and no early treatment across these different groups so we're just flying a little bit blind here at this point in time but in fact if we were going to do this really well you know what we would do if this was about public health we would have done this study which looks exactly like the earlier study except the first thing we did is we boosted everyone's terrain everybody gets vitamin d in the mail everybody has the all the vitamins and supplements they need to have a healthy active terrain because as we know there's two ways that your body fights an infection one is with this antibody response which is a very narrow thing that can be done but the other way is by having this boosted natural terrain so that your whole immune system is tuned and ready to fight a big fight and it'll do better and so how would we do that well these are all the supplements i personally take to boost my terrain i don't know i can't tell you what this has been due to i have not been sick since covet started so maybe it's because i just don't hang around people all that much anymore maybe it's because we're being more careful in general or maybe it's because i finally learned what's necessary to really boost my terrain and so my daily input includes this and this and this and this and this that's on a daily basis a pretty strong pretty strong fan of this stuff down here too um some of these other ones here i take uh when when i if if or when i get ill this and this and this they're just sitting there but i haven't really gotten ill in a long time so that's the benefit of cove this has been the most amazing part is i feel like i've learned how to regain control of my health and i've learned a lot of fairly dark things about the industry such as it's arranged that would prefer i didn't know this stuff and that you wouldn't know about this stuff either because that's not they don't make their money with you being healthy that's part of the story has been for a while conclusions for today oh wait and before i get totally down into these conclusions let me just tell you that um i'm gonna be discussing more of this here in part two and part two we're going deeper down let me just tell you this is really the subject of part two i think you can read between the lines um about what that title is going to be about so we're going to talk about that plus just yesterday at peak prosperity i sent out an alert i don't send them out very often an alert is a piece of information or a collection of data that causes me to personally take some kind of urgent actions in my own life the shortages and economic fallout from from what's happening with all the supply chain issues is very dire right now so go take a look at that alert if you want to be apprised of what's coming and go around that all right so the conclusions for today episode 34 a current vaccines do not prevent a delta variant within households that's uk data it's just data is what it is next current vaccines drop below the 50 effectiveness barrier within 5 months for infection 6 months for severe covet that's the swedish data we also learn from that same swedish data that men the elderly and those with comorbidities are even higher risk of an early drop off in that ve the vaccine effectiveness swedish data thus the all the main logic arguments for mandates are not really found in either data or logic at this point in time the only thing we can say is that for a period of time the vaccines do prevent people from getting more serious coveted and that's a good thing it's more true the effectiveness of that and the benefit of that is more true for people who are at more at risk from cove in the first place so it's a more complicated story but as you and i know the elderly and those in particular with comorbidities those are the people most at risk in this story and so the mandates then are if they're really predicated on the idea that we need the vaccine so that we can prevent the spread of covid that doesn't work anymore and if we're saying we need these vaccines because they're going to provide lasting effectiveness against severe covet and death that's not the case so we know those two things are no longer true so worse in this story for me though is that vaccinated people may falsely believe that they're safe or safer to others in society than the unvaccinated but that's not the case and so they can still transmit this disease now you might say well but on average vaccinated people are going to get a less severe course of the disease true but not completely true it's not a hundred percent true it's actually not even close to 100 true we know from the israeli data and from the uk data that the vaccinated fully vaccinated double vaccine are showing up in the hospitals and are dying that's still true so can't say it's not black and white as it's been presented it's not like you're vaccinated and safe and unvaccinated unsafe that's not the case there's risks across this whole structure so the advice here is for everybody to still keep your caution remember those four d's but particular draft and distance and the density you know being in a really uh closed air environment with a lot of other people is still risky and according to this data doesn't matter if you're vaccinated or not the only thing that really seems to matter is the younger you are the safer you seem to be and the healthier you are the safer you seem to be with one little wrinkle in there bodybuilders seem to be especially at risk from this thing it's kind of a strange thing might have something to do with their muscle mass i'm not clear about that but that data has also come through kind of anecdotally but there's too many cases there for it to be um a non-signal at this point finally but most importantly vaccines they don't deliver herd immunity they don't this is something anthony fauci should have known does know but has chosen to pretend as if he doesn't know this whole time and i've talked about that being the case right from the very beginning they can't deliver herd immunity if they don't prevent you from catching and passing on the disease it's an impossibility full stop end of story and they may vaccines may even thwart development of a more durable natural immunity because that's the end protein uk data actually we don't have data we have a statement i haven't actually seen the data yet so i'm going to go hunting for that this too deserves discussion those are my conclusions for today we should be talking about all of this what are we willing to give up what's the what are we willing to sacrifice how much are we willing to bear in order to achieve what well what are we trying to achieve that's what i think has been lost in this story is that is that articulation of exactly what the goal is here without moving the goal posts five more times what's the goal and the goal really ought to be lowering the mortality and the morbidity of people in a pandemic and if this is where the pandemic numbers would have been without interventions with interventions you'd want to see the data down here your interventions should be working in part two of this i'm going to show you strong data that suggests it's actually not working but we're going to have to examine why that might be so we'll go there next and i hope to see you there thank you so much for listening to this i hope it stays up we're just talking data this is the kind of conversation we should we should be having though is articulating the nuances of this so we can make informed decisions so be safe everyone thank you very much for listening we will see you next time [Music] Mandates Have Nothing To Do With Public Health so let's start here with their discussion first in the first yellow part up top quote households are the site of most sarsko v2 transmission globally in our cohort of densely sampled household contacts exposed to the delta variant sar was 30 uh that's the sars attack rate sar was 38 in unvaccinated contacts and 25 percent in fully vaccinated contacts this finding is consistent with the known protective effect of covid19 vaccination against infection it is consistent we did see that more unvaccinated contacts had a higher attack rate 38 percent so in a household somebody comes in carrying sars cov2 38 of that household if they were unvaccinated would get infected whereas it would be 25 if they were vaccinated so 38 to 25 the issue is when you look at the numbers that's not a statistically significant difference so it didn't achieve significance Also:endless boosters with a very tightly targetted vaccine (which imo isn't even possible if your natural immunity doesn't work), ... or natural immuinity that can at least recognize a slightly modified virus. Pipedream, they find a very well conserved section across a LOT of coronaviruses for a vaccine. This stupid spike-only / non sterilizing immunity stuff is biting us in the butt. conclusions for today episode 34
a current vaccines do not prevent a delta variant within households that's uk data it's just data is what it is next current vaccines drop below the 50 effectiveness barrier within 5 months for infection 6 months for severe covet that's the swedish data we also learn from that same swedish data that men the elderly and those with comorbidities are even higher risk of an early drop off in that ve the vaccine effectiveness swedish data thus the all the main logic arguments for mandates are not really found in either data or logic at this point in time the only thing we can say is that for a period of time the vaccines do prevent people from getting more serious covid and that's a good thing it's more true the effectiveness of that and the benefit of that is more true for people who are at more at risk from cove in the first place so it's a more complicated story but as you and i know the elderly and those in particular with comorbidities those are the people most at risk in this story and so the mandates then are if they're really predicated on the idea that we need the vaccine so that we can prevent the spread of covid that doesn't work anymore and if we're saying we need these vaccines because they're going to provide lasting effectiveness against severe covet and death that's not the case so we know those two things are no longer true so worse in this story for me though is that vaccinated people may falsely believe that they're safe or safer to others in society than the unvaccinated but that's not the case and so they can still transmit this disease now you might say well but on average vaccinated people are going to get a less severe course of the disease true but not completely true it's not a hundred percent true it's actually not even close to 100 true we know from the israeli data and from the uk data that the vaccinated fully vaccinated double vaccine are showing up in the hospitals and are dying that's still true so can't say it's not black and white as it's been presented it's not like you're vaccinated and safe and unvaccinated unsafe that's not the case there's risks across this whole structure so the advice here is for everybody to still keep your caution remember those four d's but particular draft and distance and the density you know being in a really uh closed air environment with a lot of other people is still risky and according to this data doesn't matter if you're vaccinated or not the only thing that really seems to matter is the younger you are the safer you seem to be and the healthier you are the safer you seem to be with one little wrinkle in there bodybuilders seem to be especially at risk from this thing it's kind of a strange thing might have something to do with their muscle mass i'm not clear about that but that data has also come through kind of anecdotally but there's too many cases there for it to be um a non-signal at this point finally but most importantly vaccines they don't deliver herd immunity they don't this is something anthony fauci should have known does know but has chosen to pretend as if he doesn't know this whole time and i've talked about that being the case right from the very beginning they can't deliver herd immunity if they don't prevent you from catching and passing on the disease it's an impossibility full stop end of story and they may vaccines may even thwart development of a more durable natural immunity because that's the end protein uk data actually we don't have data we have a statement i haven't actually seen the data yet so i'm going to go hunting for that this too deserves discussion those are my conclusions for today we should be talking about all of this what are we willing to give up what's the what are we willing to sacrifice how much are we willing to bear in order to achieve what well what are we trying to achieve |
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Originally Posted By exponentialpi: Because folks are too busy driving their kids 5-11 to go get jabbed. View Quote View All Quotes View All Quotes Originally Posted By exponentialpi: Originally Posted By FlashMan-7k: Why haven't certain people been tried in court and hung? Because folks are too busy driving their kids 5-11 to go get jabbed. It was a purely rehtorical question, but yeah. People who can't even look into original sources to protect their pre-teen kids to see if what they are being told is true indicates that people are ... as we humans always have been ... just buying what we want to out of what we're told. I think if you showed these people the chances of getting a case of covid as bad as having myo or peri carditis for children esp boys, vs the chances of having the same amount of damage from covid with the best data we ave ... heads would roll. |
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Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate View Quote So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. |
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"We the People ultimately control our government, not the other way around." - planemaker
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Originally Posted By planemaker: So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. View Quote View All Quotes View All Quotes Originally Posted By planemaker: Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. You forgot to add: They made the pfizer pill to replace other evil pills ... because those evil pills aren't profitable anymore! |
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Originally Posted By FlashMan-7k: You forgot to add: They made the pfizer pill to replace other evil pills ... because those evil pills aren't profitable anymore! View Quote View All Quotes View All Quotes Originally Posted By FlashMan-7k: Originally Posted By planemaker: Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. You forgot to add: They made the pfizer pill to replace other evil pills ... because those evil pills aren't profitable anymore! Generic drugs are evil and we must not allow them. Hope ya'll got expensive obamacare plans |
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Carry it, shoot it. (repeat forever)
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Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate View Quote lol |
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I took a look at the VAERS data today after reading the following article about "hot" lots of vaccines: Uh, That's Not A Conspiracy Theory - The Market Ticker
A few of these VAERS graphs I shared in another thread, but I made some more graphs this evening and I figured I would just share them all here in case anyone here isn't following other threads. There are a lot of graphs, so I'll put them in spoilers. First, here are some histograms of the age distribution of deaths for the vaccines, including manufacturer-specific histograms. I find it interesting that the age distributions look very similar across manufacturers. Another odd thing is that the Moderna distribution looks almost too perfect -- it peaks in the 81-85 age group and declines steadily toward younger and older age brackets, with no small peaks and valleys like the other two manufacturers. Not necessarily a sign of manipulation because it could happen by chance, but it stuck out to me. Click To View Spoiler Next, here are some different ways of looking at the numbers. These graphs below are for all manufacturers combined. The drop in deaths in the summer (June and July) corresponds to fewer doses of vaccine being distributed. However, the increase in deaths in August and September is qualitatively higher than I would have expected. Although vaccinations went up in those months, they didn't go up very much compared to summer. The last histogram in this group shows the time lag between vaccination and death. Notice that most deaths occur within 2 to 3 weeks of vaccination date. But there are some that have a much longer lag. Remember that VAERS data is unverified and there are probably some wacky entries in here. I didn't examine them enough to give a decisive opinion on the entire group. If I had a $6 billion budget like the FDA I would probably pay somebody to do that. Or maybe not. That yacht isn't going to pay off itself, amirite? Click To View Spoiler This first plot should be a bubble plot instead of a scatter plot, but I was lazy and didn't do it that way. Just keep in mind that some of the dots in this graph represent more than 1 death. Now some scatter plots showing date of vaccination (triangles) and date of death (circles) for each manufacturer. Notice that the spread between vaccination and death starts to increase for all manufacturers after May, in an odd nonintuitive way. It's not a gradually widening spread, it just kind of diverges after May. Many deaths after May still happen shortly after vaccination, but there is a group of deaths after May for which vaccination date is April or earlier, without much in between. Again, these scatter plots look similar regardless of manufacturer. I find that very interesting. It suggests a factor that might overshadow manufacturer-specific technology or quality control. What is that factor? I don't know. Click To View Spoiler Finally, below are a couple graphs of the "hottest" Pfizer lot (EN6201) mentioned in this article: Uh, That's Not A Conspiracy Theory - The Market Ticker I also found this lot to be the "hottest" Pfizer lot, but I only counted around 40 deaths from it instead of 117 like the article says. Maybe I made a mistake. Click To View Spoiler If anyone else looks at this data, let me know what numbers you get. I did this all in Excel rather quickly, so I can't guarantee the results are error free. |
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Originally Posted By Obelix45: I took a look at the VAERS data today after reading the following article about "hot" lots of vaccines: Uh, That's Not A Conspiracy Theory - The Market Ticker A few of these VAERS graphs I shared in another thread, but I made some more graphs this evening and I figured I would just share them all here in case anyone here isn't following other threads. There are a lot of graphs, so I'll put them in spoilers. First, here are some histograms of the age distribution of deaths for the vaccines, including manufacturer-specific histograms. I find it interesting that the age distributions look very similar across manufacturers. Another odd thing is that the Moderna distribution looks almost too perfect -- it peaks in the 81-85 age group and declines steadily toward younger and older age brackets, with no small peaks and valleys like the other two manufacturers. Not necessarily a sign of manipulation because it could happen by chance, but it stuck out to me. Click To View Spoiler https://i.imgur.com/3jxVK8Q.png https://i.imgur.com/0UGtjGC.png https://i.imgur.com/RKssQge.png https://i.imgur.com/GSC0zBQ.png Next, here are some different ways of looking at the numbers. These graphs below are for all manufacturers combined. The drop in deaths in the summer (June and July) corresponds to fewer doses of vaccine being distributed. However, the increase in deaths in August and September is qualitatively higher than I would have expected. Although vaccinations went up in those months, they didn't go up very much compared to summer. The last histogram in this group shows the time lag between vaccination and death. Notice that most deaths occur within 2 to 3 weeks of vaccination date. But there are some that have a much longer lag. Remember that VAERS data is unverified and there are probably some wacky entries in here. I didn't examine them enough to give a decisive opinion on the entire group. If I had a $6 billion budget like the FDA I would probably pay somebody to do that. Or maybe not. That yacht isn't going to pay off itself, amirite? Click To View Spoiler This first plot should be a bubble plot instead of a scatter plot, but I was lazy and didn't do it that way. Just keep in mind that some of the dots in this graph represent more than 1 death. https://i.imgur.com/hFopbIP.png https://i.imgur.com/WRpuc4O.png https://i.imgur.com/dNIOrjy.png Now some scatter plots showing date of vaccination (triangles) and date of death (circles) for each manufacturer. Notice that the spread between vaccination and death starts to increase for all manufacturers after May, in an odd nonintuitive way. It's not a gradually widening spread, it just kind of diverges after May. Many deaths after May still happen shortly after vaccination, but there is a group of deaths after May for which vaccination date is April or earlier, without much in between. Again, these scatter plots look similar regardless of manufacturer. I find that very interesting. It suggests a factor that might overshadow manufacturer-specific technology or quality control. What is that factor? I don't know. Click To View Spoiler Finally, below are a couple graphs of the "hottest" Pfizer lot (EN6201) mentioned in this article: Uh, That's Not A Conspiracy Theory - The Market Ticker I also found this lot to be the "hottest" Pfizer lot, but I only counted around 40 deaths from it instead of 117 like the article says. Maybe I made a mistake. Click To View Spoiler The axes on the first histogram below should be deaths (vertical axis) vs. age (horizontal axis). https://i.imgur.com/ukYyxfu.png https://i.imgur.com/r5IPvsv.png If anyone else looks at this data, let me know what numbers you get. I did this all in Excel rather quickly, so I can't guarantee the results are error free. View Quote The problem as I see it is you don't have the lot sizes. Without lot sizes, you can't look at actual *rates*. In theory, if you had death *rates* by lot, then you could say they are flat across lots (no QA/QC problems), normal distribution (some QA/QC problems), or disjoint (big QA/QC problems). Without having the lot sizes, you can't really compare the number of deaths directly. If one lot is 10x as large as the next, if the difference in deaths is 10x then they have the same *rate* and there really is nothing to look at relative to lots being hot or not. One other thing that is also difficult to quantify is that early on, only the elderly and those with significant co-morbidities were getting the shots. That would likely tend to skew the adverse events (particularly deaths) because of the frailty factor. So, even though Karl looked at de-coupling the age difference, there was no way to de-couple the fact that early lot numbers were given more to folks more likely to have a harsher reaction. |
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"We the People ultimately control our government, not the other way around." - planemaker
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Originally Posted By planemaker: The problem as I see it is you don't have the lot sizes. Without lot sizes, you can't look at actual *rates*. In theory, if you had death *rates* by lot, then you could say they are flat across lots (no QA/QC problems), normal distribution (some QA/QC problems), or disjoint (big QA/QC problems). Without having the lot sizes, you can't really compare the number of deaths directly. If one lot is 10x as large as the next, if the difference in deaths is 10x then they have the same *rate* and there really is nothing to look at relative to lots being hot or not. One other thing that is also difficult to quantify is that early on, only the elderly and those with significant co-morbidities were getting the shots. That would likely tend to skew the adverse events (particularly deaths) because of the frailty factor. So, even though Karl looked at de-coupling the age difference, there was no way to de-couple the fact that early lot numbers were given more to folks more likely to have a harsher reaction. View Quote I would guess that lot size varies widely, but I really don't know. It wouldn't surprise me if they do. The "hot lot" idea needs to have a question mark for now. The thing I found interesting in the data was the similar age and time distributions of deaths between all 3 manufacturers. I was also surprised that the tail of the death distribution was still thick at lower ages, more than I would have guessed. Edited to add: The similarities between all 3 manufacturers are interesting because in my view they greatly diminish the idea that a bunch of anti vaccine crusaders are entering spurious data. If there is data manipulation, it is highly coordinated. I don't think that's happening though. My opinion for now is that most of these reports were made in good faith. |
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Originally Posted By Obelix45: I would guess that lot size varies widely, but I really don't know. It wouldn't surprise me if they do. The "hot lot" idea needs to have a question mark for now. The thing I found interesting in the data was the similar age and time distributions of deaths between all 3 manufacturers. I was also surprised that the tail of the death distribution was still thick at lower ages, more than I would have guessed. Edited to add: The similarities between all 3 manufacturers are interesting because in my view they greatly diminish the idea that a bunch of anti vaccine crusaders are entering spurious data. If there is data manipulation, it is highly coordinated. I don't think that's happening though. My opinion for now is that most of these reports were made in good faith. View Quote View All Quotes View All Quotes Originally Posted By Obelix45: Originally Posted By planemaker: The problem as I see it is you don't have the lot sizes. Without lot sizes, you can't look at actual *rates*. In theory, if you had death *rates* by lot, then you could say they are flat across lots (no QA/QC problems), normal distribution (some QA/QC problems), or disjoint (big QA/QC problems). Without having the lot sizes, you can't really compare the number of deaths directly. If one lot is 10x as large as the next, if the difference in deaths is 10x then they have the same *rate* and there really is nothing to look at relative to lots being hot or not. One other thing that is also difficult to quantify is that early on, only the elderly and those with significant co-morbidities were getting the shots. That would likely tend to skew the adverse events (particularly deaths) because of the frailty factor. So, even though Karl looked at de-coupling the age difference, there was no way to de-couple the fact that early lot numbers were given more to folks more likely to have a harsher reaction. I would guess that lot size varies widely, but I really don't know. It wouldn't surprise me if they do. The "hot lot" idea needs to have a question mark for now. The thing I found interesting in the data was the similar age and time distributions of deaths between all 3 manufacturers. I was also surprised that the tail of the death distribution was still thick at lower ages, more than I would have guessed. Edited to add: The similarities between all 3 manufacturers are interesting because in my view they greatly diminish the idea that a bunch of anti vaccine crusaders are entering spurious data. If there is data manipulation, it is highly coordinated. I don't think that's happening though. My opinion for now is that most of these reports were made in good faith. I would not have expected similar data from all 3 manufacturers. Assuming we could get rates and those, too, hold across manufacturers, then I would postulate that the problem is with the spike proteins and that we shouldn't be using any of those shots. |
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"We the People ultimately control our government, not the other way around." - planemaker
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Originally Posted By Obelix45: I took a look at the VAERS data today after reading the following article about "hot" lots of vaccines: Uh, That's Not A Conspiracy Theory - The Market Ticker A few of these VAERS graphs I shared in another thread, but I made some more graphs this evening and I figured I would just share them all here in case anyone here isn't following other threads. There are a lot of graphs, so I'll put them in spoilers. First, here are some histograms of the age distribution of deaths for the vaccines, including manufacturer-specific histograms. I find it interesting that the age distributions look very similar across manufacturers. Another odd thing is that the Moderna distribution looks almost too perfect -- it peaks in the 81-85 age group and declines steadily toward younger and older age brackets, with no small peaks and valleys like the other two manufacturers. Not necessarily a sign of manipulation because it could happen by chance, but it stuck out to me. Click To View Spoiler https://i.imgur.com/3jxVK8Q.png https://i.imgur.com/0UGtjGC.png https://i.imgur.com/RKssQge.png https://i.imgur.com/GSC0zBQ.png Next, here are some different ways of looking at the numbers. These graphs below are for all manufacturers combined. The drop in deaths in the summer (June and July) corresponds to fewer doses of vaccine being distributed. However, the increase in deaths in August and September is qualitatively higher than I would have expected. Although vaccinations went up in those months, they didn't go up very much compared to summer. The last histogram in this group shows the time lag between vaccination and death. Notice that most deaths occur within 2 to 3 weeks of vaccination date. But there are some that have a much longer lag. Remember that VAERS data is unverified and there are probably some wacky entries in here. I didn't examine them enough to give a decisive opinion on the entire group. If I had a $6 billion budget like the FDA I would probably pay somebody to do that. Or maybe not. That yacht isn't going to pay off itself, amirite? Click To View Spoiler This first plot should be a bubble plot instead of a scatter plot, but I was lazy and didn't do it that way. Just keep in mind that some of the dots in this graph represent more than 1 death. https://i.imgur.com/hFopbIP.png https://i.imgur.com/WRpuc4O.png https://i.imgur.com/dNIOrjy.png Now some scatter plots showing date of vaccination (triangles) and date of death (circles) for each manufacturer. Notice that the spread between vaccination and death starts to increase for all manufacturers after May, in an odd nonintuitive way. It's not a gradually widening spread, it just kind of diverges after May. Many deaths after May still happen shortly after vaccination, but there is a group of deaths after May for which vaccination date is April or earlier, without much in between. Again, these scatter plots look similar regardless of manufacturer. I find that very interesting. It suggests a factor that might overshadow manufacturer-specific technology or quality control. What is that factor? I don't know. Click To View Spoiler Finally, below are a couple graphs of the "hottest" Pfizer lot (EN6201) mentioned in this article: Uh, That's Not A Conspiracy Theory - The Market Ticker I also found this lot to be the "hottest" Pfizer lot, but I only counted around 40 deaths from it instead of 117 like the article says. Maybe I made a mistake. Click To View Spoiler The axes on the first histogram below should be deaths (vertical axis) vs. age (horizontal axis). https://i.imgur.com/ukYyxfu.png https://i.imgur.com/r5IPvsv.png If anyone else looks at this data, let me know what numbers you get. I did this all in Excel rather quickly, so I can't guarantee the results are error free. View Quote Great info thank you very much some things to keep in mind The shots were targeted to the elderly ( and first responders ) early on so there will be age factors in the dates also to people with significant health issues early on so that will be seen in the date data. April / May is about when it opened up to regular people in lower age groups. |
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Mach
Nobody is coming to save us. . |
This is a guess but I would expect lot numbers to be uniform in size. Lot numbers are manufacturing capacity batch size limited. I would expect manufacturing capacity batch size to be fairly consistent. As manufacturing capacity grew with time I would expect more lot numbers not bigger lots.
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Mach
Nobody is coming to save us. . |
the point about needing percentages not just raw numbers made by planemaker is very valid. The distribution of age would not be consistent from lot number to lot number because of the way the vax was rolled out and to who it was offered in the time variant.
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Mach
Nobody is coming to save us. . |
After my extensive reading on ADE with many other virus infections including SAR-1, MERS, HIV, etc I think there is a good chance that the difference between a mild infection and severe infection could very well be ADE during active infections.
It fits everything I have read about ADE with the other viruses and would be dependent on what type and how many of each type of antibody is made by individual immune systems. Characteristics of ADE during initial infection. 1. ADE takes hold when neutralizing antibody levels are low ( think immune system problems due to age and health) 2. sudden reversal of trend. Starting to get better then a sudden reveral to severe disease and death 3. possible cross reactivity of antibodies with previous viral infections producing ADE early on in the progression of the disease. IE rapid severe disease right from the beginning 4. Cytokine storm is an indicator of ADE and is present in severe COVD-19 infection Most of us have been saying the authorities have not been telling us something from day 1 and continue to not tell us everything. One of the key factors in ADE taking over is when neutralizing antibodies ( NaB) wane. But when they do there are still B and T cells that will make antibodies when encountering the virus . antibody waning should not make a difference with immunity and it does not in many virus and vaccine generated immunity. Yet all we hear about is needed boosters because antibodies are waning. It should not make a difference and does not make a difference with most diseases. The one type of disease that it does make a difference when antibodies wane is disease that results in ADE I am pretty much convinced we are seeing the results of ADE in people with immune systems that can not keep NaBs in production both with the infection and with the vax. I really hope I am wrong but the pieces fit including the reactions across the world by govts. I think we may be fucked hard. Yeah this is doomer shit but the ADE pieces fit the puzzle and i am saying this as someone that got vaxed because of the major brain surgery I had to have and the post viral health condition I have from either covid or lyme disease and the top doc I am going to that specializes in this says he is seeing a lot of patients with it and the long covid is very similar to chronic lyme, presents exactly the same. I feel like a deadman walking |
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Mach
Nobody is coming to save us. . |
Originally Posted By planemaker: So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. View Quote View All Quotes View All Quotes Originally Posted By planemaker: Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. |
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Originally Posted By HighDesert6920: lol - ok, well no doubt they are milking it for all its worth financially, while the politicians milk the pandemic for all its worth in control and power grabbing....but personally, I'm glad to see treatments emerging as alternatives to the so-called vaccines... View Quote The big question though, is whether the process will be to continue with the philosophy of the individual having no say in either vaccination or treatment (vaccination is mandated, while requests for particular treatments can be denied). |
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Earthsheltered house - a reinforced bunker that even the treehuggers consider to be socially acceptable.
Earthbag house - like an earthsheltered house, but cheaper and easier to DIY. |
Originally Posted By HighDesert6920: Yes, and groceries. Not necessarily for the virus so much anymore - the fomite transmission has pretty much been shown to be minimal - but for the virus and everything else. A study from several years ago (long before the chinese virus) found feces on nearly 3/4 shopping carts. Look at the people in wally world next to you....they are wiping, picking, and licking all kinds of things....the fat hairy weirdo in line ahead of you is picking his nose, swiping his greasy hair back, farts and then reaches down to scratch his ass....then goes tap, tap, tap on the payment terminal....maybe sneezes in your direction...he was rummaging through all those bags of chips just before you picked out a bag. So his nasty crotch snot is smeared across the top of your chip bag....now you've got the munchies, and open the bag of chips, rubbing your hands through that guys snot, and then you grab a handful of chips and snarf them down....infected snot and all! What about those delicious apples you enjoy? Ever drive by an apple orchard during picking season? Of course, they're all illegals - but anyway, notice where the porta-potty units are - at the edge of the field...no hand washing stations to be seen....last night was chalupa night at Dos Gringos....makes Taco Bell look like quality...the guys in the field just went there last night for cheap beer and chalupas, now they have feel a power growler coming on right before picking shift. It's a mess in there! Unfortunately no hand washing stations...so just wipe hands on pants, and start picking fresh apples for the rich gringos. Now at the store, the apples are all coated with....something...something you're going to eat - because cleaning foods before eating is for pussy doomers! You're so brave! View Quote Are you aware the the blow style hand driers in restrooms actually blow clouds of dried feces in the air every time anyone uses them? True story. |
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World ain't what it seems, is it Gunny?
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Originally Posted By Obelix45: I took a look at the VAERS data today after reading the following article about "hot" lots of vaccines: Uh, That's Not A Conspiracy Theory - The Market Ticker A few of these VAERS graphs I shared in another thread, but I made some more graphs this evening and I figured I would just share them all here in case anyone here isn't following other threads. There are a lot of graphs, so I'll put them in spoilers. First, here are some histograms of the age distribution of deaths for the vaccines, including manufacturer-specific histograms. I find it interesting that the age distributions look very similar across manufacturers. Another odd thing is that the Moderna distribution looks almost too perfect -- it peaks in the 81-85 age group and declines steadily toward younger and older age brackets, with no small peaks and valleys like the other two manufacturers. Not necessarily a sign of manipulation because it could happen by chance, but it stuck out to me. Click To View Spoiler Next, here are some different ways of looking at the numbers. These graphs below are for all manufacturers combined. The drop in deaths in the summer (June and July) corresponds to fewer doses of vaccine being distributed. However, the increase in deaths in August and September is qualitatively higher than I would have expected. Although vaccinations went up in those months, they didn't go up very much compared to summer. The last histogram in this group shows the time lag between vaccination and death. Notice that most deaths occur within 2 to 3 weeks of vaccination date. But there are some that have a much longer lag. Remember that VAERS data is unverified and there are probably some wacky entries in here. I didn't examine them enough to give a decisive opinion on the entire group. If I had a $6 billion budget like the FDA I would probably pay somebody to do that. Or maybe not. That yacht isn't going to pay off itself, amirite? Click To View Spoiler This first plot should be a bubble plot instead of a scatter plot, but I was lazy and didn't do it that way. Just keep in mind that some of the dots in this graph represent more than 1 death. https://i.imgur.com/hFopbIP.png https://i.imgur.com/WRpuc4O.png https://i.imgur.com/dNIOrjy.png Now some scatter plots showing date of vaccination (triangles) and date of death (circles) for each manufacturer. Notice that the spread between vaccination and death starts to increase for all manufacturers after May, in an odd nonintuitive way. It's not a gradually widening spread, it just kind of diverges after May. Many deaths after May still happen shortly after vaccination, but there is a group of deaths after May for which vaccination date is April or earlier, without much in between. Again, these scatter plots look similar regardless of manufacturer. I find that very interesting. It suggests a factor that might overshadow manufacturer-specific technology or quality control. What is that factor? I don't know. Click To View Spoiler Finally, below are a couple graphs of the "hottest" Pfizer lot (EN6201) mentioned in this article: Uh, That's Not A Conspiracy Theory - The Market Ticker I also found this lot to be the "hottest" Pfizer lot, but I only counted around 40 deaths from it instead of 117 like the article says. Maybe I made a mistake. Click To View Spoiler The axes on the first histogram below should be deaths (vertical axis) vs. age (horizontal axis). https://i.imgur.com/ukYyxfu.png https://i.imgur.com/r5IPvsv.png If anyone else looks at this data, let me know what numbers you get. I did this all in Excel rather quickly, so I can't guarantee the results are error free. View Quote Ugh, I messed up when correlating the VAERS ID with manufacturers. The problem is that the VAERS data is split across three csv files, and VAERS ID is a key that can appear more than once in some files for each person. I thought I figured out how to filter it in Excel properly, but I just noticed it was incorrect. I'm going revisit this later when I have time to do something better suited to this than Excel. Anyway, the non-manufacturer specific plots should be unaffected: Click To View Spoiler |
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Originally Posted By Mach: the point about needing percentages not just raw numbers made by planemaker is very valid. The distribution of age would not be consistent from lot number to lot number because of the way the vax was rolled out and to who it was offered in the time variant. View Quote @Mach You could detect if certain lots were administered disproportionately to young or old by plotting the age distributions in the vaers data for each lot. If lot 327x was given mostly to oldsters then its distribution of adverse events should reflect that. If the lots were given randomly to all ages then the adverse events should happen similarly across ages. We know that the old have a higher vaccination rate now than the young. |
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ABCD puppies. LMNO puppies. SAR2 puppies. CMPN?
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Originally Posted By HighDesert6920: lol - ok, well no doubt they are milking it for all its worth financially, while the politicians milk the pandemic for all its worth in control and power grabbing....but personally, I'm glad to see treatments emerging as alternatives to the so-called vaccines... View Quote View All Quotes View All Quotes Originally Posted By HighDesert6920: Originally Posted By planemaker: Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate So, when people who took the Pfizer shots to prevent Kung Flu get a breakthru Kung Flu infection, they can take a Pfizer pill that may or may not keep them from going to the hospital or dying from the same Kung Flu that Pfizer's previous work didn't stop. These guys are milking this for all its worth. The pharma community, Rheumatologists, and Transplant Surgeons have known how to treat a Cytokine storm long before Covid. And since early 2020, they knew how the EXISTING drugs could effectively treat Covid as well. This whole ordeal should be an embarrassment and black eye to the entire medical community. |
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Okay, I think I'm slowly figuring out how to work with the VAERS data... I filtered it with Postgres and plotted in Excel. I only had time to look at Pfizer lot EN6201 from the Market Ticker article: Uh, That's Not A Conspiracy Theory
I also found 117 deaths associated with lot EN6201. Actually 118 because one had a blank manufacturer listing. But I just stuck with the 117 that explicitly listed Pfizer. Below are graphs of date of vax/date of death and age distribution. For context, in the spoiler, I put the symptoms listed in the "symptoms" fields for each of the 117 deaths, sorted from earliest death date to latest death date. It's a mix of sudden death, cardiac event, but also plenty of breakthrough infection deaths that happened months later. I didn't attempt to quantify any of the symptoms comments. They do show that they are not all obviously vaccine-related deaths, but some appear to be, especially the earlier entries. Click To View Spoiler ******************* SYMPTOMS *********************** PATIENT ARRIVED TO ED ON 2/9 IN FULL CARDIAC ARREST ******************* SYMPTOMS *********************** "At 10:33 am Patient pushed her pendant for staff, staff arrived to her apartment and Patient was found unresponsive in her bathroom. Patient received her second COVID-19 Pfizer vaccine about 75 minuets prior to this, she had no adverse reaction's within the first hour of receiving the second dose. CPR was started until paramedics arrived, they took over and tried to resuscitate. Patient was pronounced dead at 11:33 am at scene." ******************* SYMPTOMS *********************** "Few minutes post vaccination, after moving to observation area via wheelchair, the patient complained of dizziness. She took glucose tabs she had brought with her. Staff wheeled her to Triage # 1. Her eyes rolled back in her head and she lost consciousness. Staff (paramedics on site) transferred her to gurney and started compressions. AED placed, V- Fib was rhythm, Shock # 1 given, CPR resumed. Shocked again. Fire truck and additional EMT arrived on site and took over care. Epinephrine was given 3 times via intra-osseous route, Amiodarone given intra-osseous route. Additional defibrillation with on site AED for a total of 6-7 times. Patient had good chest rise with ambu-bag, no airway obstruction or peri-oral edema noted. Code called at 12:40 PM." ******************* SYMPTOMS *********************** "According to the patient's wife, the patient had flu like symptoms 2/11/2021. Complaints: Thirsty, sweaty and seizure with no prior history. Died at home. Not sent to hospital. Pronounced by coroner" ******************* SYMPTOMS *********************** "4:30pm slight nausea; arm pain; mild headache 5:00 pm headache more severe; up the back of head, described as unusual pain; thought a migraine was coming on. 5-7:00pm headache continues to worsen; chills; research on line side effects of Pfizer vaccine and they coincide with symptoms; 7:05 gets up to urinate (no assistance needed); screams out in pain 3 times while on toilet; starts to vomit; right side of face (eye and cheek and mouth droop like a stroke; left hand starts to curl. Loses consciousness immediately thereafter. 911 call; paramedics on the way; airway was swept and clear; gurgled breathing. Rushed to Hospital and assessed as having massive brain bleed. Pronounced dead at 10:22pm. Acute Hemorrhagic Stroke on Death Certificate." ******************* SYMPTOMS *********************** "Patient received 2nd dose of the COVID-19 Pfizer vaccine, was observed in office x 15+ minutes, and released home. Pt and his son exited the building and when they got to the car, the pt shouted out ""oh no!"" and collapsed to the ground. The patient was unconscious experiencing agonal respirations, and unresponsive to painful stimuli. There is an Emergency Room at the same location. Their staff came out and helped to transfer the pt to the ED for further evaluation. It was found that the patient had a known Anterior communicating artery aneurysm (7/28/2017) that seemed to have ruptured. The patient was stabilized and transported to our local hospital and upon arrival, he was effectively comatose with a GCS 3. CT Head notated an extensive subarachnoid and intraventricular hemorrhage most probably related to a bleeding anterior communicating artery aneurysm. Neuro-Interventional Radiologist dictation reads ""Hunt Hess 5 Fisher grade 4 extensive subarachnoid hemorrhage with intraventricular hemorrhage and early hydrocephalus secondary to rupture of a known anterior communicating artery aneurysm. Initial ICP after EVD placement noted to be in the 120s now 68 treatment complicated by aneurysm rerupture after admission and increased volume of blood although large volume of hemorrhage was seen on initial scan and no change in the patient's clinical exam on her scale was noted due to this rerupture. Patient's exam and prognosis are poor giving extensor posturing lack of extraocular movements to doll's maneuver and weak pupillary reflex as well as cough and gag. Follows no commands or instructions at this time with no spontaneous movement on ventilator set at 12 overbreathing at 14-16 at this time without any sedation."" The family opted to discontinue any further treatment to include surgical intervention given the findings. The patient was given comfort care with son and daughter at the bedside. The patient was extubated and expired at 1545h on 2/13/2021." ******************* SYMPTOMS *********************** patient passed away within 60 days of receiving a COVID vaccine ******************* SYMPTOMS *********************** Heard through a family member had some feeling badly and some respiratory symptoms. We do not have any real information. This is a coroners case. ******************* SYMPTOMS *********************** "MY WIFE DIED UNEXPECTEDLY 4 DAYS AFTER HER SECOND DOSAGE SHOT, ON FEBRUARY 17, 2021. SHE HAD BEEN HEALTHY AND HAD A RECENT CHECKUP AT WHICH THE DOCTOR GAVE HER A CLEAN BILL OF HEALTH. SHE WAS ALERT AND IN GOOD SPIRITS JUST THE NIGHT BEFORE WHEN WE WATCHED A MOVIE TOGETHER. I SAW NO INDICATION THAT SHE WAS FEELING POORLY OR OTHERWISE. I FOUND HER IN BED, DECEASED, UPON COMING HOME FROM WORK THE NEXT DAY." ******************* SYMPTOMS *********************** Ventricular fibrillation/sudden death ******************* SYMPTOMS *********************** Death after stroke . ******************* SYMPTOMS *********************** "Patient had declining health for the past 6 months, dementia and unable to walk. Patient had decreased appetite starting 1/1/21. After 1st vaccine shot patient appetite decreased further. After 2nd vaccine shot patient fatigue increased to the point where she could not get out of bed and had minimal appetite. Patient passed away 10 days after receiving 2nd shot on 2/22/21. Patient did not go to ED and was not hospitalized." ******************* SYMPTOMS *********************** "DEATH Narrative: Presented to ED via EMS c/o increasing shortness of breath, O2 sat mid to high 80s on 4L. When EMS arrived , pt was in distress, intubated by EMS and transported to ED. Pt had a PEA arrest en route but resuscitated w/ return of spontaneous circulation after receiving a dose of epinephrine and chest compressions. Pt was hypotensive on arrival to ED. He was started on sepsis protocol , volume resuscitation and empiric antibiotics. Once stabilized, he was admitted to icu at hospital. Removed from respirator 2/22/21" ******************* SYMPTOMS *********************** Patient reported as deceased 3 days after vaccination by son. ******************* SYMPTOMS *********************** "Elevated heart rate, flushing of the face and ears, vomiting, trouble breathing, pulmonary edema" ******************* SYMPTOMS *********************** SHORTNESS OF BREATH Bradycardia Hypothermia Cardiomyopathy Elevated troponin Acute renal failure (ARF) Death ******************* SYMPTOMS *********************** "DAY AFTER, PT COMPLAINED OF PAIN IN LEFT COLLAR BONE. PATIENT DECLINED IN FUNCTION OVER NEXT 11 DAYS. HOSPICE WAS CONSULTED AND PT PASSED ON 2/23/21" ******************* SYMPTOMS *********************** "2/24/21 Patient Died. 02/23/21. Patient came to ED for weakness/falls. Patient had fallen on 02/21 and 02/23. UA was done in LTC, and he was started on ciprofloxacin 02/22/21. Treatment was to put patient on comfort cares (morphine + lorazepam)" ******************* SYMPTOMS *********************** She passed away 2/24/2021 ******************* SYMPTOMS *********************** "Pt. presented to ED via EMS for emergent coma. EMS intubated patient in field due to respiratory failure. Pt. was severely hypertensive with nearly total loss of brainstem reflexes. Patient had known L MCA cerebral aneurysm with appointment to undergo intervention to address in the near future. NCCT reported massive multifocal brain hemorrhage, SAH, SDH, and parenchymal hemmorhage with midline shift and subfalcine herniation. Due to dismal/poor prognosis, family requested withdrawal of support approximately 4 hours after presentation and patient expired shortly thereafter." ******************* SYMPTOMS *********************** "Death Narrative: Patient was not previously Covid positive and did not have any predisposing factors(PMH, allergies, etc.) for experiencing an adverse drug event. The ADR did not occur at the time of the administration of the vaccine nor was there an ADR that occurred between the observation period and the date of death. Patient was 90 and suffered cardiac arrest at home on 2/25/21. Patient had afib w/ a pacemaker, cardiomyopathy, CKD4, and PVD." ******************* SYMPTOMS *********************** "1st vaccine on 2/20 and reported feeling ""lousy"" afterwards. On the evening of 2/23 felt like she was going to pass out. Felt worse when she woke the next morning. Presented to the ER on 2/24 with chest pain and ""indigestion"". Found to be in A.Fib with RVR. Vomited in ER triage. On 2/25 developed altered mental status, hypotension, hypoxemia. She was intubated and transferred to the ICU with severe lactic acidosis/shock/multiorgan failure. Had Right lower lobe infiltrate and right pleural effusion. Diagnosed with pneumonia and possible ischemic bowel. Died on 2/26. Family requested autopsy." ******************* SYMPTOMS *********************** death ******************* SYMPTOMS *********************** Death ******************* SYMPTOMS *********************** death ******************* SYMPTOMS *********************** "loss of appetite, abdominal pain, weight loss, death Narrative: 02/12/21: GI VISIT-ASSESSMENT: 1-R/O Gastric or Cecal Cancer with Peritoneal Carcinomatosis is most the cause of his weight loss and early satiety. Liver and Pancreas on CT Scan unremarkable. 2- Weight loss and early satiety may be due to Gastric Mass with metastasis or Colon Mass. 02/17/21: ED VISIT AND ADMISSION w/ CC 4 weeks of poor appetite and 2 weeks of inability to hold down food and abdominal pain, decreased BM and decreased urination Assessment on admission: acute kidney insufficiency, Possible partial Gastric outlet obstruction 2/2 malignancy, GI malignancy with peritoneal carcinomatosis as per CT scan 2/11, asymptomatic bacteruria hyperkalemia and AKI during admission 02/21/21: pt signed out of hospital AMA due to 'personal problems' 02/22/21: pt returned to hospital for continuation of care and was readmitted with same c/o 02/24/21: pt tachycardic and hypotensive w/ altered mental status; rapid response team called, transferred to icu; impression: acute severe sepsis with uremia; during procedure to place nephrostomy tubes, pt goes into wide complex vtach then vfib and ACLS done w/ compressions, ROSC @ 2255 w/ BP 70-41, Norepi started; pt intubated 02/25/21: pt extubated 02/25/21@2106: pt with inferior lateral stemi 03/01/21: pt w/ sudden deterioration with decreased LOC and increased WOB., intubated, found to be profoundly hypoxemic, developed severe metabolic acidosis and hyperkalemia, severe refractory hypotension 03/02/21: pt unresponsive without pulse or respirations, NOK declined autopsy no prior covid infection noted, no immediate reaction after covid vaccine, pt was hospitalized leading up to death with unrelenting abdominal pain, AKI, metabolic abnormalities. It is unlikely that vaccine led to patient's death." ******************* SYMPTOMS *********************** Death Narrative: On 3/3/21 an MSA from the Decedent Affairs Office received a call from the Office of the Chief Medical Examiner. The ME office informed the MSA that an autopsy was conducted on 3/2/21 and is pending results. No further information was given. A clinical review was conducted by the PCP but no conclusions could be made until autopsy results are received. The Office of Decedent Affairs will be reaching out periodically to the ME's office to retrieve these results. This Issue Brief will be updated by 3/17/21. ******************* SYMPTOMS *********************** "2nd vaccine dose given on 02/16/2021, admitted to hospital on 02/24/2021 CARDIAC ARREST RECTAL BLEEDING died on 03/03/2021" ******************* SYMPTOMS *********************** Home care treatment History of COPD ******************* SYMPTOMS *********************** "Day 1-Confusion and weakness Day2-Increase in weakness, inability to swallow, confusion, fatigue Day 3-Weakness, confusion, incontinence, hospitalized for hypoxia, pneumonia Day 20- Deceased" ******************* SYMPTOMS *********************** "On 3/5/21 at approximately 0200 became congested suddenly. Doctor was notified with N.O. Torsemide 20 mg tab via PEG-tube NOW, IM Rocephin 1 mg QD x7 days for possible aspiration, Chest X Ray, CBC/BMP in morning, and may suction resident if tolerated PRN. Received both Torsemide and the Rocephin and then deceased at 0350." ******************* SYMPTOMS *********************** Death ******************* SYMPTOMS *********************** "received word that the patient passed away on 3/5/2021. Do not know the cause of death, nor where he passed away. He does not have any significant medical history at Health Care Corporation, but did get his first vaccination here on 2/17/2021." ******************* SYMPTOMS *********************** "Death. Patient lived alone, was found dead at 11:04 the morning following his second dose of vaccine. Actual time of death is unknown. Time of vaccine administration the previous day is estimated." ******************* SYMPTOMS *********************** PATIENT DIED THE DAY AFTER GETTING VACCINE ******************* SYMPTOMS *********************** "She received the 2nd Dose on 3/9/2021. On 3/10/2021 She complained of a headache. On the morning of 3/11/2021 she complained of abdominal pain and had no appetite. We then found her unresponsive, called 911 and the medics pronounced her at around 1300." ******************* SYMPTOMS *********************** twelve hours after getting the shot my wife woke up with an upset stomach; her blood sugar was also slightly elevated; within ~the next two hours she became disoriented and confused; I called 911 and within a couple of minutes of the first 911 call she stopped breathing and could not be revived. ******************* SYMPTOMS *********************** 3/12/2021-EXPIRED AT FACILITY ON HOSPICE SERVICES ******************* SYMPTOMS *********************** "shortness of breath, dizziness death" ******************* SYMPTOMS *********************** The patient was a Hospice patient that passed away. ******************* SYMPTOMS *********************** "kidneys were unable to support life; Diarrhea; unable to get up without assistance; shaking so bad; This is a spontaneous report from a contactable consumer (Patient's wife). An 80-year-old male patient received second dose of BNT162B2 (BNT162B2) via an unspecified route of administration, administered in Arm Right on an unspecified date (Batch/Lot Number: EN6201, expiry date not reported) as single dose for covid-19 immunization. Medical history included ongoing glomerulonephritis, dementia (He had dementia prior to getting the vaccine) and walking aid user. The patient experienced kidneys were unable to support life on an unspecified date and was reported as fatal, shaking so bad on 01Mar2021, diarrhea on 02Mar2021, unable to get up without assistance on 01Mar2021. Patient's wife reports that her husband didn't have any reactions until the third day. He was shaking so bad that the car seat was vibrating. He also had diarrhea. He had dementia prior to getting the vaccine. After getting the vaccine he was unable to get out of the chair without physically being helped out of the chair. He was able to use his walker before getting the vaccine but was not able to after getting the vaccine. Her husband passed away yesterday. He was shaking so bad on 01Mar2021. It lasted for 12-24 hours and then it was not as spasmodic. He had diarrhea from 02Mar - 03Mar2021. He recovered completely from it. He was unable to get up without assistance on 01Mar2021. That did not change. He required assistance until he died. He was unable to use his walker staring on 01Mar2021. His kidneys were unable to support life. Two weeks before he received the vaccine her husband was up and walking. After he received the second dose this happened. Caller is unsure if this caused kidney failure. An autopsy is not being performed. Her husband died yesterday. He had kidney problems that he lived with for 58 years. After receiving the vaccine his kidney functions took a nose dive. She was told by some of the people taking care of him that the kidneys could have had a decrease in function from the vaccine. He was sent to a dementia facility on 02Mar2021 for long term placement. The patient received his first dose of BNT162B2 on an unspecified date. The patient died on 16Mar2021. An autopsy was not performed.; Reported Cause(s) of Death: kidneys were unable to support life" ******************* SYMPTOMS *********************** shoulder injury death ******************* SYMPTOMS *********************** Death Narrative: Death on 03/21/2021. 2nd dose administered 46 days before serious event. Patient had been admitted to the hospital for AMS of unknown etiology concerning for sepsis with multiple sources and was on comfort care measures only. There are no indications that death was related to the vaccine. ******************* SYMPTOMS *********************** This 91 year old white male received the Covid shot on 2/19/21 and subsequently died on 3/21/21. Please refer to the other details submitted within this report and contact the person who submitted this report via email for additional follow up details and investigation.. ******************* SYMPTOMS *********************** Altered mental status Intracranial hemorrhage (CMS/HCC) Hypertension Cerebral brain hemorrhage (CMS/HCC ******************* SYMPTOMS *********************** "SHORTNESS OF BREATH Pleural effusion Acute renal failure superimposed on chronic kidney disease, unspecified CKD stage, unspecified acute renal failure type (CMS/HCC) DEATH" ******************* SYMPTOMS *********************** "Patient presented to the ER on 3/28/2021 with shortness of breath and lower extremity edema and complaining of lower back pain. O2 sat high 80s on room air. Worsening renal failure since last discharge from hospital on 3/23/2021. Patient was readmitted to hospital from skilled care facility after being discharged 5 days prior with acute on chronic stage IV kidney disease as well as acute on chronic diastolic heart failure and had slowly worsening with renal dysfunction and growing concern for dialysis. Patient had developed a cough, a fever up to 101, and 1 questionable sewed of either hemoptysis or hematemesis since being discharged to skilled nursing facility on 3/23/2021. Patient was transitioned to the hospice team and expired on 4/2/2021." ******************* SYMPTOMS *********************** "had a couple of fainting episodes after first vaccine, but collapsed and was hospitalized 2 days after second dose" ******************* SYMPTOMS *********************** "Advanced Age, Likely Sudden Acute MI" ******************* SYMPTOMS *********************** "Message received from the daughter of the patient, daughter states that the 3-4 days after the administration of the vaccine that she reported to feel unfocused and ""out of it"", falling asleep more, and was seen by physician who advised to keep an eye on her, then was later found slightly unresponsive, transported to hospital and found to be suffering from stroke. Patient later discharged from hospital to nursing home and stayed there until 3/28/2021, where she was later transferred to the care of the family and passed away on 4/6/2021. Daughter of patient" ******************* SYMPTOMS *********************** "Patient felt unwell - dizzy and tired on the evening of April 5, 2021. She went to bed and died in her sleep, likely early in the morning April 6, 2021. Medical Examiner recorded her cause of death ""Sudden Cardiac Death associated with Mitral Valve Prolapse" ******************* SYMPTOMS *********************** Cardiac Arrest Death Sepsis due to methicillin susceptible Staphylococcus aureus ******************* SYMPTOMS *********************** "He received his first COVID19 shot (Pfizer) reportedly on 3/2/21, then began a new chemotherapy regimen on 3/10/21. On 3/18, he fell to the floor and could not get up. He was admitted to the hospital for sepsis, pneumonia, and chemotherapy-induced neutropenia, treated on IV antibiotics and discharged on PO antibiotics. His home insulin was also decreased but continued to have hypoglycemic to hyperglycemic events. Insulin was decreased in clinic afterward and was compliant on antibiotics. Returned to hospital again a few days later for sepsis and pneumonia/effusion. He later went to a nursing facility / on hospice. He ultimately required supplemental oxygen and breathing increasingly became labored. Patient ultimately died on 4/9/21." ******************* SYMPTOMS *********************** "CVA with residual hemiparesis - C-Diff, diarrhea, weakness. AKI" ******************* SYMPTOMS *********************** Death ******************* SYMPTOMS *********************** "DVT was twice as bad; death/natural process; This is a spontaneous report from a contactable Nurse reporting for reporter's husband. A 78-year-old male patient received bnt162b2 (reported as COVID vaccine), dose 2 via an unspecified route of administration on 20Mar2021 (Lot Number: EN6201; Expiration Date: 30Jun2021) as 2nd dose, single (at the age of 78-year-old) for COVID-19 immunisation. Medical history included diabetes, Liver cirrhosis, thrombocytopenia, Kidney stone, sarcoidosis, blood pressure abnormal, high cholesterol, pacemaker and they putted the IVC filter for blood clot. Concomitant medications included insulin, simvastatin, hydrochlorothiazide and omeprazole (PROTONIX), all taken for an unspecified indication, start and stop date were not reported; and carvedilol (COREG) taken for blood pressure, start and stop date were not reported. The patient previously received the first dose of bnt162b2 (Lot Number: EN6201; Expiration Date: 30Jun2021) on 27Feb2021 at the age of 78-year-old for COVID-19 immunization and experienced pulmonary embolism and deep vein thrombosis (DVT) on 12Mar2021, and went into the hospital 12Mar2021. Then the patient had the second COVID shot on 20Mar2021 and the reporter had taken him right back into the hospital couple days later because the DVT got twice as worst. The patient experienced DVT was twice as bad on an unspecified date in Mar2021, which required hospitalization on 22Mar2021. The patient underwent lab tests, he had lab tests on 22Mar2021 when he went in and he probably had them on 23rd and 24th of Mar2021. The reporter didn't know what all the lab tests were done in the hospital. The patient died on 12Apr2021. The reporter stated they put Reason of death as natural process because she sent him in the Hospice. An autopsy was not performed. The outcome of event DVT was unknown. The reporter considered there was a causal relationship, when he got his second COVID shot on 20Mar2021 and then he went back in the hospital on 22Mar2021 and the DVT was twice as bad.; Sender's Comments: Based on a positive temporal association, a possible contributory role of the suspect BNT162B2 cannot be excluded for the reported DVT. The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate.; Reported Cause(s) of Death: death/natural process" ******************* SYMPTOMS *********************** "Death Narrative: Patient was previously tested COVID-19 positive on 3/2/2021, but did not have any other predisposing factors(PMH, allergies, etc.) for experiencing an adverse drug event. The ADR did not occur at the time of the administration of the vaccine nor was there an ADR that occurred between the observation period and the date of death. Patient was admitted with afib with RVR on 2/17/21 and was having a HFrEF exacerbation. HR was controlled during admission and he was discharged on 2/19/21. Patient was hospitalized 4 more times over the next two months for cardiac symptoms with last hospitalization occurring 4/12/21 for hypotension/tachycardia and decompensated heart failure. Patient never recovered and transitioned to hospice before passing on 4/16/21. Patient had a PMH significant for afib s/p DCCV on eliquis, CKD, HFpEF on home O2 2L, PMR on prednisone, known R pleural effusion, Covid PNA in 11/2020 and chronic foley" ******************* SYMPTOMS *********************** "This 85 year old white male received the vaccine on 2/19/21 and went to the ED on 4/05 and was admitted with generalized weakness, hyponatremia, fever and elevated bilirubin. On 04/16/21, he went to the ED and was admitted to the hospital on 4/17 with poor appetite and hospital admission dx of ketonuria, leukocytosis, renal insufficiency, elevated troponin, hematuria, generalized weakness and died on 4/19/2021. Please refer to the other details submitted within this report and contact the person who submitted this report via email for additional follow up details and investigation." ******************* SYMPTOMS *********************** "Presents with dyspnea for a few days. Pt was tested positive for COVID 19 one wk ago (outside health system). Pt also c/o L arm numbness. Pt denied f/c, CP, n/v/d, abd pain, HA, syncope. In ED, Pt was found to have hypoxic O2 sat at 89% and was put 2L NC. Pt got loading dose of ASA and dexamethasone (7 day course), completed 5 day course of remdesivir and received tocilizumab due to increased oxygen requirements. Pt also has mildly elevated troponin and cardiology was consulted in ED. St elevation noted 4/20 AM, heparin bolus given for acute coronary syndrome and ticagrelor LD. Left heart cath on 4/20/21 showed 3 vessel disease but due to difficulty revascularizing LAD in setting of worsening K+, Bicarb, S no further revasc attempts were made. Upon return to MICU, pt found to be hypotensive and bradycardic. PEA arrest. Family contacted during code and in agreement to transition to comfort measures." ******************* SYMPTOMS *********************** Death 4/21/2021 Causes of death listed on death certificate: 1) respiratory failure 2) covid 19 pneumonia ******************* SYMPTOMS *********************** Death 4/21/2021 Causes of death listed on death certificate: 1) Acute respiratory failure (onset interval 1 week) 2) COVID Pneumonia (onset interval 1 week) Other: acute on chronic congestive heart failure ******************* SYMPTOMS *********************** "Death: 4/22/2021 Causes of death listed on death certificate: 1) Respiratory failure 2) Emphysema Other: Covid-19 pneumonia, diabetes" ******************* SYMPTOMS *********************** Died of COVID-19 illness on 04/23/2021 ******************* SYMPTOMS *********************** This 86 year old male received the Covid shot on 2/17/21 and went to the ED on 4/20 with abnormal lab of hypercalcemia and again on 4/25 with altered mental status and was admitted on 4/25 and died on 4/25/21. Please refer to the other details submitted within this report and contact the person who submitted this report via email for additional follow up details and investigation. ******************* SYMPTOMS *********************** Patient passed away on 04/30/2021 ******************* SYMPTOMS *********************** "Death A41.50 - Gram-negative sepsis, unspecified K81.0 - Acute cholecystitis E86.0 - Dehydration E83.42 - Hypomagnesemia N39.0 - Urinary tract infection E87.2 - Respiratory acidosis R06.89 - Hypercarbia T85.518A - Cholecystostomy tube dysfunction, initial encounter D72.829 - Leukocytosis, unspecified type" ******************* SYMPTOMS *********************** Death 5/2/2021 Causes of death listed on death certificate: 1) Small-bowel obstruction 2) Carcinoma of small-bowel ******************* SYMPTOMS *********************** This 74 year old female received the Covid shot on 3/12/21 and went to the ED on 4/11/21 with the diagnoses listed below and died on 5/3/21. ABDOMINAL PAIN VOMITING ******************* SYMPTOMS *********************** "This 79 year old female received the Covid shot on 2/18 and went to the ED on 2/26 and was admitted on 2/26 with chest pain and abdominal pain and again to the ED on 3/14 and admitted on 3/14 with hyperkalemia, acute renal injury, chest pain and died on 05/04/21 . Please refer to the other details submitted within this report and contact the person who submitted this report via email for additional follow up details and investigation." ******************* SYMPTOMS *********************** This 87 year old male hospice received the Covid shot on 2/16/21 and died on 5/4/21. ******************* SYMPTOMS *********************** Patient went into cardiac arrest on 05/04/2021 when she was getting into a vehicle. CPR was initiated from EMS in the ambulance to the hospital. CPR was done for approx. 30 minutes when family asked them to stop. Patient passed away on 05/04/2021. ******************* SYMPTOMS *********************** death from covid 3 months after completing series ******************* SYMPTOMS *********************** Patient died from methamphetamine/opiate overdose ******************* SYMPTOMS *********************** "My father received his vaccines through the hospital, on 1/23/21 and 2/13/21. The week of April 17, 2021, he started with diarrhea and cough. He spoke with his PCP and was told to quarantine and report any worsening symptoms. Wednesday or Thursday he began with vomiting and unable to hold down any fluids. His cough was nonproductive. On Saturday 4/17/21 he reported to Hospital ER with SOB, cough, vomiting & diarrhea. He was diagnosed with COVID PNA. He passed away 5/7/21 of COVID PNA, respiratory failure. He tested positive the week of 5/7/21 again of COVID 19. I feel this needs to be reported as he had both PFIZER vaccines in January & February and still ended up intubated and deceased from COVID 19." ******************* SYMPTOMS *********************** Bilateral retinal branch vein occlusions 1 month after. Died 5/7/21 ******************* SYMPTOMS *********************** Death ******************* SYMPTOMS *********************** Died of COVID-19 illness on 05/08/2021 ******************* SYMPTOMS *********************** J18.9 - Left lower lobe pneumonia I48.91 - Atrial fibrillation with RVR (CMS/HCC) N17.9 - Acute kidney injury (CMS/HCC) N30.01 - Acute cystitis with hematuria ******************* SYMPTOMS *********************** Z79.01 - Chronic anticoagulation J18.9 - Left lower lobe pneumonia R29.6 - Multiple falls A41.9 - Sepsis (CMS/HCC) R09.02 - Hypoxemia J44.1 - COPD exacerbation (CMS/HCC) I50.9 - CHF exacerbation (CMS/HCC) R79.89 - Elevated brain natriuretic peptide (BNP) level ******************* SYMPTOMS *********************** death ******************* SYMPTOMS *********************** Death 5/12/2021 Causes of death listed on death certificate: 1) Acute Myocardial Infarction 2) Acute Coronary Artery Thrombosis 3) COVID-19 Other: Acute Respiratory Failure ******************* SYMPTOMS *********************** Death 05/24/2021 Causes of death listed on death certificate: 1) COVID 2) ATRIAL FIB 3) CKD 3 4) Hypertension ******************* SYMPTOMS *********************** 5/20/2021 experiencing symptoms: dyspnea 5/24/2021 Admitted to hosp. and treated for COVID-19/ pneumonia 5/30/2021: died ******************* SYMPTOMS *********************** "Nontraumatic intracerebral hemorrhage, unspecified" ******************* SYMPTOMS *********************** "Patient was hospitalized due to COVID-19 from May 19, 2021 to May 22, 2021. Patient was then placed on hospice on 6/5/2021 and expired on 6/7/2021." ******************* SYMPTOMS *********************** "death N17.9 - Acute kidney failure, unspecified" ******************* SYMPTOMS *********************** "death J18.9 - Pneumonia, unspecified organism abdominal pain" ******************* SYMPTOMS *********************** "Patient developed dyspnea, diarrhea, chills and cough. Presented at the ED on 06/11 and was found to be COVID-19 positive. Admitted to ICU Despite maximal medical intervention; including deep sedation, NMB, flolan, intermittent pronation, steroids, a second round of Remdesivir, multiple pressors, and full vent support, the patient continued to decline and remained with increasing pressor requirements. He suffered severe pneumomediastinum and bilateral pneumothoraces requiring bilateral chest tubes" ******************* SYMPTOMS *********************** Death N17.9 - Acute kidney injury (CMS/HCC) J18.9 - Bilateral pneumonia ******************* SYMPTOMS *********************** death I61.9 - Intraparenchymal hemorrhage of brain (CMS/HCC) ******************* SYMPTOMS *********************** Patient passed away on 07/02/2021 ******************* SYMPTOMS *********************** Patient passed away on 07/09/2021 ******************* SYMPTOMS *********************** "COUGH, RUNNY NOSE, FOR TWO WEEKS, GENERAL MALSIE, BODY ACHE" ******************* SYMPTOMS *********************** "death N17.9 - Acute renal failure, unspecified acute renal failure" ******************* SYMPTOMS *********************** "death J18.9 - Pneumonia, unspecified organism N17.9 - Acute kidney failure, unspecified" ******************* SYMPTOMS *********************** "Received Pfizer vaccines on 2/19/21, 3/16/21. Tested positive for COVID-19 on 7/10/21. Symptoms began on 7/6/21 w/ cough, dysgeusia, fatigue. Hospitalized on 7/13/21; transferred to ICU on 7/22/21. Patient expired on 7/25/21 due to pneumonia d/t COVID-19. Patient was intubated; given dexamethasone 6 mg x9 d, 5 day course of remdesivir, one dose of tocilizumab for COVID pneumonia. PMH significant for past medical history significant for pulmonary sarcoidosis, on prednisone 5 mg daily; immune thrombocytopenic purpura, on rituximab." ******************* SYMPTOMS *********************** "death I63.9 - Cerebral infarction, unspecified" ******************* SYMPTOMS *********************** "death N17.9 - Acute renal failure, unspecified acute renal failure type" ******************* SYMPTOMS *********************** No sx. Tested due to being a resident of a long term care facility where there was a current outbreak due to a staff member testing positive during routine testing. ******************* SYMPTOMS *********************** Pt. passed from COVID19 Pneumonia on 8/6/2021 ******************* SYMPTOMS *********************** "Patient required hospitalization due to breakthrough infection. He received the Pfizer vaccine (2nd dose in series) on 03/03/21. Hospitalized from 08/10/21 - 08/14/21 (death). Below is copied from patients discharge (death) summary: Hospital Course: Patient is an 84 year old man with a past medical history of Afib (on eliquis, metoprolol), HTN, HLD, MI admitted to the ICU for acute hypoxemic respiratory failure secondary to Covid-19 pneumonia. He presented to the ED after EMS was called for fall out of bed with generalized weakness, he denies hitting his head or LOC. He was satting 78% on EMS arrival and tachypneic, he had minimal improvement with NRB. In the ED he was found to be in Afib RVR to the 160s with hypotension, levophed was begun, he was cardioverted, and was begun on amiodarone infusion. The patient reports a 1 week history of generalized fatigue and shortness of breath without leg swelling or orthopnea. He was vaccinated in March with the Pfizer vaccine. He reports his cardiologist is at another facility and doesn't remember his medications offhand but knows he takes Eliquis BID. 8/11: TTE ordered, not yet performed. K+, Mg, phos low and repleted. On HFNC + NRB 60L/92% satting high 80s/low 90s. Currently on amio drip. No other acute events. 8/12 Patient elected to be DNR/DNI yesterday. Urine culture growing >100K Staph, started on Vanc/Cefepime while waiting sensitivity. Amio gtt changed to metoprolol. Patient endorsing soreness/back pain and states he uses Percocet and fentanyl patch outpatient. On HFNC + NRB 60L/95%, satting high 80s/low 90s past 24 hours. Echo performed shows EF 50-55%, impaired relaxation, moderately enlarged RV, moderately dilated LA, PASP 45 mm Hg. 8/13: Patient elected to rescind DNR/DNI 1 day ago. Became acutely agitated throughout the night and was removing HFNC stating that he ""did not want to do this anymore"". Started on precedex gtt and haldol prn for agitation. Pt w/ improved compliance w/ HFNC and able to maintain O2 saturation between 87-89%. 8/14: Patient now DNR/DNI, daughter at bedside while patient's wife was again admitted to the hospital. Decision made to pursue compassionate wean. Started on Morphine infusion for comfort and to prevent air hunger. O2 saturation continually downtrending. Asystole at 1803, confirmed in 2 leads. No signs of life. Pronounced expired at 1803. Dr notified at 1806." ******************* SYMPTOMS *********************** COVID19 death ******************* SYMPTOMS *********************** Pt was hospitalized with covid and died ******************* SYMPTOMS *********************** Patient passed away on 08/20/2021 ******************* SYMPTOMS *********************** "7/30/21: admitted for multiple falls 8/5/21: Transitioned to Inpatient Rehab. 8/13/21: He became altered and hypoxic, prompting testing for COVID-19. Resulted positive COVID PCR on 8/13/21; breathing comfortably on 2L nasal cannula 8/17/21: completed remdesivir course, worsening confusion and altered mentation; using heated-high flow at 35L, non-rebreather 8/19/21: patient discharged to hospice. 8/22/21: patient passed. Time of death 0508." ******************* SYMPTOMS *********************** PATIENT DEVELOPED COVID19 INFECTION FOLLOWED BY SUBSEQUENT HOSPITALIZATION AND DEATH ******************* SYMPTOMS *********************** "pt diagnosed COVID positive in ED on 8/21, cough and no taste, dc'd to home; next day received monoclonal antibodies; on 8/24 pt was confused and had more SOB, O2 saturations low, placed on O2 via nasal cannula; started on full treatment for COVID; pt's condition worsened where he died in the hospital; acute respiratory failure, COVID pneumonia, metabolic encephalopathy" ******************* SYMPTOMS *********************** "Patient required hospitalization due to breakthrough infection. Patient received Pfizer vaccine (2nd dose in series) on 02/19/21. Patient was hospitalized from 08/13/21 - 08/31/21. Below is copied from patients discharge (death) summary: Hospital Course: Patient is a vaccinated 75 y.o. male with a pmhx of HTN, DM, CAD s/p PCI (10 yrs ago), CKD3 and breast cancer s/p lumpectomy and CT who presented to ED on 8/13/21 c/o SOB in setting of known COVID-19 infection. Patient recieved both doses of his vaccine (2nd dose 2/2021). Patient was admitted to hospitalist service for acute hypoxic respiratory failure in setting of COVID-19. Throughout course of stay, had increasing oxygenation requirements (requiring FFCPAP after found to have removed mask from face) with pulse ox O2 sats reportedly in 20's, lethargy, and new onset tremor. On pulmonology's evaluation at bedside, patient was A&Ox2 (person/place, thinks year is 2001). Not hypoglycemic on accucheck. Difficult to obtain hx as patient with AMS however shakes head yes when asked if he feels SOB. Admitted to ICU on 18Aug, now intubated and sedated. Bronchoscopy performed at bedside, which was unrevealing. Did not show any mucous plugging. Received solumedrol and lipitor. Toci not given due to depleted supplies. Episodes of hypoglycemia, NPH 35u TID d/c. S/p D5W drip. Continue with SSI. Oligouric AKI on CKD, requiring CRRT. Nephrology on board. New onset A-fib with RVR, now rate controlled. S/p amiodarone drip & metoprolol. Increasing leukocytosis. Continue Vanc/Aztreonam/Flagyl and empiric Caspo, follow cultures. Episodes of coffee ground emesis. Hgb downtrended. Recevied 1 unit of pRBC. Hgb stable. On Levophed. Continue proning protocol. CRRT better when placed in left position. Keep net even. Wean off Levo as tolerated, start midodrine 10mg tid. DC empiric Abx given negative cultures. Palliative care for goals of care. Shock state of unclear etiology at this time. EV1000 hemodynamics to help guide management. Currently on 40 of levophed and vasopressin. Poor oxygenation. Prone ventilation discontinued. DC'd empiric Abx given negative cultures. Spoke to patient's wife and she wants patient to be DNR with no escalation of care given his overall poor prognosis. Plan to compassionately wean. Confirmed DNR. No further escalation of care. Death Note I was called to the room of patient to pronounce that patient had died. Patient was laying motionless and unresponsive to verbal/tactile stimuli. Pupils where fixed and dilated. There were no spontaneous breath sounds. Peripheral pulses were absent. No heartbeat was heard during auscultation. Family was made aware. Condolences offered. Chaplain and postmortem services offered. Pt was DNR code. Time of death was 1724, confirmed and witnessed by Nurse" ******************* SYMPTOMS *********************** pt admitted to hospital with c/o abdominal pain; pt has dementia and failure to thrive due to inadequate home care; COVID positive; pt's condition worsened and he was placed on comfort care; pt expired in the hospital ******************* SYMPTOMS *********************** Admitted in the hospital on 08/09/2021. Date of death 09/02/2021 ******************* SYMPTOMS *********************** "pt presented to ED with SOB, cough, N/V/D x 3 days; PMH: dementia, OSA on CPAP, chronic hypercapnic respiratory failure; intubated on 8/31; developed AKI and shock; transitioned to comfort care; extubation on 9/4; pt died shortly after extubation" ******************* SYMPTOMS *********************** Patient passed away on 09/12/2021 ******************* SYMPTOMS *********************** Hospitalized for COVID and died as a result of COVID pneumonia ******************* SYMPTOMS *********************** Patient had breakthrough infection and expired while infected ******************* SYMPTOMS *********************** Patient had a breakthrough infection and expired while infected with virus. ******************* SYMPTOMS blank death date field*********************** "Death ABDOMINAL PAIN BACK PAIN J18.9, J91.8 - Pleural effusion associated with pulmonary infection E87.1 - Hyponatremia N13.2 - Hydronephrosis with renal and ureteral calculous obstruction C79.9 - Metastatic disease (CMS/HCC)" ******************* SYMPTOMS blank death date field*********************** DOD 4/27/21 AT HOSPICE. SPOKE WITH PATIENT 4/13 AND REPORTS HOSPITALIZATION NOT DUE TO COVID |
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Originally Posted By JHS: @Mach You could detect if certain lots were administered disproportionately to young or old by plotting the age distributions in the vaers data for each lot. If lot 327x was given mostly to oldsters then its distribution of adverse events should reflect that. If the lots were given randomly to all ages then the adverse events should happen similarly across ages. We know that the old have a higher vaccination rate now than the young. View Quote View All Quotes View All Quotes Originally Posted By JHS: Originally Posted By Mach: the point about needing percentages not just raw numbers made by planemaker is very valid. The distribution of age would not be consistent from lot number to lot number because of the way the vax was rolled out and to who it was offered in the time variant. @Mach You could detect if certain lots were administered disproportionately to young or old by plotting the age distributions in the vaers data for each lot. If lot 327x was given mostly to oldsters then its distribution of adverse events should reflect that. If the lots were given randomly to all ages then the adverse events should happen similarly across ages. We know that the old have a higher vaccination rate now than the young. One could but I can't. There is not enough data online. Looking at the lot numbers, shots from the same lot numbers are over anywhere from 2 to 6 months with no locations shown. I cross reference some of the dates that show the same lot number given out over 6 months and some of those shots were with lots that were expired. |
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Mach
Nobody is coming to save us. . |
Originally Posted By BlackTuono: We have a new paper to digest: https://www.mdpi.com/1999-4915/13/10/2056/htm From the journal Viruses. Synopsis - in vitro experiments have confirmed that spike proteins 1) concentrate around the nucleus in a cell 2) interfere with BRCA1 and other natural DNA repair mechanisms including 3) V(D)J recombination which is is an essential part of B and T cell development and building adaptive immunity (https://en.wikipedia.org/wiki/V) This gives a putative mechanism for two anecdotal claims that have been circulating, mainly that T cells (CD4+ and CD8 in particular) get incredibly low for some people after the second and subsequent doses, and that cancer cell activity is heightened because of the lack of immune response. In this case it isn't just the response of immune cells that is being moderated but the intracellular action to repair DNA. In case you didn't know, you all have cancer inside of you, pretty much guaranteed at any given time. Cells proliferate and encounter DNA replication errors when they split, leading to cancer eventually. Our bodies employ mechanisms to repair nicked or miscopied DNA at an intracellular level constantly. Showing that T cells can be affected is one thing, but the disruption of such a fundamental biochemical repair process is alarming when you consider we are instructing cells to churn out the spike protein itself. The authors make this point in their conclusions and propose it as a putative mechanism for some of the shot-related side effects being observed. Are we going to see a lot more cancer and AIDS-like symptoms? Hopefully not in most cases, but some people are going to get unlucky and have this effect them chronically, especially if we enter a regime where regular boosters become the norm. View Quote except the study had nothing to do with vaccine spike proteins and only virus spike proteins and it was done in vitro which means out side the body, like in a test tube. I think it is a massive jump to say if the viral spikes do something then the vaccine spikes will do it, because they are not the same. the vaccine spikes are -pre-fusion stabilized by changes in the structure. They are designed so that they can not attach to a cell. I am not saying they don't do the same thing, I am saying just because the viral spike does something doesn't mean the vax spike does it. There needs to be a follow on study with the vax spikes to know. And just because it happens in a test tube, doesn't mean in happens in a human body |
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Mach
Nobody is coming to save us. . |
Originally Posted By Mach: except the study had nothing to do with vaccine spike proteins and only virus spike proteins and it was done in vitro which means out side the body, like in a test tube. I think it is a massive jump to say if the viral spikes do something then the vaccine spikes will do it, because they are not the same. the vaccine spikes are -pre-fusion stabilized by changes in the structure. They are designed so that they can not attach to a cell. I am not saying they don't do the same thing, I am saying just because the viral spike does something doesn't mean the vax spike does it. There needs to be a follow on study with the vax spikes to know. And just because it happens in a test tube, doesn't mean in happens in a human body View Quote View All Quotes View All Quotes Originally Posted By Mach: Originally Posted By BlackTuono: We have a new paper to digest: https://www.mdpi.com/1999-4915/13/10/2056/htm From the journal Viruses. Synopsis - in vitro experiments have confirmed that spike proteins 1) concentrate around the nucleus in a cell 2) interfere with BRCA1 and other natural DNA repair mechanisms including 3) V(D)J recombination which is is an essential part of B and T cell development and building adaptive immunity (https://en.wikipedia.org/wiki/V) This gives a putative mechanism for two anecdotal claims that have been circulating, mainly that T cells (CD4+ and CD8 in particular) get incredibly low for some people after the second and subsequent doses, and that cancer cell activity is heightened because of the lack of immune response. In this case it isn't just the response of immune cells that is being moderated but the intracellular action to repair DNA. In case you didn't know, you all have cancer inside of you, pretty much guaranteed at any given time. Cells proliferate and encounter DNA replication errors when they split, leading to cancer eventually. Our bodies employ mechanisms to repair nicked or miscopied DNA at an intracellular level constantly. Showing that T cells can be affected is one thing, but the disruption of such a fundamental biochemical repair process is alarming when you consider we are instructing cells to churn out the spike protein itself. The authors make this point in their conclusions and propose it as a putative mechanism for some of the shot-related side effects being observed. Are we going to see a lot more cancer and AIDS-like symptoms? Hopefully not in most cases, but some people are going to get unlucky and have this effect them chronically, especially if we enter a regime where regular boosters become the norm. except the study had nothing to do with vaccine spike proteins and only virus spike proteins and it was done in vitro which means out side the body, like in a test tube. I think it is a massive jump to say if the viral spikes do something then the vaccine spikes will do it, because they are not the same. the vaccine spikes are -pre-fusion stabilized by changes in the structure. They are designed so that they can not attach to a cell. I am not saying they don't do the same thing, I am saying just because the viral spike does something doesn't mean the vax spike does it. There needs to be a follow on study with the vax spikes to know. And just because it happens in a test tube, doesn't mean in happens in a human body You do realize that in order for the spike proteins that are produced by the body after vaccination to even be worth using as a form of vaccination, the proteins produced have to be fundamentally the same as the spike protein that is on the surface of SARS-CoV-2, right? Actually, it's not fundamentally the same, it is the S protein from SARS-CoV-2 that your body produces.(ok, ok, there are changes that make your cells react stronger than they otherwise would to an S protein on SARS-CoV-2) That's the entire point of the vaccines, to prepare your body to combat the S protein. Well, the mRNA based vaccines anyways. This "the vaccine spikes are -pre-fusion stabilized by changes in the structure" is not about "They are designed so that they can not attach to a cell." The stabilization is to increase how much your body reacts to the spike protein that is produced by the mRNA. And the most effective ways to produce large amounts of viral proteins is...what viruses do, hijack the internal mechanisms of the cell to produce viral proteins. This is why the mRNA vaccines do the exact same thing. |
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Shit like this is why you don't give typewriters to monkeys. - L_JE
Colonialism, bringing ethnic diversity to a continent near you. - My Father |
What we need is someone to test the vaccine spikes and the viral spikes to see if they behave the same way / have the same effects.
I also have beach front property in the middle of the sahara desert to sell you really cheap too. |
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Originally Posted By HighDesert6920: This sounds promising https://www.pfizer.com/news/press-release/press-release-detail/pfizers-novel-covid-19-oral-antiviral-treatment-candidate View Quote So this should pretty much stop the need for the vax |
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“A double minded man is unstable in all his ways.” James 1:8 KJV
"Can a man who's warm understand one who's freezing?" Aleksandr Solzhenitsyn |
Originally Posted By FlashMan-7k: What we need is someone to test the vaccine spikes and the viral spikes to see if they behave the same way / have the same effects. I also have beach front property in the middle of the sahara desert to sell you really cheap too. View Quote They do as they're functionally the same protein. |
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Shit like this is why you don't give typewriters to monkeys. - L_JE
Colonialism, bringing ethnic diversity to a continent near you. - My Father |
Originally Posted By exDefensorMilitas: You do realize that in order for the spike proteins that are produced by the body after vaccination to even be worth using as a form of vaccination, the proteins produced have to be fundamentally the same as the spike protein that is on the surface of SARS-CoV-2, right? Actually, it's not fundamentally the same, it is the S protein from SARS-CoV-2 that your body produces.(ok, ok, there are changes that make your cells react stronger than they otherwise would to an S protein on SARS-CoV-2) That's the entire point of the vaccines, to prepare your body to combat the S protein. Well, the mRNA based vaccines anyways. This "the vaccine spikes are -pre-fusion stabilized by changes in the structure" is not about "They are designed so that they can not attach to a cell." The stabilization is to increase how much your body reacts to the spike protein that is produced by the mRNA. And the most effective ways to produce large amounts of viral proteins is...what viruses do, hijack the internal mechanisms of the cell to produce viral proteins. This is why the mRNA vaccines do the exact same thing. View Quote View All Quotes View All Quotes Originally Posted By exDefensorMilitas: Originally Posted By Mach: Originally Posted By BlackTuono: We have a new paper to digest: https://www.mdpi.com/1999-4915/13/10/2056/htm From the journal Viruses. Synopsis - in vitro experiments have confirmed that spike proteins 1) concentrate around the nucleus in a cell 2) interfere with BRCA1 and other natural DNA repair mechanisms including 3) V(D)J recombination which is is an essential part of B and T cell development and building adaptive immunity (https://en.wikipedia.org/wiki/V) This gives a putative mechanism for two anecdotal claims that have been circulating, mainly that T cells (CD4+ and CD8 in particular) get incredibly low for some people after the second and subsequent doses, and that cancer cell activity is heightened because of the lack of immune response. In this case it isn't just the response of immune cells that is being moderated but the intracellular action to repair DNA. In case you didn't know, you all have cancer inside of you, pretty much guaranteed at any given time. Cells proliferate and encounter DNA replication errors when they split, leading to cancer eventually. Our bodies employ mechanisms to repair nicked or miscopied DNA at an intracellular level constantly. Showing that T cells can be affected is one thing, but the disruption of such a fundamental biochemical repair process is alarming when you consider we are instructing cells to churn out the spike protein itself. The authors make this point in their conclusions and propose it as a putative mechanism for some of the shot-related side effects being observed. Are we going to see a lot more cancer and AIDS-like symptoms? Hopefully not in most cases, but some people are going to get unlucky and have this effect them chronically, especially if we enter a regime where regular boosters become the norm. except the study had nothing to do with vaccine spike proteins and only virus spike proteins and it was done in vitro which means out side the body, like in a test tube. I think it is a massive jump to say if the viral spikes do something then the vaccine spikes will do it, because they are not the same. the vaccine spikes are -pre-fusion stabilized by changes in the structure. They are designed so that they can not attach to a cell. I am not saying they don't do the same thing, I am saying just because the viral spike does something doesn't mean the vax spike does it. There needs to be a follow on study with the vax spikes to know. And just because it happens in a test tube, doesn't mean in happens in a human body You do realize that in order for the spike proteins that are produced by the body after vaccination to even be worth using as a form of vaccination, the proteins produced have to be fundamentally the same as the spike protein that is on the surface of SARS-CoV-2, right? Actually, it's not fundamentally the same, it is the S protein from SARS-CoV-2 that your body produces.(ok, ok, there are changes that make your cells react stronger than they otherwise would to an S protein on SARS-CoV-2) That's the entire point of the vaccines, to prepare your body to combat the S protein. Well, the mRNA based vaccines anyways. This "the vaccine spikes are -pre-fusion stabilized by changes in the structure" is not about "They are designed so that they can not attach to a cell." The stabilization is to increase how much your body reacts to the spike protein that is produced by the mRNA. And the most effective ways to produce large amounts of viral proteins is...what viruses do, hijack the internal mechanisms of the cell to produce viral proteins. This is why the mRNA vaccines do the exact same thing. I spent a bunch of time researching the meaning of prefusion stabilized. Prefusion is the state of the proteins before cell attachment. Fusion is when the proteins attach to the cell wall and change their protein structure to open the cell wall to allow the viral genome into the cell. Prefusion stabilized is a change in the protein structure so the spike protein can not attach and fuse with the cell wall. It is stabilized in the prefusion form and can not change. It does result in a stronger immune response but that is because if were to fuse, lacking the other parts of the viral proteins, there would be antibodies developed that could not attack in the prefusion state. So all the antibodies made due to the vax are AB that attack the prefusion spike. https://cen.acs.org/pharmaceuticals/vaccines/tiny-tweak-behind-COVID-19/98/i38 While the spikes are fundamentally the same as the virus spikes as far as antibodies are concerned, they are not exactly the same and dont have the same functional capabilities. whether that matters in this case I dont know. There needs to be a study |
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Mach
Nobody is coming to save us. . |
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