On 2021-02-03 07:20:39, user Bildung Aber Sicher CH wrote:

This study failed to mention school autumn holidays. The data they have is, in reality, from a period of low community transmission (not high as they mention) because the 2 weeks holidays coincide with the start of the second wave in the canton. <br /> The sampling starts a week after school resumed, therefore too early to for cluster build up in schools/classes, especially when looking at antibodies which will only appear some weeks after infection.

It also didn't consider any new studies as references, when plenty was available that contradicts their assumptions and conclusions at the time of publication.

On 2021-02-09 15:58:51, user David Curtis wrote:

I don't get it. Mendelian randomisation is supposed to test a causal relationship between two phenotypes. Here, you seem to be saying that your results demonstrate that smoking has a causal effect on depression and that depression has a causal effect on smoking. I don't see how you distinguish this from the alternative explanation - that there are genetic variants which increase risk of both smoking and depression. How do you distinguish causal effects from a simple genetic correlation?

On 2021-02-11 03:05:16, user Another Concerned Resident wrote:

Interesting study! Where can we find the supplementary materials? I'd like to check the ITT Table 1 because the PP Table 1 shows significant baseline differences.

A few questions:<br /> - Could you explain why you did not opt for placebo control and double blind?<br /> - What were the serology results performed at day 28?<br /> - You mention "COVID-19 infection occurred in 94% measured by RT-PCR". How were the extra 6% diagnosed?<br /> - Do you have any data on adverse events?<br /> - For the primary outcome: do you have any information on the reasons for admission?

Thanks

On 2021-02-11 19:05:46, user Dr John Tal wrote:

Eagerly awaiting the results of the trials using ciclesonide. Has been shown to slow down SARS CoV2 replication in vitro and seemed to be effective in a couple of case studies. https://jvi.asm.org/content...

On 2021-02-11 15:28:29, user Robert Olinski wrote:

You are speaking about Ct values that are not part of clinical diagnostics. What were clinical symptoms of people post-vaccination with decreased viral load? Does it mean that the vaccination did not prevent infection?

On 2021-02-20 15:56:24, user Howard Gu wrote:

It is surprising that vaccination only reduces the viral load by 4 folds. However, this could be due to the research design. Only the high viral loads are detectable and thus included in the calculation of viral load reduction. Vaccinated people might get infected but have good immune responses effectively suppressing the viral replication. This could result in 400 or 4000 folds lower viral loads which may not be detectable and thus considered not infected and not included in the calculation of viral load reduction.

On 2021-02-13 17:35:22, user Scott Aberegg wrote:

Where is the supplementary appendix? I would like to see the prior distributions upon which this analysis was based

On 2021-02-14 11:49:33, user Rafael Green wrote:

Hi,<br /> I looked at world_mortality.csv, summed the deaths by year and got this result:<br /> 2015 15747474<br /> 2016 17246133<br /> 2017 17689889<br /> 2018 16674370<br /> 2019 18004246<br /> 2020 20926842<br /> How are you explaining the decreasing in the number of deaths in 2018?<br /> Thanks,

On 2021-02-15 16:30:09, user Vana Sypsa wrote:

The paper appears now in Emerging Infectious Diseases

https://wwwnc.cdc.gov/eid/a...

On 2021-02-15 20:44:04, user Ro H wrote:

South Asians as a group, especially first generation (citizens or immigrants), regardless of income level, are less likely to voluntarily get tested or go to the doctor unless theyre really sick. People with mild to moderate disease are unlikely to get tested but will self isolate and quarantine. This is a cultural thing observed in great Britain also. This means that their positivity rates will be higher as only the really sick get tested and a higher percentage will be hospitalized. Its interesting that their death rates are lower though. Im a part of this south Asian community in New York and this is what I've experienced with family and friends.

On 2021-02-17 17:12:29, user Tim Pollington wrote:

Dear Epke and colleagues,

I would like to share some comments following reading your (v. relevant) paper on impact of COVID on VL in India at the country level. This is the second time I've commented on a preprint like this on medrxiv, and shared an 'open review' so I hope you receive it in the spirit it was intended. As I'm interested in doing similar studies your manuscript was relevant to me. And since I am funded by BMGF I thought it would be a waste of my funded time if I do not share these thoughts with you too, especially since you're at the preprint/pre-accepted stage.

I thought the paper could benefit from an additional author who has field experience of the IRS/ACD activities occurring there to back-up your assumption that "no IRS and ACD take place and that only passive case detection" during an interruption.

Given that the role of Asx in infecting others is still debated (some say recent xeno shows near zero contribution while ours last year did fit estimates consistently when relative Asx infectiousness of 0,1 or 2% were used), your use of the models E1 & E0 is a smart move to err on the cautious side.

Model structure and quantification section<br /> Thanks for much for following best practice and using PRIME-NTD. It is the first time I have seen it and I definitely plan to use it in my next modelling publication and also when initially planning a model re engagement with policymakers.

Given that the model runs for 30 years has population growth been taken into account?

Impact assessment section<br /> Although adding incidence rates in the same period is acceptable, as events share the same 'person time at risk' denominator (and if the events are mutually exclusive), I'm not sure if epidemiologically it's a correct calculation to sum up rates over the 30 years since the population will be changing in this time and thus the denominators are changing. Perhaps one can convert it into absolute cases in each year and then sum those up?

Discussion section - First paragraph<br /> It may help the reader if more emphasis was made on how a 1-year impacted delay by describing how it is amplified. ie How just one year interruption causes growth which needs to be curtailed before it turns over and falls, and the excess cases this generates. This concept of amplification could be strengthened.

Second paragraph<br /> "80% of [VL-endemic???] sub-districts..." Did this cover just Bihar or all 4/5? endemic states.

Third paragraph<br /> I think mortality rates are really relevant but can understand your caution re scant data. I think it's so important now considering the 1%CFR 2021-2030 target. Could this independent review help provide some rough estimates from pages 12-15 & 40? <br /> Even rough estimates from your model on excess VL cases and when they would likely be seen in the coming years, could be a useful starting place for resource planning of drugs.

I think a caveat needs to be noted that this analysis is country-level whereas the threshold targets are at the block-level, to avoid the reader making an ecological fallacy.

I hope that helps and also encourage you to comment on my work if I get to that stage!

All the best, Tim.

On 2021-02-24 01:18:23, user algebra wrote:

Anecdotes of people who had Covid months ago and got the vaccine are alarming. Acquaintances report the side effects of the second shot were worse than the disease itself. Are these people reporting their reactions? No they just tough it out. They were told to expect side effects. How many of them are out there? Does anybody know? <br /> My own physician has been hearing some of these stories and suggests waiting.

On 2021-02-02 22:45:20, user Elizabeth McNally wrote:

We are running similar ELISA assays after vaccination and not seeing this same robust IgG response. I would like to see more data prior making any recommendations about deviating from the vaccination protocols followed in the clinical trials.

On 2021-02-24 19:02:08, user George Orwell wrote:

The findings of this review are an outlier, in stark contrast to the rest - those produced by the WHO, FLCCC, EBM-C, and @CovidAnalysis. This pre-print says the studies considered had "7412 participants" but only reported mortality data on under two hundred of them. Even then, it shows Ivermectin reduced mortality (logRR: 0.89, 95% CI 0.09 to 1.70, p = 0.04), but reported Ivermectin was "not associated" with reduced mortality.<br /> It excluded the vast majority of the FORTY-ONE clinical trials with results, 18 published, the rest in preprint, .<br /> So even though the authors reported on a small fraction of a small fraction of the results, they still found significant improvement in the most important and elusive metric of all to show improvement in, mortality. But nonetheless, they reported this as a negative finding.<br /> As is widely reported, "The probability that an ineffective treatment generated results as positive as the 41 studies to date is estimated to be 1 in 2 trillion (p = 0.00000000000045)."

On 2021-02-01 15:59:31, user Victoria Gates wrote:

What about the studies done by the FLCCC Front Line COVID-19 Critical Care Alliance? They present strong evidence to the contrary.

On 2021-02-02 16:30:41, user Martha Albertson wrote:

This is a poorly-designed study that looked at very few trials of ivermectin. The authors picked the studies that portrayed ivermectin in the worst light and ignored the many studies showing that ivermectin is a safe and effective treatment for Covid-19. I wonder who funded this study. Ivermectin is so much more effective than the expensive treatments promoted by the pharmaceutical industry. I can't imagine this biased study will survive peer review.

On 2021-02-26 11:58:34, user Magda Bucholc wrote:

The published version of the manuscript is available here: https://alz-journals.online...

On 2021-03-02 08:33:10, user Miroslava Zeliznakova wrote:

I am so disgusted how this research was done. The ethical principles were not followed. People didnt know that research is taking place, they were not informed about it. They were forced to test otherwise they have been threatened by government that they can't come out of their house, go to work, post office etc... I am from Slovakia and so many people suffered in hands of the government and i am surprised this study states the participants consent was gained. You should now do another study about how situation is in Slovakia now. Many people had got infected during mass antigen testing actually.

On 2021-03-07 09:48:53, user Pencroft wrote:

• voluntary? Yes, it was voluntary testing. As it is described in the article itself. There were (and there are) restrictions applied regarding the COVID pandemic as they are applied elsewhere in the world. Those who preferred somehow reduced level of them were required to prove that they are not infected. This type of the test or PCR one were accepted.<br /> There was no punishment by law for not taking part in this type of testing.
• written consent?<br /> As long as the researchers evaluate output and other public data and are not the ones who performs the test on their own as a part of their research, what is the base for requiring written consent? Those are 2 separate activities.

On 2021-01-19 18:29:14, user Monika J. wrote:

As a Slovak citizen I can tell your that they are NOT telling the whole truth. Your can fact check my every single word.<br /> They claim that the testing was not obligatory... NOT TRUE<br /> People where forced to attend this mass testing. Prime minister admitted that they forced us to do this on the Press conference. Our Human rights where oppresed. Without negative test certificate your couldnt go to work, bank, post Office, all shops denied you to enter their premises. All services where denied to your without certificate. Even some doctors refused to treat patients without cerificate. You could only go to grocery store, pharmacy and drugstore without certificate. There were some exceptions, but not important. Some employers called the police on employees who wanted to go to work (they where healthy, had no symptoms) but didnt hlave the certificate. A lot of employees were fired, because they refused to get tested.

Lets talk about the study. They claim that they have participant conset.... NOT TRUE we havent sign anythig. Nobody informed people what kind of test they are using, who will hlave their samples afterwards, who will procesed their personal information..yes they hlave our personal numer and wrote some information from our ID....we dont know which information they collected.

Thay claim that tests where done ONLY by profesionals.. NOT TRUE. Tests where done by non medical personnel too - in some cities - those people braged about it on Facebook. There is NO name of person who tested you. You can not check if this person <br /> is profesionall or not.<br /> In some cities testing was done outside. People where forced to stand for multiple hours in lane just to get tested, in rain, and low tempersture...<br /> I could continue on and on and on....<br /> Now they are going to do the second round od this mass testing. They are again FORCING us to do it Once again. The second round is even worst than the first one. Now they want us to stand in lane to get tested in -10 to -15°C.<br /> Now the police will be controlling us if we have the certificate or not. If your will not have the certificate you will get a fine. And they will oppresed our human rights again. Segregstion od people to two categories is called apartheid and it is illegeal....this is what they are doing. They are creating second category people. First category Has certificate and Can live relatively normaly. Second category is treated like garbage.

On 2021-01-24 11:43:28, user Zdenko Ontek wrote:

I have to express myself as a citizen of the Slovak Republic. Several points in the research conditions do not agree with reality. Test subjects did not sign informed consent or instruction. It is also untrue to claim that testing was voluntary. The Government of the Slovak Republic created direct and indirect pressure, for example, through employers, who conditioned the entry of their employees into the workplace by passing testing. I note that the translation is machine, so I apologize for the English. Affected citizen of the Slovak Republic.

On 2021-03-03 22:58:04, user Dan Elton wrote:

The data from Phase, I, II, and III and our prior scientific knowledge on vaccines like this one indicate this vaccine is very safe and effective. It also appears to be our best weapon against the B.1.351 variant. US taxpayers have already footed the bill for 110 million doses and it's very likely millions of doses have already been produced. The US FDA should ask Novavax to submit all the data they have collected so far and their EUA application immediately and then the FDA should work overtime to approve it within a week in order to save lives. The FDA should also allow the vaccine to be pre-distributed to ensure the vaccine gets to at-risk groups as quickly as possibe. With 1,000+ people dying every day, we must act quickly to save lives! The status-quo is dangerous - the vaccine by contrast is very safe and will save lives!

On 2021-03-06 11:40:17, user Patti wrote:

I had Covid back in October 2020, I still hane no smell or little to no taste. The feeling in my nose is driving me nuts - I call it a vortex or the feeling I have when I take a breath is like a upside down tornado - it feels like clean air and yet sometimes burns. I have used nasal saline but doesn’t seem to do anything. Also slight blood when I blow my nose.

On 2021-03-08 08:44:37, user CD wrote:

"Our findings highlight the importance of monitoring how members of these known 501Y lineages, and others still undiscovered, are convergently evolving similar strategies to ensure their persistence in the face of mounting infection and vaccine induced host immune recognition ..."

The statement above makes it appear as if the SARS-cov-2 chooses where to mutate to escape host immunity, which is not the case. The pressure is put on the virus and mutations occur randomly, resulting in escape variants and some resulting in weaker variants

On 2021-03-14 10:34:35, user KalleMP wrote:

There are a number of data errors in this report. Having looked at 5 of the original 25 papers listed here I find that errors that are significant have been made in at least 4 of them.

The Turkey values are 75.5% deficient and 16.61nmol/l median instead of the listed 70nmol/l.

Bosnia reads 24.4% and should be 60.6% (their mean is 48.25nmol/l)

Italy reads 33.3% but a weighted average is closer to 30.7%<br /> Italy has used values from the highest performing Vitamin-D region and compared them to the national CoViD-19 figures which are accepted to be low.

Finland has used the native Finnish values and compared them to the national CoViD-19 figures which include immigrants who are more deficient yet represent a larger portion of the CoViD-19 figures.

On 2021-03-17 10:44:27, user Krisantha Weerasuriya wrote:

If there was the opportunity, a small simultaneous blood sample from the mother to measure the COVID19 antibodies would have provided further useful information.

Would it be possible with covering permission from the Ethical Committee to do a simultaneous blood sample for COVID 19 antibodies from mother and baby at 3 months (or the most appropriate time)?

On 2021-03-17 10:51:20, user D Greenwood wrote:

The trials registry protocol suggests n=507 symptomatic cases would be recruited and followed up, to "characterise prevalence and severity of organ volume change and damage in patients recovering from COVID-19 disease". Yet the preprint appears to focus on n=201 individuals still "symptomatic after recovery" and it is therefore not surprising that nearly 100% of them report symptoms, as this appears to be the eligibility criteria for the paper. Either that, or a substantial deviation from the published protocol. I therefore agree with previous comments on the importance of clarifying the recruitment process and inclusion/exclusion criteria so we know what the denominator is here. There is some benefit in knowing what the % of organ damage is in people with continuing symptoms, but the crucial question that health services and strategic leaders need to know is what this is as a % of all cases, or at least as a % of symptomatic cases. I hope that a revised version of this paper will make that clearer.

On 2021-03-18 09:12:13, user Bernhard Brodowicz wrote:

The summary in the last paragraph of discussion states: 'On the contrary, we found a significant, slightly increased risk of SARS-CoV-2 infection, which, however, was attenuated when taking account of older children in the same household.' The first paragraph of the discussion however is stating 'The risk of infection was amplified with increasing number of young children living in the household, but the overall association was attenuated when excluding households with older children.' and figure one, shows an increased risk associated with increasing number of children and increasing age of children.<br /> The wording in the summary (last paragraph of discussion) might be a bit misleading.

On 2021-03-23 18:30:37, user Moshe Elitzur wrote:

To CL: <br /> Do lockdowns work??

They certainly do, but we could not prove that decisively because lockdowns were implemented, on average, just before "flattening of the curve" was already occuring. So lockdowns were not put to the test during the first wave.

On 2021-03-23 20:14:18, user Gustavo Bellini wrote:

Great article, congratulations to everyone involved in this research!

Could you replicate the tests by adding sufficient levels of vitamin D to these cells? I believe that the behavior of macrophages in this case can be changed from the pro-inflammatory pathway to the anti-inflammatory pathway, thus avoiding the "storm of inflammatory cytokines" and restoring (?) their "normal" phagocytosis behavior.

Vitamin D has an immunomodulatory action that affects both the innate and the adaptive system.

Sufficient levels of vitamin D are needed for immune cells to produce IFN-y:<br /> - Vitamin D Is Required for IFN-? – Mediated Antimicrobial Activity of Human Macrophages<br /> https://stm.sciencemag.org/...

A 2010 study showed that sufficient levels of vitamin D are also necessary for T lymphocytes to be activated correctly:<br /> - Vitamin D crucial to activating immune defenses<br /> https://www.sciencedaily.co...

Macrophages and dentritic cells have the CYP27b1 gene and are able to transform 25OHD into Calcitriol (the active hormone).

All immune cells have VDR and are subject to the biological actions of the active form of vitamin D.

Here are two great recent reviews on the action of vitamin D on immune cells:<br /> - Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory<br /> https://doi.org/10.1002/jbm...

• MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19<br /> https://doi.org/10.1530/eje...

Many studies are showing a significant correlation between vitamin D deficiency and the increased risk for severe symptoms / mortality from Covid. This website lists some of these studies: https://vitamin-d-covid.sho...

I hope this comment is useful in some way.<br /> Thanks.

On 2021-03-29 21:57:10, user Carl Steinbeisser wrote:

Great work. Really minor comment: In the acknowledgement only the Grant Agreement number is mentioned not the name of the project. Many IMI projects (and H2020 projects) do mention the name of the project too. Suggest to add the project name EHDEN.

On 2021-04-06 09:29:36, user gerardencinallamas wrote:

The peer-reviewed published version of this pre-print can be found here: https://www.nature.com/arti...

On 2021-04-09 12:25:07, user Keish Gonzalez Acosta wrote:

Hi. I am a breastfeeding mother. I took the JJ vaccine 4 days ago. I am pumping milk. If your team is interested in collecting milk samples after JJ vaccine I would like to participate.

On 2021-08-30 22:44:45, user Rachel Ezzour wrote:

Is the follow up study available yet?

On 2021-04-14 16:38:58, user Anke Huels wrote:

This work has been published in The Lancet's EClinical Medicine: https://www.thelancet.com/j... (open access)

On 2021-04-20 02:03:34, user Hector Moises Chip / Micro Chi wrote:

By "reasoning" - that is according to Kant's a priori approach - to keep schools open would be a source of virus transmission. Basically because in spite of gathering "in bubbles", it breaks the gold epidemiologic principle of social distancing, particularly difficult in youngsters besides the fact that they wander (usually) in several unchecked other bubbles... Also there are on the empiric side, cases of intra school viral circulation that the present article has not searched . The whole script is therefore incomplete enough to draw firm conclusions. In any case, it would mean to stay in the prudent side, which is do not open school if the sanitary system is on crisis.

On 2021-04-20 11:46:33, user Sahithi Reddy wrote:

may i know where can i get the source code of this article

On 2021-05-10 06:59:28, user Maria Ban wrote:

The 42% protection after first dose is not a very good protection. How about protection from severe Covid after first dose, is it higher? The reason for my question is that I am not allowed to have a second dose (due to severe allergic reaction) and I fear that I will have to avoid other people for ever.

On 2021-08-10 16:31:12, user Jeff Brender wrote:

"The 95% confidence interval (CI) of the IRR was calculated using an exact method described previously.(ref.12)"<br /> ref 12 Sahai H, Khurshid A. Statistics in Epidemiology: Methods, Techniques and Applications. CRC Press; 1995

The exact method should probably be specified here

On 2021-08-19 11:53:03, user Brian Mowrey wrote:

Er.. Is anyone able to discern how "unvaccinated" subjects were located? The authors refer to them as "patients" - patients of what? At times in the text it seems like the study is using retroactive performance of individuals who were vaccinated - say, that if someone is vaccinated in May, they are eligible for matching for the previous months. But I don't see how that would allow them to have enough subjects for July.

On 2021-08-11 12:11:31, user Truenorth 1960 wrote:

I'm not sure I understand this study. While I understand this is a report that is intended for professionals, the l language is not English, it is "technobable" for lack of a better expression. For covid , these studies should have a translation into something more akin to regular English. Narrative should help understand the results. In this case I find the narrative is not helpful, it is easier to look at the tables.

On 2021-08-11 18:43:00, user questionable02848 wrote:

I am interested in seeing a similar study done on Recovered versus Vaccinated cases over some years. It is **theoretically** possible that Recovery (despite original virus death rate) confers greater defense than Vaccinated (despite lower original virus death rate) because Recovery forms a superior, longer-lasting, or greater-breadth immune response. This is important to consider for coronavirus specifically due to its tendency to mutate. The studies I have seen indicate that the Recovered do have a greater immunity than the Vaccinated, as studied here: https://www.biorxiv.org/con...

And so, if Recovered do in fact fare better when exposed to mutations, we really want to know this before we vaccinate the young, who do not face a statistically significant threat from coronavirus but have many years ahead of them facing its mutations.

On 2021-08-26 14:59:31, user Holger Lundstrom wrote:

So, to summarize:

• COVID-19 cases after dose 2: 77 (vax) vs. 850 (placebo) hinting at 91.3% protection
• no difference in cases for those with prior infection
• deaths during blinded period: 15 (vax) vs. 14 (placebo)
• COVID deaths during blinded period: 1 (vax) vs. 2 (placebo)
• deaths during total period: 20 (vax) vs. 14 (placebo)

Conclusion: <br /> 1.) Vaccine allows for 91.3% relative risk reduction. Total risk reduces from 3,9% (placebo) to 0,35% (vax) within the study timeframe. A decrease of 3% efficacy per month is expected - but is likely to be much larger, according to recent reports from Israel.<br /> https://www.sciencemag.org/...

2.) People with prior infection benefit very little from the vaccination, if at all. No benefit is recorded within study period. According to assumptions made here of about 70% protection (prior infection) vs. 90% protection (vax), a vaccination for people with prior immunity would reduce total risk from about 1% to 0,35%. However, it is more likely that prior immunity awards better protection than a vaccine does, due to the involvement of other aspects of pathogen defense, such as IgA antibodies. Again, no benefit was recorded in the study.<br /> https://stm.sciencemag.org/...

3.) No significant benefit is recorded concerning deaths due to coronavirus (1 vs. 2). Overall deaths are higher in vaccinated group than in placebo group, however total numbers are small (20 vs. 14).

Supplement tables:<br /> htt...

On 2021-08-11 18:35:08, user UGApaul wrote:

So, should we therefore assume that by reducing mutations, that vaccines or immunity in general, reduces the potential for new variants of concern?

Such thinking would run counter to our many decades of understanding of flu.

It is not necessarily important that vaccines might reduce the numberof mutations, what is important, is whether there already exists, variants that can partially escape immunity and/or there exists a sufficient mutation rate within a partially immune population to generate future variants that can escape immunity.

Delta is most likely a classic benefactor of antigenic drift in a partially immune population.

On 2021-08-13 10:22:44, user Javier Mira wrote:

Correlation doesn't mean causality. One can't infere any conclusion from just a correlation between 2 variables because there can be higher order variables governing those 2. If we made that we could conclude that bringing storks to our village would help increase the population growth rate, which is obviously false.

On 2021-08-12 02:48:52, user Johanna wrote:

It would be useful to report the interval between doses - or at least the interval regime in place in the region at the time of the study - due to the significant difference in efficacy for AstraZeneca with a 12-week interval as opposed to a shorter interval. In Australia, the AZ interval regime is 12 weeks, but a lack of data on efficacy with the longer interval, and consequent reporting of the relatively low efficacy with the shorter interval compared to Pfizer, has resulted in AZ being seen as the poor cousin, contributing to vaccine hesitancy. Lack of data means it remains unclear how great the difference in real-world efficacy between the two actually is. Reporting the interval between doses would at least clarify the applicability of results.

On 2021-08-12 16:39:53, user Mika Inki wrote:

I have several questions about the normalization. How precisely are the ages matched? You only mention that the participants’ ages were over 18. There is no normalization on whether the people belong to a risk group? Of course, that latter information may not be easily available. I would assume that older people and people in risk groups (including the immunocompromised) have vaccinated themselves at a much higher rate than younger and presumably healthier people, or at least people that believe themselves to be healthier. And lately there have been more infections in these younger groups, which would bias the probabilities. A young person in a risk group (even after vaccination) may have a much higher risk of severe illness than a typical person of the same age. Therefore, the overall effectiveness of both vaccines would likely seem significantly lower than what their true effectiveness is. Therefore, I would assume that the comparison between the vaccines may very well be valid, but the comparison between the vaccinated and unvaccinated may be significantly distorted.

On 2021-08-12 19:48:21, user Pasco Fearon wrote:

Hi Sean, and colleagues. Fascinating paper, but the scores are so low I worry something might not be right. Could the testing have been affected by the pandemic measures directly - e.g., mask wearing during testing? I could imagine some impacts but these are extreme, which leads me to worry that it's an administration issue. Can this be checked or ruled out somehow? I get asked this question a lot (how much have babies been affected by the pandemic), hence why I'm keen to be pretty confident in what I say.... Thanks!

On 2021-08-13 07:20:28, user Technicus AcityOne wrote:

Where exactly did the first discovery occur? And when ?

On 2021-08-13 10:16:11, user Earth Med Research wrote:

Please break down the PhD's according to what their field is, if it has not been done already. It would be very interesting if the sciences had stronger hesitancy, for example.

On 2021-08-20 02:48:13, user gospace wrote:

I would be willing to wager that if they separated out engineers, real ones, not software engineers, and non-degreed people working in engineering type professions, that they've got the highest rate of dreaded covid vaccine rejection. Not hesitancy, rejection. Maybe the software engineers too, I don't know enough of them to make a call on it.

On 2021-08-19 07:37:44, user dixon pinfold wrote:

The bulk of these comments cover in a more or less cogent manner the various ways the survey results could be wrong—the portion, that is, concerning respondents who reported holding doctoral degrees. No one questions the other findings, which are all congenial to ordinary educated prejudices.

Few are dissatisfied with the survey's respondents having self-selected, which I view as the chief problem with it. I am inclined to say quite flatly: Not a random sample, not valid. But then, if self-selection were the main objection in these comments, all the education-category results would fall under similar doubt, not just one. Is that why this objection seems not to have occurred to many?

I read anxiety and indignation into the tone of most of the comments. I confess to a slight doubt about the depth of their sincerity. I feel quite certain that if the survey showed a mere 1% of doctorate holders were vaccine-hesitant, the commenters would instead be saying "See? The more educated you are, the less likely you are to be vaccine-hesitant" and would express at least qualified approval of the survey.

Needless to say, these are mere opinions of mine. I should be interested to hear other people's.

(N.B. I myself have received two Moderna doses and mention it to establish my bona fides, not wishing to be pilloried for a lack of it.)

On 2021-08-27 21:37:41, user Infinite Monkeys wrote:

Why has the updated version of this article removed ~4,000 respondents from figure 1, of whom ~1,000 were PhDs? This affects the results of the survey regarding vaccine hesitancy by education, after it has been reported in the press. An explanation for discarding those results should be provided.

On 2021-08-16 21:15:27, user Mike Ronnie wrote:

"While vaccines continue to provide outstanding protection against severe

disease and mortality, the durability of this protection cannot be

reliably predicted. Therefore, it is essential for public health policy

to encourage vaccination while also planning for contingencies,

including diminished long-term protection."

--> I strongly recommend deleting these last sentences, as your study did not investigate this issue at all. Therefore, based on yourstudy design, this statement has absolutely no justification.

On 2021-08-18 04:47:32, user Andrew Iannaccone wrote:

Do the authors specify how their samples were obtained? All I can find in the text is that they came from a "single large contract laboratory" "in Wisconsin" "between June 29 2021 and July 30 2021." Does that mean the criterion for inclusion in this study is having had a covid test done during that period?

On 2021-08-03 11:51:04, user cinnamon50 wrote:

Don't we have to know that testing occurs the same for vaxxed and unvaxxed people ?<br /> am I missing something there in how the selection for testing occurs ?<br /> what if unvaxxed people are selected for testing differently ?

thanks

On 2021-08-18 19:00:42, user FABIO LIPIANI wrote:

very interesting, the immune system undergoes a very evident reprogramming of which no long-term effects are known,

On 2021-08-23 09:13:18, user Isatou Sarr wrote:

Hi,

is there any approved, readily available prophylaxis (ready to use existing drugs or re-purposed) that can be taken particularly by children to add up to the set-out plan for reducing/stopping the transmission cycle of the virus? I just don't know how effectively applicable the non-medical preventative measures will be in resource limited settings where classrooms are not usually structured to accommodate the COVID-19 preventative measures and access to clean water supply is a problem for atleast the hand washing aspect to be adhered to as it should be.

Thank you.

On 2021-08-25 20:16:42, user Tom wrote:

As all 12-16 year-old teenagers were not vaccinated at the time of the study, could you answer this question please:

Why did the study include 12-16 year-old teenagers in the group : adult/teenager household contacts that were vaccinated but not isolated?

On 2021-08-26 14:47:37, user bbeaird wrote:

The science looks solid. I think the challenge is how to interpret the findings. I did expect antibody concentrations to decline over time, in both vaccinated and convalescent populations. The 'aha moment' revolves around the difference in decay rates. But...my interpretation is not that people should avoid vaccination. The penalty of death or serious illness is too great. Nor can you expect people to take booster shots annually forever. I believe the path out of this misery is to get vaccinated, and then subsequently most vaccinated people will still contract the virus, though the effects will be minimal as compared to being unvaccinated and getting sick. Thus, the vaccination provides a safe bridge to a level of antibodies for which the decay rate is much more gradual and sustainable. One more comment...I believe there is an error in the text, on the percent of vaccinated people who have antibody concentrations below the minimum protection level, listed as 5.8% at 3 months. Yet the accompanying graph shows 5.8% at 1 month and 9.2% at 3 months. This error doesn't change the findings. Just a friendly note that the figures should be changed to match.

On 2021-08-26 19:32:16, user Aubrey Bailey wrote:

A few problems:<br /> 1. The authors count single dose vaccine as "vaccinated". That's not anyone's accepted definition.

1. The authors include naturally infected individuals in the vaccinated group if <br /> they got vaccinated later. Why? Were there not 16K fully (double) vaccinated people<br /> in a giant medical database?

2. This is the big one - <br /> I admit to skimming, but I didn't see any control for time intervals since infection.<br /> This<br /> is absolutely critical because we know that the antibody response <br /> wanes over about 8 months. Since the vaccine has been around for more <br /> than 8 months, it makes sense that more people will be at the tail end <br /> of that. Thankfully many more people get vaccinated than infected.

In light of all of these and in light of the un-reproduced nature of these findings (which should have been observable since Februrary), we should consider the first sentence of the conclusions to be at best, strongly overreaching, and at worst irresponsible phrasing.

On 2021-08-27 13:34:21, user Luke Bartelt wrote:

The authors should correct table 1a and 1b where group demographics appear identical.

On 2021-08-28 02:02:31, user Marxtinks wrote:

It is not surprising that natural infection elicits stronger immune responses than the current vaccines. Covid 19 encodes 24 individual proteins. In contrast, only a single protein, the Spike antigen used by both Moderna and Pfizer in their vaccines. Furthermore, it is likely that the large scale S antigen mRNA immunization will lead to development of mutant strains not neutralized by sera or T cells of people vaccinated by the S antigen. It would be wise to develop novel vaccine strategies

On 2021-08-28 08:55:21, user Martijn Weterings wrote:

In table 1a we see that the comorbidity factors correlate strongly with the main factor (vaccinated/natural). For instance the vaccinated group has two and a half times more immunocompromised people (420 Vs 164).

This means that there is high degree of multicollinearity which makes the coefficients of the fitted models meaningless. We see for example in table 2a several negative coeffients for factors like diabetes, COPD and immunosuppression. These coeffients have a large estimated error and are not 'significant' but they *do* influence the other coefficients in the entire model.

Errors that follow from this might also be increased due to the logistic function which 'pushes' coefficients to extreme values when the frequency in certain classes is close to 1 or 0.

https://stats.stackexchange...

https://stats.stackexchange...

Asside from the correlated variables and the influence of this on model coefficients... The correlation is also an indication that the matched groups are still very different from each other, despite the matching. This means that the experiment is prone to selection bias.

Despite these two facts these results are still very interesting. It would be nice if they could be presented in a more raw form such that the pattern may be better seen (e.g. do the cases all occur in the high risk group with comorbidities?), and not just the output of fitted coefficients from models.

On 2021-08-31 00:14:58, user chelsea wrote:

Yes figures and tables would be nice.. they do not provide what extra level of protection you get if you have had sars cov2 and then get vaccinate... is it measured in folds like the actual infected over the vaccinated or is it like 13%?

On 2021-09-13 14:36:27, user Chadwick wrote:

It is incredibly odd that the study authors provide us copious odds ratios but never the number of participants in each condition with each outcome. It's absence is quite strange.

On 2021-08-26 08:55:34, user William Richard Dubourg wrote:

Because of the voluntary nature of testing, testing rates as an outcome measure are on their own unreliable. There is reason to think the propensity to get tested is different between the vaccinated and infected groups. You need a model to predict testing propensity.

Your Table S1 does not match the text. Odds ratios and CIs are different.

My main concern relates to underlying health status. The infected group will exclude people who have previously died from COVID. The vaccinated group will not. Thus, there is reason to believe the infected group will have better underlying health status than the vaccinated group. This might explain why there were marginally more hospitalisations (a better and less biased outcome measure) in the vaccinated group than the infected group.

It should also be noted that there was no difference in deaths between the two groups.

Your conclusions about the beneficial effect of infection vs vaccination are therefore unwarranted.

On 2021-08-27 15:57:52, user Jacky wrote:

The study does not account for survivor bias (i.e., those who got COVID and died; however, hardly anyone--probably nobody--who got a <br /> vaccine died); the estimates they report are confounded and not <br /> interpretable. Also, it does not account for time differences of when <br /> the person was vaccinated and when when the person got COVID. If most <br /> individuals were vaccinated say 6 months ago and they are compared <br /> individuals that got Delta recently, then of course the latter will have<br /> more antibodies than the former (antibodies will wane in both groups). <br /> Thus, this study has sever methodological challenges.

On 2021-08-29 03:38:56, user julie kemp wrote:

I've heard many different reports , and most agree , that if you recover from Covid 19 your immunity is greater than a vaccinated person. A lab test would prove it. I had the vaccines, my friend had the Covid 19 virus, and doesn't want the vaccine. Why can't she just have a lab test to check her immunity ,and that should suffice.If she's immune. why force her to take a vaccine.??

On 2021-08-29 08:15:47, user Jeroen Boschma wrote:

The group of unvaccinated persons are truly survivors of their first infection, this means that many of the weak and problematic health cases have died during their first infection and are no longer present in that group. If Covid has a mortality of 1.5%, then this subgroup is 240 cases for the 16000 large group. However: all those cases of weak and problematic health who likely die from an unprotected infection are still present in the group of SARS-CoV-2-naïve vaccinees. So a selection was done where the most vulnerable persons were taken out of the unvaccinated group (death), but that selection is not done in the vaccinated group simply because it is not possible to predict at forehand who will die from an unprotected Covid infection. Although the groups are finally selected on equal risk factors, the above observation will always introduce a huge statistical bias.

I am quite sure that the group of cases found in the 'vaccine' group are largely those persons who would have died from an unprotected Covid infection. Because those persons are by definition not present in the unvaccinated group (they died during the first infection) you can explain the number of cases in both groups precisely by the above described mechanism. The conclusion then is that the found cases have nothing to do with 'better resistance due to an earlier infection'.

EDIT: I see now below that William Richard Dubourg made the same comment about the deaths due to Covid. I had problems with my Disqus account and could not post for a couple of days. Moreover: yesterday I saw 0 comments below this article while today suddenly comments appear that are 3 days old. Strange behavior....

On 2021-08-30 19:37:56, user 0/0 wrote:

It's ironic that so many lay-people from the US are commenting on (and mostly complaining about) a study that shows something contrary to the public narrative. They are clearly not aware of the large number of studies showing the effectiveness of natural immunity that have been published since the first of the year.

To the point, survivor bias is not relevant to the study or the conclusion; it's an attempt to extrapolate, or more accurately to correct for the lack of, alignment with a desired narrative. The study examines cohorts of existing people to determine effectiveness of the sources of immunity in those *already protected* cohorts. These findings do not recommend a course of action for those who are not yet protected - that's an entirely different study, and the explanatory narrative explicitly reinforces the importance of vaccination for those populations.

On 2021-09-01 10:08:16, user Jonh Peter wrote:

About Graphene’s health effects summarised in new guide (European Commission Feb.2015)<br /> At the level of the whole body, the authors indicate that there are two main safety factors to consider regarding exposure to CNTs and graphene. The first is their ability to generate a response by the body’s immune system; the second is their ability to cause inflammation and cancer.

On 2021-08-27 10:14:26, user Guy André Pelouze wrote:

I have a question: is there any further details about the AU used in this recent paper? Are WHO equivalent mentioned anywhere? <br /> Thank you.

On 2021-08-28 16:03:15, user Grammymidge wrote:

Hate to say but with how the US political machine is working to push the vaccine and affecting the Medical research community and leaders (i.e., the Surgeon General) here I have suspect of any finding produced in a US study that is opposite of findings in other parts of the world (i.e., Isreal). The latest Israeli study is based on a higher population, ~46,000, then what was used in this. The metrics of the study show that natural immunity provides a higher protection then the vaccine. But it does indicate the natural immunity coupled with one does of vaccine provides the individual with slightly higher protection against Delta. I found it very informative and worth a read.

On 2021-08-29 07:53:30, user Swami Ganesh wrote:

It is not clear how the average IFR (e.g. 0.21%) was obtained. Report says it was based on reported Covid fatalities. There is also mention of estimating IFR based on government mortality data for the subject area. How do you derive that? The standard way is to divide the cumulative death for the representative population (on, say, the date the sero survey collection ended), by the infected population (average seroprevalence X population). Of course, if one doesn't believe the reported fatalities, then some use excess mortality data, but that is a can of worms and strains credibility because the baseline mortality from pre-Covid years are equaally unrelaible if one doesn't trust the reported Covid deaths. Will appreciate your clarification. Thanks

Swami Ganesh (PHD, MBA) retired engineering professional, NY, USA

On 2021-08-06 02:14:00, user Peat Floss BS MS MD wrote:

Assuming the 60 million + people served by this healthcare system are roughly representative of the united states, roughly 5% of them would be expected to be between 12-17. That's roughly 3 million people. CDC estimated infection rate in that age group is about 36%. That's about 1 million covid infections in this cohort if its roughly representative. You can throw some pretty massive error bars on there to account for seeking outside care and the possibility of an unusually old or young sample and never get close to the numbers used in this paper

On 2021-08-07 18:55:51, user Ted Libson wrote:

Here's an idea. COVID is been going around the world since November 2019. Coming up on two years ago.

By now every medical person on the planet could have conducted their own double-blind, random ivermectin study . Twice.

How come we're not reading through thousands of double-blind, random ivermectin studies right now?

On 2021-08-09 10:52:29, user old farmer wrote:

It's my understanding that this study was conducted in the summer of 2020 and that ivermectin has been widely used in several countries like Brazil & India with very serious Coronavirus outbreaks for some extended period. If ivermectin was so effective why hasn't it been widely acknowledged. I can not believe that tens of thousands of doctors would ignore a really effective treatment if it existed in the face of this pandemic.

On 2022-01-07 15:49:40, user Franciska Ruessink wrote:

The study heavily relies on vaccinated and unvaccinated people being equally eager to be tested. But unvaccinated test less https://covid19danmark.dk/#... so probably they only test with more severe symptoms. If the secondary case for unvaccinated is 28-29 % for both Omicron and Delta, there may be a lot more untested Omicron cases behind that than untested Delta, as Omicron is milder.

On 2022-01-08 03:40:41, user Robyn Chuter wrote:

In Supplemental Table 2, deaths following hospitalisation for myocarditis are differentiated by vaccine dosage status, and SARS-CoV-2 test positivity.<br /> Given the increased rate of system adverse events after vaccination in COVID-recovered individuals, it would be helpful to differentiate between myocarditis deaths that occurred after vaccination in never-infected vs COVID-recovered individuals.

On 2022-01-08 14:44:03, user Jack wrote:

It appears from the opening paragraph and the references to hospitalization and death and death certificates, that these incidents of myocarditis are referring specifically to severe myocarditis. Is anyone able to confirm if this is the case because, if it is, with mortality for severe myocarditis being as high as 50% after 5 years, that would make the vaccine a greater risk than Covid-19 for men under 40 who have no significant comorbidities.

On 2022-01-12 16:00:26, user Robert Nelson wrote:

Regarding the matching based on vaccination status. The percentage of the matched delta having any vaccine was 64% vs 69% of matched Omicron cohort. (no vaccine = 36% and 31% respectively). The percentage of delta (matched) with 2 doses = 54% vs 58% for Omicron. So we're looking at about a 7 to 8% advantage to omicron cohort if we assume less severity or decreased chance of death. But when you apply that differential to the HR it doesn't change the outcome very much.

On 2022-01-13 13:55:45, user Kirk Kelln wrote:

IMPORTANT DATA ERROR in "Table 2: Demographic and clinical characteristics of cases tested in outpatient settings with SGTF and non-SGTF SARS-CoV-2 infections", line "Hispanic 7,762 (6.6) 23,894 (45.8) 1.29 (1.24, 1.34) 1.26 (1.21, 1.32)" The percentage of Hispanic is stated as 6.6 but this is incorrect. Should be about 45.9%. Thanks for this interesting report!

On 2022-01-21 00:18:18, user Myssi Graves wrote:

It's disappointing to see the final published abstract. I have to wonder if the authors had to agree to adding the political 'vaccinate and boost' in order to be published, or if it was fear of backlash. The paper was a warning of possibilities, not a push to continue using a vaccine that fit the very failures the article warned of, or at least it was.

On 2022-01-22 07:07:07, user JanLotvall wrote:

Vaccine equity is certainly important, but does this data really support the conclusion that vaccination rates explain difference in COVID mortality?. If you use the January 2021 rCFR numbers as a baseline, it was 1.83 (95% CI: 1.24-2.43) in highly vaccinated countries, and in rest of the world it was 2.32 (95% CI: 1.86-2.79). This suggests that other factors than vaccination may explain presumed differences in mortality between the different countries, presumably quality of health care, and perhaps other public health variables in the different countries. Tobacco smoking is potentially one factor that could explains differences in trends between countries.

On 2022-01-24 08:12:11, user giu.nanni@tiscali.it wrote:

As the Authors declare, one of the limitations of their study is “the relatively small numbers of tested samples in time groups”. More than this, it seems inappropriate comparing an unknown number of sera of the 31 Sputnik vaccinated individuals with 51 sera of the 17 Pfizer vaccinated. How many sera of the Sputnik group, in the different study times, are compared with the sera of the Pfizer group? Which is the number of Pfizer vaccinated in the three different study times? The 15 Sputnik individuals studied <3 months after the second dose are not the 16 studied 3-6 months later? Moreover, the figures, in particular the number 1, do not show the differences between the two vaccines.<br /> Among the criteria for comparing the changes in the titre of NtAbs determined by two different vaccines is ‘how many fold’ sufficient?<br /> Since several reports underscore the efficacy of the booster of the mRMA vaccines in the protection against Omicron variant, it should be more relevant to compare the third dose of two different vaccines.

On 2022-01-28 20:28:06, user Charlie Jones wrote:

Does the background of the person affect their suicidal ideation (ie socioeconomic status, family situation).

On 2025-09-15 13:27:23, user Maksim wrote:

The manuscript is now accepted for publication.<br /> DOI: 10.2174/0113816128412495250824132514<br /> Curr Pharm Des 2025

On 2022-02-11 20:36:21, user Lou Edi wrote:

I'm not sure how the conclusions follow. The study does not research incidence of infections among the groups, after all. It researches the incidence of false alarms.

This is worsened by the exclusion criteria. Self-tested positives get excluded, and may then be counted as negative subjects if they had another test. Fervent testers get a lot of false alarms. While hesitant testers (i.e. tests when they had a close contact and got sick) get high positive rates.<br /> Since these behaviors likely correlate to some extent with vaccine uptake and previous infection, this needs to be accounted for.

Additional distortion: by the criteria, someone who got sick before and after the booster, only gets his unboosted positive counted (presumably rare, but most significant).<br /> While someone who got negatively tested before and after the booster, only gets his boosted negatve counted.

Note on the conclusion: waning effects, both for infection and severity, need to be mentioned. However for this, countries that boosted early will be the main indicators. Same for the results of a 2nd booster.

On 2022-02-14 08:23:23, user kdrl nakle wrote:

Poorly written paper that looks like a hodge podge and has diagrams lacking clarifications, one has to search in the main body of paper for relevant references.

On 2022-02-15 04:05:10, user Vijayaprasad Gopichandran wrote:

This is a very important analysis of the role of COVID 19 vaccination on ICU admission and mortality due to COVID 19 in Tamil Nadu. This is a secondary data analysis and it concludes that having two doses of COVID 19 vaccine resulted in significant reduction in severe COVID 19 (ICU admissions) and death due to COVID 19. The strength of the study is that it analyses the effectiveness of the vaccine in reducing severe disease and mortality from real time data. However, some more clarity on some details in the methods, and analysis will help interpret the results better. How was the vaccination status obtained? Was it obtained from the hospital database, which in turn is obtained from self report by the patient or their caregivers? Or was it obtained or confirmed from the Co-Win national COVID 19 vaccination portal? This is important because, self report could be biased (more likely to be overestimate with the various restrictions and penalties sanctioned by the state for not accepting the vaccine). It is important to know whether the researchers confirmed the vaccination status from the CoWin Portal data. Secondly what were the standard criteria recommended by the state for ICU admission? To what extent were these criteria strictly adhered to? What was the ICU bed availability status during this period? Is it likely that some of the severe cases were misclassified due to non-availability of ICU beds? It would have been better to have a more objective criterion for classification of sever disease such as SpO2, PaO2/FiO2 ratio, respiratory rate, arterial blood gases or any such parameters rather than ICU admission rates as the ICU admission rates could be influenced by availability of ICU beds as well as the clinical judgment of the admitting health care provider. Thirdly, conspicuous by its absence in the paper is the odds ratio of admission to health facilities compared to care in CCC or Home Isolation. The data has been captured as described in the methods section, but this analysis is not reported. This is very important data. The researchers themselves start the paper by describing the importance of COVID 19 as a disease which burdened the health system. Prevention of hospitalisation is an important outcome from this perspective. It would be helpful to know this result also. Finally, the researchers should explain why they have limited themselves only to a bivariate analysis and why they have not attempted any multivariable model adjusting for age, sex, comorbidities, time period of admission and other such important variables which are likely to influence the severity of illness as well as mortality. Overall, this is important information. But if given more clarity on these lines, it would add more value to scientific literature on COVID 19 vaccines.

On 2021-10-26 07:55:37, user TheUnderdog wrote:

Why is the 40% and 63% 'effectiveness' solely attributed to the vaccine, and not to the individual's own immunity (including natural immunity)?

I would argue this shows an opposite effect. The vaccinated group only have a 40% effectiveness of not getting infected, whilst the natural immunity group have a 63% effectiveness rate of not being infected.

If it was just the individual's own vaccine that was preventing onward transmission to others, then we'd expect the percentages to both groups to be the same. In-fact, if the vaccines even worked we'd expect the effectiveness percentages to be flipped around, with vaccinated people seeing more effective protection.

This study just appears to reinforce natural immunity as offering better protection, which correlates with the Israel datasets showing natural immunity works better against Delta (see: https://www.timesofisrael.c... "https://www.timesofisrael.com/study-covid-recovery-gave-israelis-longer-lasting-delta-defense-than-vaccines/)").

On 2021-10-26 18:07:58, user Daniel Lidstone wrote:

Hi, very nice paper. Was the anti-correlated DMN-DAN edge showing the mediation effect an anterior or posterior DMN parcel? I didn't see specific labels in the preprint.<br /> -Daniel

On 2022-02-24 03:46:50, user Kevin Kavanagh wrote:

Deaths appear to be spiking in South Africa. It might be the H78Y mutation. Deaths are also spiking in Denmark. The current data in the 4 weeks after this study are not reassuring.

On 2022-04-13 23:10:02, user D.R. wrote:

This study unfortunately missed an opportunity. It purports to have “[ established a Phase 3 pragmatic trial to evaluate the effectiveness of a test-and-treat approach to identification and treatment of vitamin D insufficiency for prevention of COVID-19 and other ARIs in U.K. adults” ].

When the trial failed to determine a statistically significant prevention of ARI with the dosing followed, the authors say that “ultimately, however, this trial was designed to investigate the effectiveness of a pragmatic ‘test-and-treat’ approach to boosting population vitamin D status, rather than biologic efficacy of vitamin D to prevent ARIs, and our findings should be interpreted accordingly,” essentially abandoning the prevention of ARIs.

In any trial there has to be a target serum concentration of the drug under study.<br /> Participants should be determined as having reached it, IF sufficiency for prevention of ARI is to be assessed. This trial did not appear to have a target, other than the presumption that over 75nmol/l was sufficient which has no scientific basis.

As regards the “pragmatic test-and-treat approach to boosting population vitamin D status”, the strategy has to get the participants to a target within a short period of time as it will take many weeks to become effective. A fixed dose across six months and across all BMI types is ill-advised. The approach should at the start reflect current primary care practice to get the participant to a target level within 5 weeks, and confirm that it was reached as a prerequisite for observation of effectiveness at prevention of ARIs. The difference here should have been to then assess whether participants has achieved the required level and not just abandon the effort as currently practiced by primary care in the UK. <br /> More than 50% of participants were over-weight or obese, and would struggle to get to a target within 5 weeks unless calcifidiol was used, or a specifically tailored regimen employed. This absorption challenge was known in advance of design. So not only was the evaluation of a pragmatic approach compromised, but the foundation for the proper assessment of prevention of disease was too.

The data on the effectiveness of the dosing by BMI should be detailed in the paper, and raw data made available.

In any event, the trial found that a mean of 102.9nmol (s.d. 23.6) did not produce a preventive effect. The failure to have a prerequisite specific serum level in a timely fashion for the observation of prevention, when the virus was most prevalent, most likely compromised the outcomes of the trial.

The conclusion would be better worded to state that “Among adults with a high baseline prevalence of apparent vitamin D insufficiency, implementation of a test-and-treat approach to vitamin D replacement using a maximum uniform 3200IU/d over six months for all participants, regardless of BMI type, did not reduce risk of all-cause ARI or Covid-19.”

On 2022-05-04 09:04:40, user helene banoun wrote:

Thank you for your work

Have you considered the possibility that it is not directly the vaccine antibodies that are transferred from vaccinated to non-vaccinated but rather the vaccine mRNA?

There are indeed studies that show that this passage is possible through sweat in both directions.

People not directly vaccinated would thus be indirectly vaccinated by transdermal diffusion of the vaccine.

And indeed, as indicated in the previous comment, the antibodies can come from a previous infection rather than from a vaccination followed by a transfer of antibodies

Bart, Geneviève, Daniel Fischer, Anatoliy Samoylenko, Artem Zhyvolozhnyi, Pavlo Stehantsev, Ilkka Miinalainen, Mika Kaakinen, et al. "Characterization of nucleic acids from extracellular vesicle-enriched human sweat. BMC Genomics 22, no. 1 (June 9, 2021): 425. https://doi.org/10.1186/s12....

https://bmcgenomics.biomedc....

https://www.frontiersin.org....

Karvinen, Sira, Tero Sievänen, Jari E. Karppinen, Pekka Hautasaari, Geneviève Bart, Anatoliy Samoylenko, Seppo J. Vainio, Juha P. Ahtiainen, Eija K. Laakkonen, and Urho M. Kujala. "MicroRNAs in Extracellular Vesicles in Sweat Change in Response to Endurance Exercise". Frontiers in Physiology 11 (2020): 676. https://doi.org/10.3389/fph....

Inhaled RNA Therapy: From Promise to Reality

https://linkinghub.elsevier... October 2020

Outer membrane vesicles derived from E. coli as novel vehicles for transdermal and tumor targeting delivery

http://xlink.rsc.org/?DOI=D...

Recent Advances in Extracellular Vesicles as Drug Delivery Systems and Their Potential in Precision Medicine

Intranasal, oral, intraocular and subconjunctival delivery of extracellular vesicles capable of carrying drugs

https://www.ncbi.nlm.nih.go...

Plant Exosome-like Nanovesicles: Emerging Therapeutics and Drug Delivery Nanoplatforms

https://www.sciencedirect.c...

RNA Aptamer Delivery through Intact Human Skin

https://www.sciencedirect.c...

Large RNA molecules can penetrate intact skin and retain their biological activity

Passive inhaled mRNA vaccination for SARS-Cov-2

https://www.ncbi.nlm.nih.go...

https://www.fda.gov/regulat...

virus or bacteria-based gene therapy products (VBGT products)

the term "shedding" means release of VBGT or oncolytic products from the patient through one or all of the following ways: excreta (feces); secreta (urine, saliva, nasopharyngeal fluids etc.); or through the skin (pustules, sores, wounds)

On 2022-05-09 16:36:22, user eduardo quiñelen wrote:

Dear,<br /> Please, we need you to explain the information on true positives, true negatives, false positives and false negatives disaggregated for each test.

On 2021-11-20 19:22:50, user John Tyler wrote:

We’re aren’t statisticians. This is meaningless to the masses unless put into layman’s terms. I have no idea if this studies supports or refutes vaccination.

On 2022-08-21 14:21:09, user Gerard Job wrote:

This article was published in the journal of clinical trials.....Author Info<br /> Gerard Job1,2*, Jennifer Okungbowa-Ikponmwosa1 and Yijia M1<br /> 1Department of Emergency, Jackson Memorial Hospital, Miami, Florida, USA<br /> 2Department of Emergency, Miami Dade Fire, Air and Ocean Rescue, Miami, Florida, USA

Citation: Job G, Okungbowa-Ikponmwosa J, Yijia M (202 1) Feasibility of Establishing a Return-to-Work Protocol Based on COVID-19 Antibodies Testing. J Clin Trials. 11:480.

Received: 22-Jan-2021 Accepted: 05-Feb-2021 Published: 12-Feb-2021 , DOI: 10.35248/2167-0870.21.11.48

On 2020-04-03 12:58:04, user Kate wrote:

How can you find a correlation in an observational study? I'm not even touching on the issue of not controlling for any confounding variable

On 2020-04-04 12:23:52, user Jess wrote:

Hi...I am a Malaysian & in Malaysia, all newborns hv been vaccinated with BCG since 1961.

However, you can see fr the statistics that Malaysia is still struggling with Covid.

I am sorry to inform that this hypothesis needs to be re-evaluated so as not to be over zealous over this.

On 2020-04-04 14:52:54, user jwcross wrote:

BCG is also used as intravesical therapy for bladder cancer (BC). Since BC is more common among the elderly, it would be interesting to know if BC patients and survivors treated with BCG have a higher survival than age-matched peers and BC patients and survivors who had been given alternative therapies.

On 2020-04-04 19:54:04, user Paul Constantine wrote:

The first published study on this subject was made by Dr.Mihai Netea. The distinguished researcher is an authority in citokyne storm and he based his research on a correlation of the clinical evolution of SARS 19 in countries where the BCG vaccination is compulsory, i.e. Romania, Germany, Portugal, Republic of Korea, Malaysia, Japan.

On 2020-04-05 21:45:02, user Tom Johnstone wrote:

There’s a multitude-centre RCT to test the protective effects of the vaccine against Covid-19 in healthcare workers in Australia. https://www1.racgp.org.au/n...

In the mean time, it would be prudent to remove the causal language from the article and abstract (“reduced”), as any results are purely associations.

On 2020-04-12 00:48:21, user Oleg Gasul wrote:

I am not sure about data correctness from the countries Turkmenistan, Uzbekistan and Kazakhstan, but all of them have very small number of cases (event zero in Turkmenistan).

But if we take a look on the map http://www.bcgatlas.org/ there is information that all of them have "Multiple BCG". That I understood the BCG vaccination is carried out several times (After birth, 6-7 yrs and 15 yrs).

On 2020-03-31 05:51:15, user Dmitry Shiryapov wrote:

Very interesting and promising speculations are reflected in the article. Definitely, some amendments should be done later, in conjunction with the pandemic development in Russian Federation, as a successor of Soviet Union. In any case, the authors have revealed a fertile soil for a number of publications in the future.

On 2020-04-03 00:18:23, user Alessandro Crimi wrote:

Interesting, but you should also correlate with geographic accessibility to airports connecting main epidemic epicenters. I suspect that that's the main factor, and the BCG policies are confounding factors. Also you should discuss in the limitations about the fact that elderly in Italy and Spain have the BCG vaccination

On 2020-05-03 18:38:20, user nomad monkey wrote:

In this chart, the circle colors indicate the BCG vaccine policy for different countries. The circle locations are plotted according to the the median age and % urbanization of the population. The circle size is proportional to covid-19 deaths per capita. As we have all noticed, the older and more urbanized populations tend to have greater per capita covid deaths (i.e. bigger circles). But notice how huge the circles are for the countries that don't do universal BCG (green & pink circles), as compared to similarly aged & urbanized northern Asian countries that have universal BCG policies (blue circles).

Ecuador strongly supports the the BCG theory, as Ecuador has comparatively high per capita covid deaths for a relatively young and less urbanized population. And Ecuador (pink circle) doesn't do universal BCG vaccination like the rest of South Amercia (blue circles).

https://uploads.disquscdn.c...

On 2020-04-04 03:15:45, user Charles Baker wrote:

Why are some states peaking in the model almost 30 days behind all the states around them? If you look at virginia and then all the states around them they peak almost a month after. How or why would that be?

On 2020-04-07 14:53:16, user Quinctius Cincinnatus wrote:

I was glad to see the Imperial College estimate. I'm equally glad to see this work in progress. What happens if only 20% of the population is susceptible to the disease? Diamond Princess had a max of 20% (and no one did a "heat map" of the ship which boggles my mind), Italian hospital workers have a rate of 20% (assuming they have been equally exposed to the virus). We know that the Black Death didn't strike everyone, and it didn't kill everyone it struck. What was the asymptomatic rate used in this study? Did Page four doesn't relay. In Diamond Princess and the Italian village Vo, it appeared to be almost 50%. finally, did anyone look at the potential impact of weather? I suspect Wuhan had more cases than Hong Kong - one reason was the warmer climate. So, as this work in progress continues - it would be good to see those assumptions and look at those variables. .

On 2020-04-02 10:24:38, user ansgarjohn wrote:

The output seems similiar to what Michael Levitt has observed. Here Netherland (growth rate slowing by 1% per day is the guesstimate) https://sinaas.blogspot.com...

On 2020-04-04 10:47:57, user Lorenzo Sabatelli wrote:

Hi Laura, very interesting, thanks for sharing. One thing that may be useful to account for is the differential impact of social distancing on age group mixing, e.g. that could be done by taking into account household demographic structure in Seattle and perhaps finding additional data (or making some assumptions) on the proportion of mixing between age-groups happening at the household level vs. external world. Another thing one could add is a separate group of adults with higher risk of infection and transmission accounting for health workers and other essential workers exposed to the public, e.g. apparently in Italy about 10% of currently diagnosed cases are among healthworkers, and explore the impact of transmission due to healthcare and/or other essential services (e.g. supermarkets, drugstores, etc)

Lo.

On 2020-04-06 16:17:40, user Maxim Sheinin wrote:

Given that people dying from Covid-19 are primarily the elderly (60+), and BCG vaccine is given only in childhood, does it make sense to look at the correlation using current status of BCG vaccination? It would seem that status 60+ years ago will be more relevant. This will likely complicate the picture, as many European countries that do not mandate BCG today used to have it in the past, and conversely some other countries have introduce BCG not that long ago (http://www.bcgatlas.org/) "http://www.bcgatlas.org/)").

On 2020-04-07 13:48:42, user Erin Beaver, MS, LCGC wrote:

I am a genetic counselor. I have been following the ABO COVID19 outcome correlation. I know many are discounting the data because they can’t fathom how ABO is associated with susceptibility to a respiratory pathogen. As a genetic counselor, I started thinking in a genetic linkage type of way and looked to see what was located near ABO blood group genes on chromosome 9. It turns out there is a gene, GBGT1 that sits next to ABO blood group and so this is a relatively conserved haplotype for polymorphisms in those genes. GBGT1 encodes a glycolipid called Forssman glycolic is which is thought in humans to be a major attachment site for pathogen binding to cells. This gene is highly active in lung tissues. I find all of this interesting a something worth investigating, but as a clinical genetic counselor with no access to a research lab, I don’t have the means to investigate my theory that perhaps GBGT1 aka FS glycolipid plays a role in infection from COVID19. Thoughts? Anyone that can look at this relationship?

On 2020-03-26 02:27:01, user Cristian Orrego wrote:

Its a small sample, right, but it doesnt seem to unvalidate the study. The only thing that i think in this case (if i read it right) that could be wrongly interpreted would be the conclusion. Because the sample of the sick people was obtained in the hospitals, so maybe the O type doesnt have less chance to get the virus, but insted it has less probabilities of develop synthoms that get people into the hospitals. So maybe the virus attack them (O type) with less severity. New studies should get infected people from random tested people among the general population to confirm if the O type gets lower rates of infection or the O type gets lower rates of worsening sympthoms once infected.

On 2020-04-08 03:48:43, user iBonus iBonus wrote:

The biggest reason why Coronavirus is so easy to spread in the community is that infected persons have an incubation period of about 14 days, and there are no obvious surface symptoms. Many people do not know if they have been in contact with incubators.

The most effective way to implement the mathematical model is to use the smartphone registration app and also to install dedicated terminals in public places such as a library, cinema, school, and gym to record where and when the citizens have visited.<br /> When a person is reported as virus-infected by medical authorities, the system immediately puts all persons who appear in the same place at the same time as the confirmed patient in the past 14 days into an Alert list and transmits it to all terminals.

• 10% public participation of our program, will reduce COVID19 spread by 40% <br /> • 30% public participation of our program, will reduce COVID19 spread by 80%

https://uploads.disquscdn.c...

https://covid2019system.com/

On 2020-04-08 15:02:17, user Dr. Noc wrote:

I think that we have to be careful to not interpret these results the wrong way. We know that older patients are at higher risk of mortality. By selecting for patients who have recovered from disease, the patient group may be biased toward those who had stronger production of nAbs (especially in the most at-risk group).

That is to say that, although it may appear that higher titers of nAbs are correlated with the groups that tend to have more severe disease outcomes, that doesn't necessarily mean that nAbs are contributing to the severity of outcomes, but rather that they may reflect a "survivorship" type of bias.

On 2020-04-08 18:01:50, user Terry McInnis wrote:

What are LabCorp and Quest using? Are they using the same 9 probes on their PCR tests?

On 2020-04-10 20:14:05, user laurencerowe wrote:

The UK appears to be misclassified in this study as 'currently mandated'. It phased out routine BCG vaccination in 2005.

See: https://www.nhs.uk/conditio...

On 2020-03-19 09:12:47, user ReviewNinja wrote:

ddPCR is a great technique, and can be of value and is less dependent of PCR-effciencies.<br /> However, if you have a qPCR slope -6.3 or -6.5, that means that there is a problem with your qPCR efficiency (<50%!!!).... So, a better primer set, optimized assay conditions, ... are necessary here. <br /> Furthermore, a one-step qPCR is compared with a two-step ddPCR. RT is a very variable factor. So if you want to compare qPCR with ddPCR, almost all factors need to be kept constant (and definitely RT), which is not the case here.

On 2020-03-20 00:15:32, user RKM wrote:

The second paragraph in bold blue in this article says it all, "yet to be evaluated."

Is it 2 days, 9 days, do you really know?

The CDC is telling us this:<br /> https://www.cdc.gov/coronav...

But research tells us something completely different:<br /> https://www.news-medical.ne...<br /> If you have problems with the following link, then click on the link above and scroll down to the link that says, “The Journal of Hospital Infection.” <br /> https://www.journalofhospit...

On 2020-03-23 03:36:38, user Sinai Immunol Review Project wrote:

Main findings<br /> The authors performed single-cell RNA sequencing (scRNAseq) on bronchoalveolar lavage fluid (BAL) from 6 COVID-19 patients (n=3 mild cases, n=3 severe cases). Data was compared to previously generated scRNAseq data from healthy donor lung tissue.<br /> Clustering analysis of the 6 patients revealed distinct immune cell organization between mild and severe disease. Specifically they found that transcriptional clusters annotated as tissue resident alveolar macrophages were strongly reduced while monocytes-derived FCN1+SPP1+ inflammatory macrophages dominated the BAL of patients with severe COVID-19 diseases. They show that inflammatory macrophages upregulated interferon-signaling genes, monocytes recruiting chemokines including CCL2, CCL3, CCL4 as well as IL-6, TNF, IL-8 and profibrotic cytokine TGF-b, while alveolar macrophages expressed lipid metabolism genes, such as PPARG. <br /> The lymphoid compartment was overall enriched in lungs from patients. Clonally expanded CD8 T cells were enriched in mild cases suggesting that CD8 T cells contribute to viral clearance as in Flu infection, whereas proliferating T cells were enriched in severe cases.<br /> SARS-CoV-2 viral transcripts were detected in severe patients, but considered here as ambient contaminations.

Limitations of the study<br /> These results are based on samples from 6 patients and should therefore be confirmed in the future in additional patients. Longitudinal monitoring of BAL during disease progression or resolution would have been most useful.<br /> The mechanisms underlying the skewing of the macrophage compartment in patients towards inflammatory macrophages should be investigated in future studies.<br /> Deeper characterization of the lymphoid subsets is required. The composition of the “proliferating” cluster and how these cells differ from conventional T cell clusters should be assessed. NK and CD8 T cell transcriptomic profile, in particular the expression of cytotoxic mediator and immune checkpoint transcripts, should be compared between healthy and diseased lesions.

Relevance<br /> COVID-19 induces a robust inflammatory cytokine storm in patients that contributes to severe lung tissue damage and ARDS {1}. Accumulation of monocyte-derived inflammatory macrophages at the expense of Alveolar macrophages is known to play an anti-inflammatory role following respiratory viral infection, in part through the PPARg pathway {2,3} are likely contributing to lung tissue injuries. These data suggest that reduction of monocyte accumulation in the lung tissues could help modulate COVID-19-induced inflammation. Further analysis of lymphoid subsets is required to understand the contribution of adaptive immunity to disease outcome.

References<br /> 1. Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395, 497–506 (2020).<br /> 2. Allard, B., Panariti, A. & Martin, J. G. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection. Front. Immunol. 9, 1777 (2018).<br /> 3. Huang, S. et al. PPAR-? in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection. J Virol 93, e00030-19, /jvi/93/9/JVI.00030-19.atom (2019).

Review by Bérengère Salomé and Assaf Magen as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai.

On 2020-03-23 18:10:30, user Sinai Immunol Review Project wrote:

Summary:<br /> The authors of this study provide a comprehensive analysis of clinical laboratory assessments in 75 patients (median age 47 year old) hospitalized for Corona virus infection in China measuring differential blood counts including T-cell subsets (CD4, CD8), coagulation function, basic blood chemistry, of infection-related biomarkers including CRP, Procalcitonin (PCT) (Precursor of calcitonin that increases during bacterial infection or tissue injury), IL-6 and erythrocyte sedimentation rate as well as clinical parameters. Among the most common hematological changes they found increased neutrophils, reduced CD4 and CD8 lymphocytes, increased LDH, CRP and PCT

When looking at patients with elevated IL-6, the authors describe significantly reduced CD4 and CD8 lymphocyte counts and elevated CRP and PCT levels were significantly increased in infected patients suggesting that increased IL-6 may correlate well with disease severity in COVID-19 infections

Critical analysis:<br /> The authors performed an early assessment of clinical standard parameters in patients infected with COVID-19. Overall, the number of cases (75) is rather low and the snapshot approach does not inform about dynamics and thus potential relevance in the assessment of treatment options in this group of patients.

Importance and implications of the findings in the context of the current epidemics:<br /> The article summarizes provides a good summary of some of the common changes in immune cells inflammatory cytokines in patients with a COVID-19 infection and. Understanding how these changes can help predict severity of disease and guide therapy including IL-6 cytokine receptor blockade using Tocilizumab or Sarilumab will be important to explore.

On 2020-03-23 19:01:15, user Sinai Immunol Review Project wrote:

Summary:

Study on blood biomarkers with 80 COVID19 patients (69 severe and 11 non-severe). Patients with severe symptoms at admission (baseline) showed obvious lymphocytopenia and significantly increased interleukin-6 (IL-6) and CRP, which was positively correlated with symptoms severity. IL-6 at baseline positively correlates with CRP, LDH, ferritin and D-Dimer abundance in blood. <br /> Longitudinal analysis of 30 patients (before and after treatment) showed significant reduction of IL-6 in remission cases.

Limitations:

Limited sample size at baseline, especially for the non-severe leads to question on representativeness. The longitudinal study method is not described in detail and suffers from non-standardized treatment. Limited panel of pro-inflammatory cytokine was analyzed. Patients with severe disease show a wide range of altered blood composition and biomarkers of inflammation, as well as differences in disease course (53.6% were cured, about 10% developed acute respiratory distress syndrome). The authors comment on associations between IL-6 levels and outcomes, but these were not statistically significant (maybe due to the number of patients, non-standardized treatments, etc.) and data is not shown. Prognostic biomarkers could have been better explored. Study lacks multivariate analysis.

Findings implications:

IL-6 could be used as a pharmacodynamic marker of disease severity. Cytokine Release Syndrome (CRS) is a well-known side effect for CAR-T cancer therapy and there are several effective drugs to manage CRS. Drugs used to manage CRS could be tested to treat the most severe cases of COVID19.

Review by Jaime Mateus-Tique as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai

On 2020-03-26 05:18:54, user TreeHugginEnergyWonk wrote:

This is thrilling! People who have already been infected and cleared the coronavirus could donate their blood plasma immune factors to help those suffering more extreme cases of the disease! People could get back to work!

On 2020-03-26 18:01:31, user j2hess wrote:

The point is controlled rate of spread. This on-again off-again proposal reminds me uncomfortably of the sawtooth dynamcs of a predator-prey relationship. (The rabbits breed, coyote population grows until there are too many for the food supply, so there's a population crash of rabbits first and coyotes next.) There are other ways.

A British research group modeled the growth rate using graph theory. We're not a single uniformly-connected population; there are clusters of dense connections linked by fewer connections, and spread within is faster than spread without. The power law that results is a better fit than the standard exponential growth model.

So perhaps rather than on/off, you open up retail service businesses - hairdressers, coffee shops. You don't open the big venues - concerts, major league sports, mega-conferences. This provides a somewhat controlled spread of the virus, a more stable social environment, and less economic stress.

On 2020-03-27 20:03:16, user Brian Coyle wrote:

Important and significant study. Should lead to policy. One question: (only) 1 of 347 asymptomatic infected people transmitted to someone. But study also says the rate of asymptomatic transmission is .0033%

On 2020-03-28 01:06:18, user Sinai Immunol Review Project wrote:

Summary: Analyzing the eGFR (effective glomerular flow rate) of 85 Covid-19 patients and characterizing tissue damage and viral presence in post-mortem kidney samples from 6 Covid-19 patients, the authors conclude that significant damage occurs to the kidney, following Covid-19 infection. This is in contrast to the SARS infection from the 2003 outbreak. They determine this damage to be more prevalent in patients older than 60 years old, as determined by analysis of eGFR. H&E and IHC analysis in 6 Covid-19 patients revealed that damage was in the tubules, not the glomeruli of the kidneys and suggested that macrophage accumulation and C5b-9 deposition are key to this process.

Limitations: H&E and IHC samples were performed on post-mortem samples of unknown age, thus we cannot assess how/if age correlates with kidney damage, upon Covid-19 infection. Additionally, eGFR was the only in-vivo measurement. Blood urea nitrogen and proteinuria are amongst other measurements that could have been obtained from patient records. An immune panel of the blood was not performed to assess immune system activation. Additionally, patients are only from one hospital.

Significance: This report makes clear that kidney damage is prevalent in Covid-19 patients and should be accounted for.

On 2020-03-28 20:30:39, user adycousins wrote:

In Table 1 the estimate for the UK peak daily Covid-19 fatalities is 260 and a peak date of 5th of April, however 260 people died in the last 24 hours in the UK. Events seem have overtaken this study before its even reached peer-review.

On 2020-03-30 14:54:38, user Emma Cairn wrote:

Data is not an object in itself. Data is sometimes profoundly affected by the political, social and economic environments.

1.There are differing political criteria for selecting who is tested in different countries. Some select only those with severe symptoms and some sample test over their country. Some tests are inaccurate and sometimes not enough test kits are distributed. Some testing centres are inconvenient and sometimes multiple tests to the same person are negative until nucleic acid high enough.

1. There is political variation in what constitutes a corona death. It is possible that some are only reporting it as corona if there is no underlying condition. Or in other words if some have a heart attack it is being listed as that rather than Corona. If some die out of hospital untested this is also not a Corona death.

3<br /> I suggest that if people in countries knew the true number there would be widespread panic and disruption, economic turmoil and political unrest.

Conclusion Unless standardisation of political, economic viewpoints there will be no standardisation of empirical data. Virus will only slow down when it has learnt how to live with us harmoniously.

On 2020-03-29 12:55:46, user Rosemary TATE wrote:

I'm about to submit a review for this - my first attempt on medrxiv although (as a medical statistician) I have vast experience. However, all I really needed to do was look at their Cherries checklist. It is very incomplete and missing many details of how the study was carried out. These checklists are very important and shouldn't be added as an afterthought.

On 2020-03-29 22:38:51, user Sinai Immunol Review Project wrote:

Key findings:<br /> This study investigated the profile of the acute antibody response against SARS-CoV-2 and provided proposals for serologic tests in clinical practice. Magnetic Chemiluminescence Enzyme Immunoassay was used to evaluate IgM and IgG seroconversion in 285 hospital admitted patients who tested positive for SARS-CoV-2 by RT-PCR and in 52 COVID-19 suspected patients that tested negative by RT-PCR. A follow up study with 63 patients was performed to investigate longitudinal effects. In addition, IgG and IgM titers were evaluated in a cohort of close contacts (164 persons) of an infected couple.

The median day of seroconversion for both IgG and IgM was 13 days after symptom onset. Patients varied in the order of IgM/ IgG seroconversion and there was no apparent correlation of order with age, severity, or hospitalization time. This led the authors to conclude that for diagnosis IgM and IgG should be detected simultaneously at the early phase of infection.

IgG titers, but not IgM titers were higher in severe patients compared to non-severe patients after controlling for days post-symptom onset. Importantly, 12% of COVID-19 patients (RT-PCR confirmed) did not meet the WHO serological diagnosis criterion of either seroconversion or > 4-fold increase in IgG titer in sequential samples. This suggests the current serological criteria may be too stringent for COVID-19 diagnosis.

Of note, 4 patients from a group of 52 suspects (negative RT-PCR test) had anti-SARS-Cov-2 IgM and IgG. Similarly, 4.3% (7/162) of “close contacts” who had negative RT-PCR tests were positive for IgG and/or IgM. This highlights the usefulness of a serological assay to identify asymptomatic infections and/or infections that are missed by RT-PCR.

Limitations:<br /> This group’s report generally confirms the findings of others that have evaluated the acute antibody response to SARS-Cov-2. However, these data would benefit from inclusion of data on whether the participants had a documented history of viral infection. Moreover, serum samples that were collected prior to SARS-Cov-2 outbreak from patients with other viral infections would serve as a useful negative control for their assay. Methodological limitations include that only one serum sample per case was tested as well as the heat inactivation of serum samples prior to testing. It has previously been reported that heat inactivation interferes with the level of antibodies to SARS-Cov-2 and their protocol may have resulted in diminished quantification of IgM, specifically (Xiumei Hu et al, https://www.medrxiv.org/con... "https://www.medrxiv.org/content/10.1101/2020.03.12.20034231v1)").

Relevance:<br /> Understanding the features of the antibody responses against SARS-CoV is useful in the development of a serological test for the diagnosis of COVID-19. This paper addresses the need for additional screening methods that can detect the presence of infection despite lower viral titers. Detecting the production of antibodies, especially IgM, which are produced rapidly after infection can be combined with PCR to enhance detection sensitivity and accuracy and map the full spread of infection in communities, Moreover, serologic assays would be useful to screen health care workers in order to identify those with immunity to care for patients with COVID19.

On 2020-03-30 02:38:57, user Sinai Immunol Review Project wrote:

Summary of Findings: <br /> -Transcriptomic analysis using systems-level meta-analysis and network analysis of existing literature to determine ACE2 regulation in patients who have frequent COVID-19 comorbidities [eg- cardiovascular diseases, familial pulmonary hypertension, cancer]. <br /> - Enrichment analyses indicated pathways associated with inflammation, metabolism, macrophage autophagy, and ER stress. <br /> - ACE2 higher in adenocarcinoma compared to adjacent normal lung; ACE2 higher in COPD patients compared to normal. <br /> - Co-expression analysis identified genes important to viral entry such as RAB1A, ADAM10, HMGBs, and TLR3 to be associated with ACE2 in diseased lungs.<br /> - ACE2 expression could be potentially regulated by enzymes that modify histones, including HAT1, HDAC2, and KDM5B.

Limitations:<br /> - Not actual CoVID-19 patients with co-morbidities, so interpretations in this study need to be confirmed by analyzing upcoming transcriptomics from CoVID-19 patients having co-morbidity metadata. <br /> - As mentioned by authors, study does not look at diabetes and autoimmunity as risk factors in CoVID-19 patients due to lack of data; would be useful to extend such analyses to those datasets when available. <br /> - Co-expression analysis is perfunctory and needs validation-experiments especially in CoVID-19 lung samples to mean anything. <br /> - Epigenomic analyses are intriguing but incomplete, as existence of histone marks does not necessarily mean occupancy. Would be pertinent to check cell-line data (CCLE) or actual CoVID-19 patient samples to confirm ACE2 epigenetic control.

Importance/Relevance:<br /> - Study implies vulnerable populations have ACE2 upregulation that could promote CoVID-19 severity. Shows important data-mining strategy to find gene-networks associated with ACE2 upregulation in co-morbid patients. <br /> - Several of the genes co-upregulated with ACE2 in diseased lung might play an important role in CoVID-19 and can be preliminary targets for therapeutics.<br /> - If in silico findings hold true, epigenetic control of ACE2 expression could be a new target for CoVID-19 therapy with strategies such as KDM5 demethylases.

Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai.

On 2020-04-01 22:22:34, user Sui Huang wrote:

Nice, important work. Question: Mechanical ventilation has been associated with increase of ACE2 expression in the lung post-mortem. Do you find support for this previous finding in your data?

On 2020-03-30 11:14:51, user Mark Pepin, PhD wrote:

The statement claiming "positive effects" of ARBs on morbitity/mortality is invalid given the nature of their study design. It should claim association only.

On 2020-03-30 21:51:40, user Preci Genome wrote:

Digital PCR appears to be a very powerful tool to diagnose the infection of COVID-19.

On 2020-03-31 20:27:36, user Andrew Singer wrote:

Can the authors please check the validity of the first reference that is cited. It does not report SARS-CoV-2 in stool. It is a paper on: "Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids"

A second comment is that you state: 17 patients (23.29%) remained positive in feces after viral RNA was undetectable in respiratory tract, however, there were only 39 patients that initially tested positive for viral RNA in the stool, so it should be 17/39 (43.58%). Yes?

On 2020-03-31 22:30:20, user Aaron wrote:

While the author claims that "The data suggest that at least two strains of the 2020 SARS-CoV-2 virus have evolved during its migration from Mainland China to Europe", no such data is presented or referenced. The title of the piece should be changed to reflect that this is a hypothesis, not a finding established by any analysis found within the paper.

On 2020-04-02 09:24:44, user Ákos Török wrote:

What do you think about this? If we pool an aliquot of e.g. 5 samples (collect swabs from 5 different persons in the same tube with transfer medium.) then extract RNA, then pool 10 such RNA samples? This would result in 50X pooling.

On 2020-04-02 22:35:05, user Yuri Utsunomiya wrote:

The companion app to this manuscript can be accessed at: https://www.theguarani.com.br/<br /> The source code is available at: https://github.com/adamtait...

On 2020-04-27 17:01:13, user Paul Floto wrote:

It should be worthy of research to examine whether copper compounds are as toxic to the virus causing COVID-19 as they are to poliovirus. Since the toxicity level of copper to humans is already well established, if a lower level is effective against viral protease, then drug development could be quite rapid.

A letter that appeared online recently in the New England Journal of Medicine demonstrated that the COVID-19 virus had a shorter life span on a copper surface than on many other materials.

Since copper has an essential role in human health, it might be possible that the growth of the COVID-19 virus is impacted by the copper level in the host organism. Copper levels vary significantly by diet, and are significantly reduced by even small quantities of molybdenum in the diet.

Widely varying rates of infection and death might be explained by variation in typical copper levels in the diet which would influence serum level of copper in blood and tissue. Has any measurement of serum copper level been made in patients with differing response to COVID-19 infection?

On 2020-04-28 04:37:59, user Choplifter wrote:

I applaud the authors for publishing this study. It is not without its flaws, obviously you can pick apart whether the sample was reprsentative of the community given the limited way testing candidates were solicited, but it is important to get tests like this out to the public quickly rather than wait months to get statistically perfect data. I suspect the estimate of fatality rate they give is a little low, but the scale is consistent with similar studies out of NYC and elsewhere, all suggesting that the fatality rate from COVID-19 is far, far, far less than the terrifying 5% that continues to be touted on the CDC website and by people who support contined lockdowns. The real rate is likely well under 0.4%, making it worse then seasonal flu (even the historically virulent 2017-2018 flu season) but still orders of magnitude less than the 5% Armageddon numbers that were used to scare the public into accepting complete lockdowns and the widespread ruin to economies and livelihoods, that they caused.

On 2020-05-01 10:16:00, user mendel wrote:

The specificity trials on page 19 are not normal.<br /> 7 trials show 100%, with N=30,70,1102,300,311,500,99, sum 2412.<br /> The 6 remaining trials:

368/371 = 99.2% (97.7-99.8)<br /> 198/200 = 99.0% (96.4-99.9)<br /> 29/31 = 93.6% (78.6-99.2)<br /> 146/150 = 97.3% (93.3-99.3)<br /> 105/108 = 97.2% (92.1-99.4)<br /> 50/52 = 96.2% (86.8-99.5)

Pooling these, I get 896/912=98.3% (97.2-99.0).

"We use the pooled test performance based on the available information:<br /> Sensitivity: 82.8% (exact binomial 95CI 76.0-88.4%)<br /> Specificity: 99.5% (exact binomial 95CI 99.2-99.7%)"

There is no trial that has exactly 1 false positive. There are 3 <br /> trials that don’t have 99.5% in the 95% CI (4 trials if you include <br /> 1102/1102). There is no trial that falls inside the 99.2-99.7 range (one<br /> straddles it). The specifity range they’re using is an empty space <br /> between the values that the trials are actually at. This is not a normal distribution.

187 samples had loss of smell and taste in <br /> the past 2 months. This is a very specific indicator for Covid-19, ~70% <br /> of patients (well, 33,9–85,6%, depending on the study, e.g. <br /> Mons/Belgium, Heinsberg/Germany) have that, and I don’t think this kind <br /> of nerve affliction has been reported for any other common illness. Yet <br /> only 11% of these samples test positive. For the 59 more recent samples,<br /> it’s 22%.

This looks like the prevalence this study should have measured is <br /> 267/3330 = 8%, and the test failed to pick up on that. It would fail to <br /> pick up on recent infections, because they wouldn’t have seroconverted <br /> (created enough antibodies) yet, and it would fail to pick up on <br /> infections that happened too long ago (because the antibody levels would<br /> have fallen off below the sensitivity of this test). This study really <br /> needed a more sensitive test, like an ELISA, which is actually available<br /> at Standford, and is able to detect much lower levels of antibodies.

This kit has not been validated against people who had the infection a month ago.

The presence of false positives is an indication that cross-reativity <br /> with outher cold viruses exists. If you test a sample with few people <br /> who haven’t had a severe cold recently, which probably includes most <br /> samples taken of people who check into the hospital for elective <br /> surgery, or samples taken in the summer months, you get an optmistic <br /> sensitivity that does not apply to the general population in early <br /> spring.

The WHO Early investigation protocol (Unity protocol) for the <br /> investigation of population prevalence mandates the use of an ELISA <br /> test, or the freezing of samples until a time when such a test becomes <br /> available. The WHO does not endorse the use of lateral flow assays for <br /> this kind of testing.<br /> —-<br /> P.S.: No study that does not measure prevalence in the older <br /> population where the majority of deaths occurs should speak on fatality <br /> rates. This study had 2/167 positives in the age 65+ population, that’s <br /> 0.1-4.3% (95% CI), a 30-fold spread, and hardly a representative sample,<br /> since I don’t expect residents from care homes were able to attend the <br /> drive-through testing.

On 2020-05-07 03:35:17, user Mazyar Javid wrote:

I left a comment for the first version expressing my astonishment on how<br /> many seem to be obsessed with tearing this study apart and discrediting its<br /> findings altogether. I agree that the study has limitations (as a scientist and<br /> a peer reviewer, I am yet to see a “perfect” study). Nonetheless, the authors<br /> have made substantial attempts to address the limitations reasonably and adjust<br /> their results accordingly.

Since the publication of the original report, we have seen results of multiple<br /> serologic studies that have largely corroborated these findings: Studies in<br /> less affected areas (e.g. Czech Republic) which indicated very low prevalence<br /> of seropositiveness (effectively undermining the notion that most of positives<br /> in these studies are false positives, otherwise we would have seen similar<br /> relatively high prevalence of “positives” there too), to studies in heavily<br /> affected areas such as NYC which show higher prevalence but smaller ratio of<br /> seropositives to confirmed cases (due to higher frequency of testing).

The implications, that the IFR is significantly lower than what is publicly<br /> portrayed, and that in many areas, the prevalence is possibly much higher than<br /> can be practically managed with containment strategies, requiring other mitigation<br /> strategies with focus on vulnerable populations are enormous, yet I rarely see<br /> anyone among our decision makers taking any of these data into consideration<br /> despite all the claims that decisions are driven by nothing but “data”.

Somehow this reminds of Plato’s Allegory of the Cave: We saw the projections<br /> and took them as the reality, until one dared to escape and saw what really<br /> lied outside and came back to inform us of the findings, yet we, mesmerized by<br /> the shadows, could not believe it and rushed to chastise the messenger. So is our story, preferring model projections over actual data and getting upset when the latter does not support the former...

On 2020-04-29 17:12:43, user Deirdre wrote:

It isn't clear whether you are aiming to predict mortality or identify causal risk factors. There is a difference, they have distinct approaches. The title for the final figure is confusing, instead of "Survival by symptom onset", do you mean "Risk of mortality"? There are limitations in BMI as a proxy for total fat mass in elderly populations that may be underestimating the relationship of obesity, and is a notable limitation.

On 2020-05-01 00:11:26, user Dr. Amy wrote:

Most interesting differences from the Mexico cohort are that pregnancy is not a significant increased risk factor, and immunodeficiency isn’t specifically mentioned. Pretest probability (if you will) of obesity in U.K. 27.8%, 36.2% US, Mexico 32.4% so that could artificially lower comorbidity of obesity in U.K.

On 2020-05-05 17:25:01, user Hannah Sally wrote:

Are all patients included in the study, patients whom were admitted because of COVID-19 or does this cohort also include patients whom were admitted to hospital for other reasons but concurrently were diagnosed in hospital with COVID-19? I may have missed something, but not sure if this is clear in the methods. This could impact the overall hospital admission mortality statistic.

On 2020-04-30 04:10:22, user Tom Turek wrote:

So.. how much Vit D3 is good? To get the optimum blood level of Vit.D3 of 60nano gms/mL of blood,we need either 5 minutes of sun a side, between 10am and 2pm in the lower latitudes. Longer time for darker skins.. or supplement with 8000IU of D3/d, BUT at t his high dose´ also Vit. K2 to stop calcium pumping into artery walls. )Ignore the outdated, idiotic RDA of 800iu of D3.. and avoid the synthetic, toxic D2 in nearly all multis.

On 2020-04-30 13:54:19, user Charles R. Twardy wrote:

Nice. As A. Kumar notes in Twitter, this is productive engagement rather than just critique.

Note: The result in the abstract & discussion seems to combine two estimates from the results section: the [0.27%, 1.72%] unweighted estimate and the [0.49%, 3.21%] using the original authors' re-weighting. Not sure if this is copy/paste error or deliberately using widest range.

On 2020-04-30 16:31:03, user Dr SK Gupta wrote:

Authors have reported the high prevalence of Mycobacterium Tuberculosis infection in Covid19. Authors have tried to portray not only the Higher prevalence of MTBI but also more severe and rapid progression of disease. However, since their findings are not in tune with observational data on the subject all across the world. Rather corona infection has been found to be low in South East Asia, Africa and other places where the tuberculosis is rampant. Also burden of Covid-19 has been highest in United States and Europe where the prevalence of Tuberculosis is low.

These Observations have prompted the scientist to look for the role of BCG vaccination/ past TB infection in prophylaxis and treatment of Covid 19.

Authors have erroneously relied upon use of Interferon gamma release assay (IGRA) to diagnose MTB Infection using a kit X.DOT-TB kits (TB Healthcare, Foshan, China). Not much has been described in article about the methodology used in these kits, but as the name suggests probably it is T-spot test which measures the number of IFN-?-secreting T cells via an enzyme-linked immunospot (ELISPOT) assay.<br /> Two types of IGRAs available, the QuantiFERON-TB Gold In-Tube test and the T-SPOT.TB blood test. Though both these tests are approved by the Food and Drug Administration as indirect tests for TB infection (including active disease) when used in combination with other medical and diagnostic evaluations. Since aging leads to a decline in the strength of immune responses, it is also argued that these tests loose their sensitivity with advancing age.

Overall Interferon gamma release assay (IGRA) has a poor sensitivity and specificity for the diagnosis of Tuberculosis.<br /> In patients with Non Tuberculous Mycobacterial Disease specificity of only 74% for infection and a relatively high indeterminate rate was found for QuantiFERON®-TB Gold(QTF) test assay with a sensitivity of 81.7 %. Hence the test is not able to discriminate between tuberculosis(TB) and non-tuberculous mycobacterial (NTM) disease with high degree of specificity.

The problem gets compounded even more in countries like China and India where the prevalence of TB is high and use of Tuberculin Testing and BCG vaccination is a routine and such cases have all the likelihood of being labelled as positive despite no active disease.<br /> Contrary to current practice Authors have also not used the available gold standards to define active TB based on either a positive Mycobacterium culture or a positive TB polymerase chain reaction/Gene expert/CBNAAT.

Not only that present investigators have also not describe any base line x-ray lung findings like cavitation, fibro-infiltration, lymph node enlargement, Spirometry based poor Lung function suggestive of tuberculosis in patients with positive MTBI or active tubercular disease which may have contributed to the rapid progression of superimposed pneumonia of Covid 19 in these patients.

In Covid-19 disease pathogenesis initially it is the role of Innate immunity mediated by Neutrophils Macrophages which mount a protective response. In tuberculosis Cell mediated immunity or the adaptive immunity involving T cells and B cells is at work. This has prompted world scientists to look for the role of BCG in treatment and prophylaxis of Covid-19. BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS) (NCT04348370) in USA and Brace trial by an Australian University are such attempts.

The current study needs the support of larger data which doesnot seem to be coming from other countries like India where TB is rampant. Till now the observations don’t support the hypothesis of increased susceptibility of TB patients for Covid-19 nor are there any indicators of more severe/ rapid progression of disease in patients with TB infection.

Dr S K Gupta <br /> Senior Consultant Physician <br /> Secretary Community Health Care Foundation<br /> Dr Prabhat Prakash Gupta <br /> Dr Mrs Praveen Gupta

References:<br /> 1.Comparison of the Sensitivity of QuantiFERON-TB Gold In-Tube and T-SPOT.TB According to Patient Age Won Bae,Kyoung Un Park,Eun Young Song,Se Joong Kim,Yeon Joo Lee,Jong Sun Park,Young-ae Cho,Ho Il Yoon,Jae-Joon Yim,Choon-Taek Lee,Jae Ho Lee <br /> Published: June 3,216 https://doi.org/10.1371/jou...<br /> 2. Sensitivity of the QuantiFERON-TB Gold test in culture-verified NTM disease and TB in a Danish setting Thomas Stig Hermansen, Vibeke Østergaard Thomsen, Pernille Ravn <br /> European Respiratory Journal 2012 40: P426; DOI:<br /> 3. https://clinicaltrials.gov/...<br /> 4. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression Dan Zhou , Sheng-Ming Dai and Qiang Tong J Antimicrob Chemother<br /> doi:10.1093/jac/dkaa114<br /> 5. Covid-19 coronavirus pandemic. https://www.worldometers.in...<br /> 6. 1. Mehta P. Mc Auley DF, brown M et al. Covid-19, consider cytokine storm syndromes and immunosuppression. Lancet. 2020. doi.org/10.1016/S0140-6736(...

1. Roitt I, Brostoff J, Male D. Immunology (Fifth Edition). Philadelphia: Mosby; 1998. ?

2. Wang L, Cai Y, Cheng Q, Hu Y, Xiao H. Imbalance of Th1/ Th2 cytokines in patients with pulmonary ?tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi. 2002; 25 (9) : 535-537. ?

3. Collins FM. Cellular antimicrobial immunity. Crit Rev Microbiol. 1979;7:27–91. ?

4. Bretscher PA. An hypothesis to explain why cell-mediated immunity alone can contain infections by ?certain intracellular parasites and how immune class regulation of the response can be subverted. ?Immunol Cell Biol. 1992;70:343–351.

On 2020-05-01 01:23:45, user DAEYOUNG LIM wrote:

It's not clear how you did the following in your paper regarding the Google Mobility Reports data:<br /> "We aggregated these points to get a single mobility index per day for each trend chart."

On 2020-05-03 20:07:28, user PatriotsNE wrote:

This is the ONLY model 95% confidence interval gets SMALLER at one to three months out. You'd expect greater uncertainty for forecasts months out, but this model is the opposite (greater uncertainty in short-term, but less uncertainty in the long-term forecasts, with 100% certainty of zero cases in July.

On 2020-05-06 15:16:10, user Sinai Immunol Review Project wrote:

Summary: Using peripheral blood samples collected from 8 COVID-19 patients with moderate to severe acute respiratory distress syndrome (ARDS), the authors showed that COVID-19 patients exhibit lower CD3+ T cell counts as well as increased CD4:CD8 ratio. In addition to population analysis, PBMCs were stimulated with three pools of either overlapping peptides of SARS-CoV-2 spike (S) protein or HLA Class II or I predicted epitopes covering all viral proteins except S designed to activate CD4 and CD8 T cells, respectively. While stimulation of PBMCs with all three peptide pools led to detection and activation of SARS-CoV-2 specific CD4 and CD8 T cells, spike (S) peptide pool elicited the strongest response, indicating that the S surface glycoprotein is a strong inducer of both CD4 and CD8 T-cell responses. Phenotyping of activated T cells (CD4+CD69+CD137+ or CD8+CD69+CD137+) showed that the majority of activated CD4 T cells were central memory T-cells (CD45RA- and CCR7+) while activated CD8 T cells were mostly effector memory T cells (CCR7-) and terminally differentiated effector T cells. Cytokine analysis of cell culture supernatants from PBMCs stimulated by S-peptide pool led to a strong production of Th1 cytokines IFN?, TNF? and IL-2. Lastly, the authors profiled the kinetics of both humoral and cell-mediated response in four different time points using ELISA of virus-specific serum IgG and quantifying expression of cell surface markers induced by S peptide pool activation. Throughout the patients’ stay at the ICU, both levels of virus-specific IgG antibodies and frequencies of virus-specific CD4 cells increased significantly over time.

Limitations: A couple of additional assays done in parallel could have further strengthened the paper’s findings. Simultaneous profiling of cytokines from PBMCs could have easily answered whether these T cells which are capable of producing Th1 cytokines upon activation are indeed producing them in patients. Furthermore, it would have been informative to have added a couple of functional exhaustion markers (i.e. PD-1, Tim-3, etc.) and compare their expression between pre- and post-activation by S peptide pool—thereby addressing the effect of functional exhaustion in T cells reported in severe COVID-19 patients. Follow-up studies investigating which epitopes out of the S protein peptide pool elicited the most potent T-cell response would have yielded informative results for possible vaccine design efforts against the spike protein. Lastly, comparing the quality of virus specific T cells immunity between patients in ICU (the focus of the study) and patients with mild /moderate disease would have been very informative.

Significance of the finding: For the most part, the study design has been well established to answer the following questions: a) are there T cells reactive to spike (and other HLA-reactive) protein of SARS-CoV2 even in cases of COVID-19 with moderate to severe ARDS (which has been characterized with lymphopenia)? b) what are the phenotype and cytokine profile of CD4 and CD8 T cells upon activation? Answering these questions do advance the field’s understanding of T cell response to COVID-19 and add to much-needed effort to devise a vaccine against SARS-CoV2. Building on this article’s findings, perhaps future studies could perform mechanistic assays the function of T cells from COVID-19 patients in the context of systemic inflammation (i.e. adding IL-1, IL-6, TNF? in the culture media) as well as correlating epitope-specific immune response of patients with their clinical severity.

Review by Chang Moon as part of a project by students, postdocs and faculty at the<br /> Immunology Institute of the Icahn school of medicine, Mount Sinai.

On 2020-05-07 12:01:23, user Alex Cranberg wrote:

The authors’ conclusion about being far from herd immunity is based on the questionable assumption that the population is homogeneous. If population has variation in susceptibility herd immunity may be close or even reached. https://www.medrxiv.org/con...

On 2020-05-09 21:33:19, user christopher starling wrote:

What positive HCQ evidence does anyone have that provides usable scientific data and answers the same questions being asked here?

On 2020-05-12 20:31:26, user Erwan Gueguen wrote:

The methodology used raises several questions:

• Why were 6 patients with a negative PCR included in a study on Sars CoV2, which means we don't even know if they have the disease? They should have been excluded from the study.

• In Figure 1 describing the flowchart of the studied population, Patients were divided into 2 groups. A HCQ + AZI group (n = 45), and an "other regimen" group (n = 87). It is very strange to find in this "other regimen" group patients who have not all undergone the same treatment. For example, there are 9 patients who also took HCQ+AZ but for a shorter period of time before transfer to ICU or death, 14 patients who took lopinavir/ritonavir, and even 28 patients who took AZI alone. This group is therefore not a control group since patients who have taken the same drugs are in the two groups being compared.

• Following the description of these 2 groups, we discover figure 2 which compares not these 2 groups but 3 groups. The "other regimens" group was divided into 2 groups AZI (n=26) and SOC (n=61) (SOC = standard of care which includes no targeted therapy, or lopinavir/ritonavir or treatment received <48h until unfavorable outcome (transfer to ICU or death). Why 2 patients were removed from the AZI group? (figure 1 n=28, but n=26 in figure 2). Figures suggest that 2 patients from the AZI group were placed in the SOC group. This could change the statistical analysis of the data. It is essential that the authors clarify this point because the results are not publishable as they stand.

• Finally, table 1 shows 2 groups. Statistics are made on 2 groups but actually also on 3 groups for the therapeutic data (see table 2).

Conclusion: The study suffers from numerous methodological biases that make it difficult to interpret the data. The groups are not equivalent and the control group is made up of an agglomeration of patients who have undergone different treatments including HCQ+AZI treatment. It seems to me indispensable that the authors clarify the points raised before a submission to a peer-reviewed journal. I hope that the above comments will enable them to improve their study.

On 2020-05-13 14:21:49, user Sinai Immunol Review Project wrote:

Main Findings: <br /> Given the urgent need for diagnostic testing for COVID-19, this study uses enzyme-linked immunoabsorbent assay (ELISA) to measure serum antibody levels against recombinant spike protein ectodomain as well as its receptor binding domain (RBD) to angiotensin-converting enzyme (ACE2). Twenty RT-PCR confirmed COVID-19 patients as well as 99 healthy donors were tested for IgG titers in their serum. Antibodies to spike protein ectodomain were detected in 17 out of 20 patients, of which 5 showed borderline levels. 15 out of 20 patients tested positive for antibodies against spike RBD, of which 7 indicated borderline levels. These findings suggest that while majority of COVID-19 patients develop antibodies against the RBD, some patient responses may target other epitopes of the spike protein. Furthermore, they show that circulating antibody levels (ie: positive vs borderline) do not correlate with clinical severity or recovery from COVID-19. Strikingly, 1 patient who recovered did not have detectable IgG antibodies against RBD, suggesting a potential role of cellular immunity in the clinical resolution of COVID-19. In addition, they report that 4 out of 10 healthy donor serum collected since January 2020 tested positive. This indicates that apparently healthy individuals may be asymptomatic carriers, which underscores the importance of developing effective methods for community wide testing.

Limitations: <br /> The authors cite a study in their introduction that demonstrates minimal cross reactivity of antibodies between SARS-CoV and SARS-CoV-2 patients suggesting a specific antibody response for each disease. However, their study showed that five out of 89 serum samples collected from healthy donors between 2017 to 2019 tested positive for antibodies against spike protein ectodomain, and acknowledge a possible cross reactivity from prior exposure to other strains of coronavirus. This result also stands in contrast with other recent studies*. Understanding whether or not there is indeed such cross reactivity would be important for interpreting their results and designing vaccines against this specific virus. Furthermore, their thresholds for determining positivity versus borderline antibody levels are arbitrary and can significantly influence the outcome of their assay. It will be critical to obtain a larger cohort to further validate the robustness of their thresholds for determining circulating antibody levels.

Significance: <br /> This study establishes a straightforward assay in testing for circulating antibodies against spike protein in the serum of COVID-19 patients. This is important not only for surveying the population for people with immunity, but also improves sensitivity for diagnosis when combined with RT-PCR. In addition, their finding of a patient who recovered without detectable antibodies against spike protein RBD provides important insights to designing therapies for COVID-19.

Reviewed by Joel Kim as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

References:<br /> *Amanat, F., et al. A serological assay to detect SARS-CoV_2 seroconversion in humans. medRxiv preprint (2020)