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More on T Cells, Antibody Levels, and Our Ignorance

I wrote here about the reports of rather short antibody persistence in recovering coronavirus patients, and what’s been coming out in the two weeks since then has only made this issue more important. In that post, I was emphasizing that although we can measure antibody levels, we don’t know how well that correlates with exposure to the virus nor to later immunity from it, and that T cells are surely a big part of this picture that we don’t have much insight into.

This Twitter thread by Eric Topol is exactly what I mean, and this article that he references is an important read. Its schematic at right (see also here) will help make clear that antibody levels are only one aspect of the immune response to the infection – it’s an important one, but we’re making it look even more important than it is because it’s by far the easiest part of the process to measure. The T-cell response (much harder to get good data on) is known to be a key player in viral infections, and is also known to be highly variable, both between different types of pathogens and among individuals themselves. The latter variations are also beginning to be characterized among patients in the current pandemic. We have to get more data on it across a broader population of patients in order to make sense of what we’re seeing.

Many readers will have seen, for example, this new paper from The Lancet on a large study in Spain. Testing tens of thousands of people across the country continues to show that (on average) only about 5% of the population is seropositive (that is, has antibodies to the virus). There are a lot of interesting findings – such as rather large differences in those positive testing rates in different regions of the country, as well as the realization that at least one-third of the people who now test positive never showed any symptoms at all. But we are still not sure if this means that 95% of the Spanish population has never been exposed to the virus, because we don’t know how many people might have cleared it without raising enough of an antibody response to still be detectable. This paper does show that seroprevalence was about 90% in people 14 days after a positive PCR test, which indicates that most people do raise some sort of antibody response, but we don’t know how many of these people will still show such antibodies at later testing dates. Remember the paper discussed in that link in the first paragraph above, which found that 40% of asymptomatic patients went completely seronegative during their convalescence.

In other words, the Spanish survey may appear to show that 95% of the country has not yet been exposed to the coronavirus, but that’s almost certainly not true. The authors do mention that cellular immunity is important and not something that they were able to address, but the combination of that factor plus the apparent dropoff in antibody levels with time makes these large IgG surveys almost impossible to interpret. But note that if there are indeed many people who have been exposed but do not read out in such surveys, that we also have no idea how immune they are to further infection. At a minimum, you’d want to know antibody levels over time, T-cell response over time, and (importantly) what a protective profile looks like for both of those. We barely have insight into any of this: the large-scale data are just a snapshot of antibody levels, and that’s not enough.

We have similar data here in the US: several surveys of IgG antibodies show single-digit seroconversion. You could conclude that we have large numbers of people who have never been exposed – and indeed, the recent upswing in infections in many regions argues that there are plenty of such people out there. But we need to know more. We could have people who look vulnerable but aren’t – perhaps they show no antibodies, but still have a protective T-cell response. Or we could have people who look like they might be protected, but aren’t – perhaps they showed an antibody response many weeks ago that has now declined, and they don’t have protective levels of T-cells to back them up. Across the population, you can use the limited data we have and our limited understanding of it to argue for a uselessly broad range of outcomes. Things could be better than we thought, or worse, getting better or deteriorating in front of our eyes. We just don’t know, and we have to do better at figuring it out.

133 comments on “More on T Cells, Antibody Levels, and Our Ignorance”

  1. Daniel says:

    Why are T-cells harder to study than antibody levels? Do they require a BSL-3 level lab, or are the experiments just more complex/expensive?

    1. Laurent says:

      Yes, it’s much more difficult (but not impossible). Antibodies are relatively immutable proteins that are easy to target. A cell (of any type) is difficult to target, and targeting a specific t-cell is not fun. You also have to draw A LOT of blood if you’re looking for one specific t-cell.

    2. x says:

      The difference between detecting COVID antibodies and detecting T cells with an effective anti-COVID response is kind of like the difference between detecting guns and detecting assassins. One of these is relatively straightforward; the other one requires extensive investigation.

  2. Daniel says:

    Why are T-Cells harder to measure than antibodies? Do they require a BSL-3 lab or are the experiments just more expensive/complex?

    1. Patrick says:

      Antibodies are specific reactive proteins which interfere with the virus, generally by binding to it directly.

      The T cell response is much more varied, and does not include anything much you can extract and put in a tube and see what it does to viral particles. The T cell response does stuff like kill infected cells. It’s dramatically more subtle in its mechanisms than “this chemical gums up the virus”. And there’s also a memory component – where T cells can recognize past pathogens – which I believe does not always come in to play, and has the possibility of fading with time.

      So in essence, yeah, the experiments are harder, and I think in many cases can’t be done outside of a full human immune system (ie, a living person).

      1. Steve Scott says:

        B-cells are also important (shown in that complicated diagram Derek posted)
        “B lymphocytes are the cells of the immune system that make antibodies to invading pathogens like viruses. They form memory cells that remember the same pathogen for faster antibody production in future infections.”
        Some of the potential vaccines claim to stimulate T-Cell and B-Cell response as well as antibodies. One of them even claims to work on people already infected- (Developed by researchers at the Duke-NUS Medical School in Singapore.” Note that I use the word “claims.”

        “Most vaccines are purely preventive, but this vaccine may also be able to treat an active case of coronavirus, the scientists added.

        The vaccine activates “two arms of the immune system,” explained study author Dr. Eng Eong Ooi, deputy director of the Emerging Infectious Diseases Program at Duke-NUS Medical School in Singapore.

        One “arm,” Ooi explained, prevents a coronavirus infection by teaching the body to recognize the virus. The other kills off infected cells, preventing the illness from spreading within the body.

        “In preclinical studies, that’s come true—that we can develop both arms of the immune response against coronavirus,”

        1. Ross Hetzel says:

          Wait, do b-cells only form memory cells or do both t-cells and b-cells create memory cells? Are the memory cells then only a type of t-cell created by b-cells?

          1. Blake Gossard says:


            Resident Memory T Cells in Human Health and Disease
            Rachael A Clark
            Affiliations expand
            PMID: 25568072 PMCID: PMC4425129 DOI: 10.1126/scitranslmed.3010641
            Resident memory T cells are non-recirculating memory T cells that persist long-term in epithelial barrier tissues, including the gastrointestinal tract, lung, skin, and reproductive tract. Resident memory T cells persist in the absence of antigens, have impressive effector functions, and provide rapid on-site immune protection against known pathogens in peripheral tissues. A fundamentally distinct gene expression program differentiates resident memory T cells from circulating T cells. Although these cells likely evolved to provide rapid immune protection against pathogens, autoreactive, aberrantly activated, and malignant resident memory cells contribute to numerous human inflammatory diseases including mycosis fungoides and psoriasis. This review will discuss both the science and medicine of resident memory T cells, exploring how these cells contribute to healthy immune function and discussing what is known about how these cells contribute to human inflammatory and autoimmune diseases.

        2. Jonathan B says:

          The article says “So far, it appears this vaccine requires only one dose because it has a replicating effect that makes the vaccine “expand in the body,” Ooi explained. The vaccine will likely be the first of its kind to get this far in clinical trials if the trials proceed as expected.”

          Arnt Pfizer/BioNTech already testing a self-amplifying RNA vaccine candidate? What is unique/different about the NUS one that makes it “the first of its kind”??

          How long do RNA vaccines confer presentation of the antigen? As in, even with the self-amplifying/non-canonical base pairs how long does the template persist and do the cells express it for hours, days, or weeks? Would love to know how this compares with the antigen persistence of traditional subunit/vlp vaccines with adjuvant. Links to papers would be welcome

          1. A Nonny Mouse says:

            As mentioned previously, the Imperial vaccine (self replicating) will have a second dose given after 1 month, so it won’t replicate for that long.

            This is in the second week of testing, so there ought to have been 15 people dosed with 300 more to follow shortly.

        3. Steve Scott says:

          Update: (from Newsweek, on the Novavax vaccine that has now been awarded $1.6 billion by the US Govt., citing the Novavax CEO) “The Novavax vaccine will take a different approach from the others, focusing on boosting the body’s immune response by stimulating T helper cells and high levels of neutralizing antibodies.

          Whether this approach has an advantage compared with other companies’ vaccine candidates, which are solely focused on stimulating antibodies, has yet to be determined.

          “Nobody knows for sure,” Erck said Tuesday morning during a Squawk Box segment on CNBC. “It is hypothesized the T-cell response will augment what an antibody response is.” The vaccine’s success will be determined through the company’s clinical trials, he added.”

    2. Kendall Square is not square says:

      For a T cell read out looking for antigen-specific responses, you generally are going to run an ELISPOT or flow cytometry, both of which require cells from blood, whereas an antibody is just a protein, and antigen-specificity can be measured using a relatively simpler ELISA. T cells also only bind to antigens (peptides) when they’re presented on an MHC, unlike antibodies, which bind directly to the antigen. For the MHC presentation, antigen-presenting cells can be combined with pools of peptides that represent potential antigens. There are peptide-MHC tetramers (cell-free) that can be used in flow cytometry to look at binding to T cells, but you need to know what specific peptide sequences are relevant.

  3. Dixon says:

    And we’re putting all our vaccine eggs in the Spike antibody basket.

    1. Dr. Manhattan says:

      Most (but not all) of the vaccine candidates are in fact some variation of the “spike” S protein which enables cell attachment and infection by the virus. And yes, most studies are measuring antibody levels to the protein. But the use of the S protein does not preclude that you would also get a T-cell response to the S protein as well as neutralizing antibodies.

    2. Barry says:

      not exactly. Current vaccine approaches mean to elicit
      antibodies to Spike
      killer T-cell response to fragments of Spike as displayed on MHC

      1. splat says:

        I was vaccinated a week ago with a vaccine based on the very premise you mentioned.

        1. LA says:

          How/where were you able to get this? Clinical trial or … ?

          1. splat says:

            The underground railroad of vaccination. Made from reformulation of unproduced SARS and MERS vaccines that were never needed. Get a booster next week. A week after that ‘ll do an antibody test/assay.

  4. Tom Maguire says:

    Derek had a terrific article last May 21 describing how COVID-19 jams up the immune system by switching off the interferon response.

    Unless my searches have failed, the possible efficacy of interferon therapy has not garnered a follow-up post, although I have seen some early results published. Description and link here:

    Another open question raised by the astute commenters here (NOT by me!) is whether a person exposed to COVID while the interferon arm of their immune system is already active fighting a different infection (eg, a common cold) might result in a mild/asymptomatic case of COVID. Evidence might include the seemingly benign spread of COVID in homeless shelters, where co-infection seems likely.

    Co-infection as a defense strategy? The implications are vast – for starters, does that suggest that the ordinary fall cold/flu season will *mitigate* the spread of COVID? Should the young and healthy (again, not me) skip this years normal flu shot? And how would these hypotheses be tested?

    All above my pay grade. But not Derek’s!

    1. EJ says:

      In this political climate, discouraging *any* vaccine is dangerous.

      Which is really sad…

  5. dearieme says:

    I’ve formed the impression over the past few weeks that virology is not as advanced a science as, say, bacteriology. Such a sweeping statement is unlikely to be exactly, comprehensively true, but does it contain enough truth to be useful to a biological layman like me?

    I mean virology broadly: I accept that a novel virus causes novel problems that can’t be solved with the flick of a switch.

    Second question: wonderful as a well conducted RCT can be, what is a suitable role for old-fashioned clinical reports and observational studies in deciding on treatment options for patients? Surely there will be times when one won’t have the luxury of time to design RCTs, get “ethical” approval, and run them? What then?

    1. Calvin says:

      I see where you are coming from. While virology and microbiology might appear to be bed-fellows, they are actually very different. Virology is just different. Viruses live only to replicate. They, in themselves, do not do anything else. Disease caused by viruses is solely about the level to which they replicate. The presence of a virus is the diagnostic measure of disease. Bacteria are more subtle. You can have MRSA in your nose and it’s doing nothing.

      And then the other thing is that viruses are mysterious. Many of the proteins they encode for have no known function. Or at least we have no idea what they do. Take HCV. We have a very successful NS5a inhibitor on the market but we do not yet really understand what NS5a does, nor how the compound actually inhibits it.

      And they are hard to study. Getting them to replicate in vitro can be a challenge (COVID is not straightforward), and in vivo in animals it’s even harder. When a new virus appears we’re often starting virtually from scratch (not all the SARS CoV1 tools have been transferable).

      And of course, we’ve spent the last 20-30 years spending ever less on virology both in the academic sector and the industrial sector (outside of HIV and HCV). So the community is tiny (and I would say this is shared with microbiology). So right now our reservoir of experts is pretty small.

      So maybe not “less advanced” just “less well understood”

      1. Dr. Manhattan says:

        Just a few clarifying points to the above. There are viruses that live in us and do not cause outright disease or cause very mild diseases (adeno associated virus being an example). And yes, bacteria and viruses require different methodologies for study. ” Many of the proteins they (viruses) encode for have no known function.” Unfortunately that is true for bacteria as well. Depending on the bacterial genus, 30-50% of the genes are classified as “Open Reading Frames” for which no functions are as yet assigned. “So right now our reservoir of experts is pretty small.” Sadly true. I spent 14 years in academia and 26 years in industry on antibiotic R&D. I retire at the end of this month.

      2. Cjones1 says:

        The study of microphages is newer and likely underfunded.

        1. Phagers to stun says:

          As I understand it, and it;s not my field, a lot of work went into phages some decades ago (1950s?, 1960s?) in the Soviet Union and led nowhere, so it’s not new, just coming back into fashion.

          1. x says:

            Bacteriophage therapy was studied early in the 20th century but got knocked out by penicillin and sulfa in the 30s. After that, it continued to be studied in Russia, Georgia, and (IIRC) Poland. For approximately the past few decades, it’s been possible to buy phage preparations for common infections over the counter in those countries, and there are clinics that exist to provide targeted phage therapy for difficult infections.

            Whether any of that actually works is questionable. The science coming out of those countries is… disputable, and some of it seems more like self-promotion for the aforementioned clinics than real objective research.

            Nevertheless, the appearance of MDR bacteria has reinvigorated phage research in the West. There are several (a bit more than several, actually) case studies demonstrating excellent results, some demonstrating little or no efficacy, and a small number of randomized studies with mixed results. Phage treatments for non-medical use (e.g. spraying on produce) are already approved by the FDA. The major barriers to commercializing phage therapy are the difficulty of stabilizing viral cultures and inherent variability (phages mutate like any other virus), which the FDA is not really equipped with policy to handle. There’s also IP concerns but those seem to be more settled than not these days.

            In any case, bacteriophages attack bacteria, not viruses; AFAIK, there are no “viriophages”. So they would be useless against COVID.

    2. Alan Goldhammer says:

      Good observational studies are more difficult to do than RCTs. When I was at PhRMA back in the oughts we started a project to look at how this could be done better. We were able to get funding for a pilot project that stalled for a couple of years until the investigators decided to move it to an independent platform (the whole story is too long). It lives on as OHDSI and they spent a week back at the end of March trying to come up with some COVID-19 projects. They are have two big ones underway and are generating data. See: for more information.

      Most of the observational work that comes out in pre-prints have too few patients in the study and are near to worthless.

      1. dearieme says:

        My thanks to C, Dr M, and AG for those replies.

  6. Adrian says:

    Not related to this post, the linked study also contains interesting data on another topic:
    “chest computed tomography (CT) scans showed focal ground-glass opacities in 11 asymptomatic individuals (11/37, 29.7%) and stripe shadows and/or diffuse consolidation in ten individuals (10/37, 27.0%), whereas 16 individuals (16/37, 43.2%) had no abnormalities”

    It is an interesting data point that even the majority of asymptomatic individuals did have abnormalities in the lungs.

    1. Jason says:

      Isn’t this also true with certain other viruses? I recall reading a research study about individuals infected with H1N1 who had no visible symptoms but chest scans showed GGO, which slowly healed over time.

      1. confused says:

        Do you know where this was? Would be interesting to see.

        Was this the 2009 pandemic H1N1? If so, and if the effects are comparable, that might be pretty promising re: long term effects. Tons of people had it in 2009 (something like 60 million in the US) so I think we’d know by now if there was long-term lung damage in a significant proportion of them.

  7. gcc says:

    I really hope there are research groups working on measuring all of these things (levels of neutralizing antibodies, levels of non-neutralizing antibodies against various viral proteins, numbers of different types of T-cells directed against various viral proteins, etc.) in people who were infected and then testing those people regularly over time for re-infection. I’m not an immunologist, but it seems like establishing the correlates of protection based on natural infections would be really helpful in prioritizing vaccine candidates.

  8. myst_05 says:

    All these questions could be answered with a human challenge trial. Get recovered volunteers with various levels of antibodies and T-cells plus some unexposed volunteers as a control group, then get them infected with COVID and see what happens. This experiment should’ve been completed 3 months ago, but now is still not too late.

    1. Moses says:

      Most ethics boards would rule this out for the obvious reason: infecting people with a disease for which there is no cure is a bad idea.

      1. Will says:

        Challenge trials that have a well done consent process are eminently ethical. Standing in the way of them is far more unethical. People do far more dangerous things with little social benefit. Why stop them from doing this?

        1. EJ says:

          No one knows the long term effects, as spelled out in a previous post.

  9. Matt Gruner says:

    As far as I know testing T-cell activity requires at least 24 hours, BSL3 cell culture facility and a FACS sorter. Antibody testing can be performed in the clinic and take as little as 15 minutes using a lateral flow assay

  10. Marko says:

    “This paper does show that seroprevalence was about 90% in people 14 days after a positive PCR test, which indicates that most people do raise some sort of antibody response, but we don’t know how many of these people will still show such antibodies at later testing dates.”

    At later testing dates , perhaps , but for the purposes of this study , we do know that the vast majority (~90%) of PCR+ patients were seropositive fourteen or more days after PCR positivity , which means that the estimate of 5% cumulative exposure is likely very close to correct for the time period examined. In other words , if you were ever PCR+ , whether asymptomatic or not , you reliably showed up on the antibody survey as long as it was more than 14 days from the PCR test. The antibody survey also picked up positives in those patients who had previously tested negative by PCR , at a bit higher rate than in those who had never been PCR tested , which is what you’d expect ( i.e. some with symptoms get a PCR test that’s a false negative , which the antibody test later captures ).

    “In other words, the Spanish survey may appear to show that 95% of the country has not yet been exposed to the coronavirus, but that’s almost certainly not true. ”

    “Exposed” , I don’t know. I’m interested in “infected”. it appears to me that the Spanish serosurvey is in the right ballpark on the “infected” metric.

  11. Esteban says:

    The question of how many have been truly exposed is at the center of everything. I’ve no doubt mask wearing is better in the NYC metro than in many places, but I’d still think the curve there wouldn’t have remained as tamped down if only 20-25% had been exposed as suggested by the antibody studies. I’m more inclined to think that the virus has just run its course there and exposure is much higher than suggested by the antibody studies. This suggests that in perhaps 2 months it will be the same for Miami and Houston.

    1. Marko says:

      Since COVID-19 was recognized as a serious threat , most countries around the world have been operating under mitigation policies that have brought down the effective “R” from the initial high level of ~2-4 to something close to 1.0 , +/- a bit . If below 1 , caseloads have been dropping , if above , rising , but not at rates reflecting the original high “R”. These days , an estimated effective “R” of 1.2 for a given region would be considered bad.

      Taking R=1.2 as an example , 100 infected people would be expected to pass the infection on to 120 people in an unexposed population. In a population with 5% immunity , that figure would drop to .95 x 120 = 114 , i.e. still expanding , but not quite as fast. In a place like NYC , the figure would drop to .75 x 120 = 90 , meaning caseloads would be dropping.

      In other words , all other things equal , an immunity level of 20-25% vs one of only 0-5% makes it significantly easier to control outbreaks in the current “average” mitigation environment.

      1. Adrian says:

        The model behind your math assumes all people would have equal number of contacts, which is far from reality.

        If you take in NYC the 10% people with most contacts due to job or hobbies, I would expect the vast majority of them already had COVID-19.

        If past COVID-19 infection does create immunity, and if it lasts long enough, then NYC should be in a better position than what your math suggests.

        1. Marko says:

          I don’t disagree. My point was only to illustrate that a seemingly low immunity level of 20-25%, as in NYC ( and assuming that it’s an accurate measure ) would provide a significant benefit regarding ongoing infection dynamics relative to , say , states in the South that are currently experiencing outbreaks , where the baseline immunity was likely much lower.

          I still believe all or most of the 70-75% in NYC who presumably show no immunity are still at risk. Whether those who have been infected once are , or will be , susceptible to re-infection is an open question.

    2. Colleen Hackett says:

      Agreed. There are other ways to gather data on what percent of gen pop has been exposed / who made anti-body to covid indicating exposure such as re-running banked blood collected at blood banks or re-running routine lab work run on all PG women. For example, from March 22nd onward in NYC, all pregnant women coming to the hospital to deliver were covid tested to determine if they needed isolation. In other words a cross section of female population of NYC having in common only being of child bearing age were tested. This cross sample avoids skewing for only those who are ill or front line workers and provides gen pop data.

      The results of the NYC women in labor study: 16 % were covid positive, only 3% or so were symptomatic. That was late March. Perhaps if labs checked all of the serial blood work done on PG women throughout the course of their pre-natal care in every US city, we could see the map of when covid actually entered the US and how it picked up speed ( start in March and go back in time ) test: BHCG samples, glucose challenge samples, H/H, any amniotic fluid that may have been drawn for genetic testing.

  12. Phil says:

    Just a patent attorney, and the last biology class I had was in middle school, so not much experience here. I’ve read here and elsewhere about the T-cell response possibly being a factor, but how could that be interpreted in view of the relatively large number of seronegative samples? Aren’t T-cells part of the adaptive immune system? Is it possible that some component of the innate immune system is clearing the infection before seroconversion?

    Is that normal in a viral infection? Are there things we could be doing to boost the innate immune system? Is that even possible?

    1. PUI Prof says:

      No. The innate immune system by definition is the same from the day you are born for the rest of your life. With an asterisk in that most people will agree that elderly innate immunity doesn’t work as well.

      1. Marko says:

        There is evidence that it may be possible to enhance innate immunity with vaccines. BCG and polio vaccines have been proposed for COVID-19 on that basis.

        1. Colleen Hackett says:

          what about using the dengue vaccine in areas of the world like USA where dengue is rare.

  13. bacillus says:

    For the record, not a single vaccine has ever been approved based on a T-cell mediated immune readout, even when that is the mechanism by which the vaccine is known to work. Instead, people go out of their way to find vaccine generated antibodies against some part of the pathogen or its secreted products that happen to correlate well with the protective T cell response, but do not themselves play a major role in protection. We’ve been working on a vaccine against an intracellular bacterium for well nigh 2 decades now. We know how to produce it at scale, lyophilize it for long-term storage, the immune responses it generates etc. However, since day 1 we’ve been looking for a good cell- or antibody- mediated correlate of protection and still keep coming up empty. What we really need is to try to produce a vaccine lot that doesn’t work then compare the immune responses in various animal models immunized with an effective formulation of the vaccine. However, trying to make a dud version of a vaccine is very hard indeed.

  14. T-cells and Antibodies – it’s a perpetual question. There’s no question that (CD8+, MHC Class-I restricted) T-cells provide long-lasting (10s of years) protection against viral disease; EBV may be the classic example. On the other hand, those of us who were vaccinated against smallpox as children have measurable antibody titres even now (in my case, 50 years later). Many people know this, but fewer appreciate that these CD8 cells keep the virally-infected cells locked up and contained, and this may not necessarily mean that all the viral particles are eliminated. It’s interesting to speculate that, in the absence of a viral depot, such as we see with EBV and B-cells, it is indeed antibodies that provide “long-term” protection.

    Does anyone know if there are data on CD4 or CD8 exhaustion markers in CoV-2 disease?

    Then there’s the question of whether many people failed to appreciate that, because T-cells are by design promiscuous in their affections, individuals who have previously mounted an effective response to similar coronaviruses may well be two streets ahead and round the corner when it comes to responding to CoV-2 [See: PMID 92520].

    So, the controversies surrounding effective T-cell and B-cell epitopes for CoV-2 vaccination, whether the PCR test detects non-infectious viral nucleic acid fragments and not only intact viral genome, and whether some people may have pre-existing T or B cell immunity, aren’t going to go away soon [See: Well, not until 11-04-20.. 😉


  15. nobody says:

    The underlying trend, however, is that the blanket under which meaningful population-level immunity to reinfection could possibly be hiding keeps shrinking. If the area where the effect you want could be hiding in the data keeps shrinking, it’s usually in indication that the effect you want isn’t there.

    It does look like grasping at straws to think that there’s a hidden immune response that changes the picture from what antibody persistence studies suggest, specifically that SARS-CoV-2 can reinfect people every few months until it eventually kills them.

    The shift in messaging among mass-media talking heads with ties to government and industry to talk down expectations about vaccine efficacy (sub-50% is the current talking point) and start talking up mAbs again suggests that early vaccination results aren’t too promising, either.

    SARS-CoV-2 is so heavily evolved to kill humans that it’s not going to give us any victories.

    It’s very hard to see how this pandemic doesn’t end with complete economic collapse followed by a mass die off.

    1. Adrian says:

      Right now the situation is pretty bleak only in the Americas, but this can change quickly.
      It would not be a surprise if by late October the US economy would already be in a strong recovery.

      Most countries in Oceania and East Asia and Southeast Asia have already scored victories against COVID-19.

      Poor countries like Vietnam or Thailand have scored victories against COVID-19.

    2. Derek Lowe says:

      This is an odd thing to say, given that I haven’t seen any reports of confirmed reinfection. And the virus is not evolved to kill humans, since it’s just recently started infecting us.

    3. confused says:

      This seems really excessively pessimistic to the point of completely unrealistic.

      >>specifically that SARS-CoV-2 can reinfect people every few months until it eventually kills them.

      This seems very unlikely, for two reasons.

      – Presumably duration of protection would have some variation, not just turn off for everyone at the same exact time. So if the *usual* duration of protection was only a few months, we should expect to see rather a lot of reinfections in the US and Europe. We don’t observe this.

      (There probably will be a few reinfections, not everyone gets immunity even with diseases that *normally* grant it. I had chickenpox twice, personally.)

      – Losing (complete) immunity isn’t incompatible with retaining some protection, i.e. disease is less severe next time.

      >>talk down expectations about vaccine efficacy (sub-50% is the current talking point)

      Flu vaccines are often about that range. And that’s enough to help a lot.

      And less than 50% of what? If it “only” reduces your chance of *catching* the disease by, say, 40%, but makes it much less likely to progress to hospitalization/ICU/death if you do get it (comparable to flu vaccine) … well, that would probably drop the severity of COVID into the “normal respiratory illness” range, assuming most people were vaccinated.

      >>SARS-CoV-2 is so heavily evolved to kill humans

      No, it isn’t! This virus is very new to human populations, and viruses don’t “evolve to kill humans” – that is, there is not a selective advantage in killing more people.

      Nor is SARS-CoV-2 that deadly *in absolute terms*. It’s terrifying now because we (at least in the US, etc.) have pretty effectively gotten rid of the incredibly lethal stuff – smallpox is eradicated, yellow fever is no longer present here, rabies and bubonic plague are now very rare, Ebola never got a foothold here, we have quite effective treatments for HIV, etc.

      >>It’s very hard to see how this pandemic doesn’t end with complete economic collapse followed by a mass die off.

      That will not happen. People adapt pretty quickly to new situations; sooner or later the fear of COVID will recede, even if the actual risk doesn’t decrease much. So economic damage from fear will rapidly decline.

      *Direct* economic damage (from death and sickness in the workforce) will not be that destructive… COVID is far deadlier in the retirement-age population than in the workforce, and most mild cases recover relatively quickly.

    4. Charles H. says:

      Just a nitpick, but COVID isn’t evolved to kill humans, but rather to successfully reproduce. That some humans die in the process is an inconvenient side effect. (If they didn’t die, the reaction against it would be weaker, so it would spread more successfully.) In the ideal case, from its point of view, humans would only have a mild reaction, and the human immune system would pretty much ignore it, so it could go on spreading for years from any one individual.

  16. immune says:

    If the loss of detectable circulating antibodies is a fairly widespread feature in infected individuals and this loss of antibodies leads to susceptibility to reinfection wouldn’t we have expected to see more verified cases of reinfection?

    There have been over 10 million infections worldwide and little evidence for bona fide reinfection. This lack of reinfection in the short term seems to suggest some mechanism for longer term protection even in the absence of neutralizing antibodies.

    1. Antibody guy says:

      Memory B cells persist for decades.

  17. Lane Simonian says:

    One potentially important element is that T cells are damaged/disabled in some oxidative/inflammatory diseases. If that is the case with this novel coronavirus then certain anti-oxidants/anti-inflammatories would somewhat paradoxically have an anti-viral effect.

    There are a number of anti-oxidant/anti-inflammatory clinical trials being conducted against this virus. The results so far have been rather muddled. In the case of artemisinin little beneficially response was noted except for when combined with coffee (a lot to probably untangle there).

    Another clinical trial involves the combination of artemisinin and curcumin. In this case, curcumin might be worth are time. The advantages of the addition of curcumin for the treatment of the novel coronavirus may be the following.

    Inhibits Angiotensin II receptor activity
    Increases Angiotensin coverting enzyme II protein expression
    Inhibits Nuclear Factor-kappa B activity
    Increases T-cell levels under conditions of oxidative stress

    If T Cell levels are already low due to age and/or comorbities, an approach like this might be worthy of consideration and exploration.

  18. bacillus says:

    It could just be that innate anti-viral immunity decreases the viral burden to a level that isn’t then sufficient to trigger an adaptive antibody (or T cell) response . If this is the case, then SARs2 is essentially a commensal virus with an ability to act as an opportunistic pathogen in certain populations.

    1. Marko says:

      You may be right. New paper in Cell :

      “…SARS-CoV-2-reactive antibodies could be isolated from three SARS-CoV-2- naïve individuals, although these antibodies were only weakly binding (Wec et al., 2020b). Whether the observation of such antibodies is a consequence of prior exposure to other human coronaviruses, as has been suggested for SARS-CoV-2-reactive T cells from healthy donors (Braun et al., 2020; Grifoni et al., 2020), and whether such antibodies and cells can provide background immunity remains to be elucidated. Importantly, our deep sequencing analysis of the naïve B cell receptor repertoires of 48 individuals sampled before the pandemic identified potential heavy and/or light chain precursors of potent SARS-CoV-2-neutralizing antibodies in every single individual. In addition to the limited mutation rate and broad usage of antibody gene segments across potent SARS-CoV-2-neutralizing antibodies, these results suggest that protective antibodies can be widely and readily induced by vaccination. “

  19. Innate says:

    T-Cells and antibodies aren’t the end of the story, either. The body has other ways of dealing with SARS-CoV2. Alpha-1 Antitrypsin, naturally present in the lungs, inhibits SARS-CoV2.

  20. MStriker says:

    Just to toss an added complication in (based on my experience with psych meds):

    Some people may express ACE2 differently than most, using it in a different role than “immune response in” the tissues it usually apears in/on. (I’m not saying this has high likelihood, but this may explain some of the “no response” results. Their systems aren’t vulnerable in the same way. Kind of like the anti-malarial effect of being a sickle cell carrier.)

    By comparison, my body apparently uses dopamine in neural feedback to/from organs. Welbutrin, an SNRI with SDRI interactions, killed my lower GI feedback. I had no pain from my lower GI, even when hit with nauseating levels of something (sudden pervasive nausea and faint rippling cold hints, but no pain). And I could not force activity, unlike usual. Another SNRI (Effexor generic) did not have that effect. Nor did Prozac or Paxil (SSRIs).

  21. steve says:

    It’s pretty clear that most commentators on this thread aren’t immunologists. Yes the cellular immune response could dominate but I don’t know of any viral disease that is so completely controlled by cellular immunity that people totally fail to make antibodies. The relative contribution of the two arms can be debated but cellular immunity to a respiratory virus in the complete absence of any humoral immunity? I can’t think of any examples.

    1. Steve – if you’re still reading – Does that mean, where covid-specific t cell responses were detected but no covid-specific antibodies found, that there would’ve most likely _been_ an antibody response which simply wasn’t detected? (e.g. not many made in the first place, timescale meant they’d disappeared before the test, false negative?)

  22. Geff says:

    The question worth finding the answer to has always seemed to me – why were the number of fatalities on the diamond princess so low? Let me assume everyone on that ship was exposed to the virus, there was obviously something non obvious going on.

    It seems like finally, the voices of some decent immunologists seem to be cutting through and getting to the bottom of this. I think a lot of scientists have really let personal panic cloud judgment in public proclamations and interpretation of studies in biased ways. Even today we have the royal society advocating face coverings for everyone – an impractical suggestion extrapolated from weak data. Maybe they should start reading cell instead of nature down at st. James’s

    1. Adrian says:

      The Diamond Princess numbers were not that low.

      Wikipedia says:
      Deaths: 14
      The median age of the crew was 36 while the median age of the passengers was 69.
      Of the 712 infections, 145 occurred in crew and 567 occurred in passengers.

      All 14 deaths were among passengers, 2.5% of infections among passengers were fatal.
      This is low for their age group, but keep in mind that old people on a cruise ship are not poor and also much healthier than people their age who are living in retirement homes.

      1. Geff says:

        Sorry, They were low.

        There were 3,711 people on the ship and 14 died.

        There were 712 infections as measured by pcr. That is not the whole story. Its a highly contagious respiratory disease and that is getting everywhere on that ship.

        We have subsequently pushed the world economy off a cliff. Is that proportionate?

        Might be worth reading some of the cell papers the immunology story is getting interesting.

        1. Adrian says:

          What you are writing is a conspiracy theory.

          There might have been undetected cases on the ship, but claiming everyone must have been infected is not a realistic assumption.

          1. Geff says:

            Interesting that scientific hypotheses are thrown away with conspiracy theory tags these days if they don’t fit a specific veiwpoint.

            Also interesting It comes up in a High level discussion thread about the possibility of hidden immunity through t cell response that otherwise can’t be detected.

            I worry Immensely about the level of scientific discourse around covid 19.

          2. Adrian says:

            You are claiming something would be true that likely isn’t, and then argue based on that.

            With “That is not the whole story. Its a highly contagious respiratory disease and that is getting everywhere on that ship.” you are claiming that all people on the ship must have been infected, and this is the basis for your “there was obviously something non obvious going on”.

            After the outbreak was detected passengers were confined to their cabins.
            Your “everywhere” claim is not true based on what is known, 20% infections is plausible and estimates are that there might have been less than 100 infections had the ship been evacuated when the first infection was detected.

            COVID-19 is a highly contagious respiratory disease and spreads quickly on a cruise ship, but quickly does not imply “everywhere” or “everyone” or even “everyone immediately”.

          3. Geff says:

            Sorry Adrian, i don’t think you understand the immunology discussion in this blogpost well enough to comment in the confident manner you are doing so.

          4. matt says:

            Geff, are you sure you aren’t projecting?

            Your statements don’t betray a great wealth of immunology knowledge, either. I think Adrian accurately characterized the limitation of your train of thought: ignoring the actual isolation and removal of sick patients on the cruise ship and shelter-in-room orders, which likely made your assumption of universal exposure invalid.

        2. Riah says:

          Geoff, this might go some way to answering your point. Fits in with the infection pattern aboard the ship:
          Cross-reactive SARS-2 T cell epitopes revealed pre-existing T cell responses in, wait for it, 81% of unexposed individuals! The other really interesting thing is that the more severe cases of COVID-19 they looked at showed a higher level of AB response, whereas diversity and intensity of T-cell responses was associated with milder symptoms of COVID-19 ( and little or no AB response). Does this mean the T cell responses is way more important than the AB response in CoVID??? This is only a pre print but the implications are enormous – do you agree? Makes some sense given that AB’s are useless against pathogens inside cells. Only T-cells can detect those – via the MHC’s.
          A British/Scottish coy is actually trying to use a TCell approach here :
          Interesting one to watch…

  23. DTX says:

    dearieme questioned how little we know about viruses versus bacteria. One aspect of this is how they cause morbidity. With bacteria, we usually know: they usually secrete a toxin.

    In contrast, it’s often unknown how viruses kill. We know they need to be able to replicate in humans and avoid the immune system, but the mechanism of how they actually cause death often isn’t known.

    Around 10 years ago, I remember reading a commentary by one of world’s top flu experts who noted he knew much more about flu 20 years ago. His point was previously, we had thought of the flu virus as much more simple than it really is.

    E.g., we don’t know why the H5N1 strain of flu kills ~60% of its victims. You can read lots of speculation as to why. In contrast, lethality of botulinum and tetanus are well understood, down to the molecular mechanisms of action of their toxins. These mechanisms were known at least 30 years ago.

    (articles on H5N1 will give differing theories on how it causes death with caveats of: “likely” “probably” “is in part due to” “might arise from many different mechanisms”. A few are more definitive than others, but the definitive studies contradict each other. If there is a “definitive” one, I’d love to read it.)

    1. Agda says:

      Very interesting, maybe we know more about the course of disease caused by non (or rarely lethal) viruses?

  24. rtah100 says:

    @ Geff, I don’t follow your logic. What is the link between the Diamond Princess outbreak and the low number of fatalities and the Royal Society advocating for masks?

    Masks are cheap and simple to use and public masking is an easily audited and enforced requirement. For any level of transmission risk and susceptibility, universal masking will reduce the likelihood of infection to near zero.

    Why in the world would we not advocate for masks, while we wait for the elegant retrospective studies and their confirmative prospective RCT’s on the Diamond Princess phenomenon?

    1. Adrian says:

      Based on the limited data available, the ineffective scarf/shirt masks used in many places let half the virus through. Your claim they would “reduce the likelihood of infection to near zero” is absurd.

      People who think they could reduce social distancing because they are wearing a mask are a public health risk.

      1. steve says:

        Adrian – You totally and completely misunderstand the entire purpose of wearing a mask. It’s not to protect you from the virus it’s to protect others from aerosols you emit. This virus is spread by asymptomatic individuals who aren’t even aware they’re infected. It’s spread by aerosols. Wearing a mask – even a simple one – greatly reduces the aerosols people emit. If everyone wore them here we’d have the levels of transmission like they do in Asia rather than having the worst record of virtually every other country on earth.

        1. Adrian says:

          I do know the difference between a surgical mask and a respirator.

          “greatly reduces” seems to be “halves” for scarf/shirt masks.
          Which is better than nothing.
          But it means it only doubles the contact duration necessary for the same likelihood of infection.

          People in Asia are wearing surgical masks, they let only 10% of the virus through instead of 50% when using only a scarf/shirt mask.

          I live in a country where the infection numbers went to near zero despite noone wearing a mask (Finland), which disproves claims masks would be necessary. I have never seen a supermarket employee wearing a mask.

          If you are wearing a mask while maintaining maximum social distancing, I do see the point that it can be helpful as an additional measure.
          If you have stupid idiots who are reducing social distancing because they are wearing a scarf mask, the overall effects of masks might be negative.

          1. steve says:

            Again, nonsense. Sorry but the science is clear.

          2. Adrian says:

            The nonsense is actually your “science” that is clear rubbish. Your “science” is “After April 3, the only difference in the regulatory measures between NYC and the United States lies in face covering on April 17 in NYC.” And then they argue that decreasing numbers in NYC compared to stable numbers in the US excluding NYC proves that masks are necessary.
            Maryland made masks mandatory at the same time as NYC (this is the same regulatory measure), and their numbers did not decrease.
            This “sound science” you are quoting conveniently presents only examples that support its conclusion.

            I am living in a country that has defeated COVID-19 without masks.
            This always makes me a bit itchy when “scientists” make claims that are contradicted by the facts I am seeing first-hand.

          3. Barry says:

            Finns raised Social Distancing to a cultural norm long, long before Covid19. Masks are unnecessary where people don’t meet. That’s a poor model for the rest of the world

          4. Adrian says:

            It is true that the Finnish mentality is helpful in the current situation, but your stereotypical description of Finns is not literally true.

            When you are saying “Masks are unnecessary where people don’t meet” this is not really different from my “stupid idiots who are reducing social distancing because they are wearing a scarf mask” – masks might be an inferior option when social distancing is not possible, they are not a replacement for social distancing.

          5. steve says:

            Adrian’s right – we should ignore scientists and just believe our anecdotal evidence. All those silly scientists who say the earth revolves around the sun are clearly wrong – believe your eyes that it’s the sun that revolves around the earth. The earth is round? Ridiculous! Your own eyes show that it’s flat. A publication in PNAS that shows that wearing masks is the single most effective means of prevention of transmission? Rubbish! I know better! Why? Because I said so! So sad that a discussion in Science of all places comes down to such denial of what science is all about.

          6. Adrian says:

            It is not science to treat one single article published as gospel.

            Maryland did not see a decrease in numbers despite making masks mandatory at the same time as NYC, Finland never had mask usage but numbers went down quickly.

            Their claim “the only difference in the regulatory measures between NYC and the United States lies in face covering on April 17 in NYC” is rubbish, Maryland added face covering at the same time but in their number they are counting the not decreasing numbers in Maryland into their non-mask-using control group.

            It is not science when they selectively pick the evidence that might support their theory, while ignoring all contradictory evidence.

          7. steve says:

            I posted multiple articles below. What’s not right is to deny science because you live in a small, sparsely populated country that was able to shut everything down, seal its borders and reduce COVID transmission. It’s just stupid to say that masks don’t work based on that. Read and learn something before spouting off.

      2. Russ says:

        You have it exactly backwards; masks protect the wearer, not others.

        1. steve says:

          No, you have it backwards. The purpose of universal masks is NOT to protect the wearer. Read the PNAS article I posted, listen to Fauci, read any of a hundred articles about it. The idea is to prevent emission of aerosols from you, not your inhalation of virus. If everyone wore them then the pandemic would be stopped in its tracks as it has in most Asian country where mask wearing in public is routine.

          1. steve says:

            And I’m afraid that Adrian has no clue either. The science is clear, and just yelling “rubbish” doesn’t change it. That’s just not how science is done I’m afraid.

          2. Charles H. says:

            IIUC, ordinary masks are much more effective on particulates (fomites) than on aerosols. They’re still slightly effective on aerosols, but a whole lot less.

            OTOH, they’re still arguing about what the principle means of transmission is. WHO has been reluctant to include aerosols without good evidence, and they rate the existing evidence as only suggestive. I, personally, a programmer and not a medic, rate aerosols as the major mode of transmission, noting that they are often accompanied by larger particles. I base this on a model which says the stuff needs to get down into the lungs to be very contagious. I could be wrong, but to me it looks consistent with the evidence I’ve seen.

            So. Masks are still a good step, but unless you run everything you breathe through a tight filter, you still need social distancing. But masks plus moderate (5-6 feet) social distancing may well be enough to take R well below 0.9.

        2. matt says:

          Problems with this twelve-year-old study: they used particle sizes of 0.02 to 1 microns, which are 1/100 to 2/5ths the size of droplets which are now considered to be the small end of the respiratory droplets carrying infectious doses of SARS-CoV-2. There are arguments about whether 2.5 micron particles have caused some transmission, or whether it’s 10 microns plus, but I think most epidemiologists have concluded if the particle sizes are smaller than 2.5 microns, many many more people would be getting infected, including those we have tested in contact-tracing situations. Those smaller particles can float in the air much longer, which would be seen epidemiologically with infections in people who just happened to wander through an area where an infected person had been. As I understand it, the opposite is true: people actually have to share the space for a good amount of time before the infection risk goes up. Hence the conclusion that larger particle sizes are the ones responsible for transmitting COVID-19.

          Second problem: they modeled a world in which those too-small particles were uniformly present everywhere. They burned candles in the room to generate large quantities of particles. This is fine if you want to model, say, an indoor political rally or sporting event where everybody is shouting for hours in a closed space, and see which masks might save you. But less applicable to shorter duration interactions which would be more typical of people who are trying to follow health guidelines.

          Third problem: for outward protection, they measured right next to the outward side of the mask. That test is fine when you are concerned about whether there are leaks around the mask, as you might for an N95 mask. But it “masks” the benefit of outgoing protection for non-close contact: the particles, especially in the size range considered applicable for SARS-CoV-2, are not jetting forward, but stay largely in the vicinity of the mask wearer.

          You wear a mask, your funk stays around you. They wear a mask, their funk stays around them. You stay six feet away from them, your funk and their funk don’t mix, and transmission does not occur. Even though your mask is only moderately effective.

          This study captures the basic assumptions health authorities were making in January when they said masks weren’t worthwhile for the general public. But since then, a lot more attention has been paid to the subtleties (read “oversimplifications and assumptions”) of the test setup versus real-life situations. There are country wide indications that cloth masks can be effective (Austria, Czech Republic, Slovakia, Japan, Hong Kong), as well as individual hospitals in the US which saw reductions by mandating cloth masks for all personnel not wearing the higher grade masks.

          And yes, Adrian, I get it, in your country masks were not necessary. That’s great–no one said they were an absolutely necessary ingredient in all situations. There are lots of ways you could avoid using them: shut down all inter-border travel, test vigorously, and isolate, contact-trace, and retest vigorously, as an example. Quite a few countries did that. Unfortunately, for the US, that horse left the barn months ago. So did extensive enforced or even voluntary social-distancing, politically speaking. So we get to sit in the dunce’s chair, and in this situation, masks are one of the few critically important measures that are in reach.

          1. Adrian says:

            When it comes to closing external borders, the US government was actually acting more swiftly than European governments.

            Initially tests were few and testing was very restricted here in Finland, even nurses with symptoms had problems getting tested – people with symptoms were just told to stay at home for 14 days.
            Some employers had their staff tested by a private healthcare provider, who shipped the samples to a laboratory in South Korea.
            When the government finally ramped up testing and offered low-threshold testing in late April, infections had already decreased so much that they never managed to find enough people to test for reaching testing capacity.

            Last month California made masks mandatory and reopened nightclubs.
            Why is are the Democrats thinking that masks would be more important than social distancing?

  25. steve says:

    Hi Guys – Immunologist here again. To answer DTX and others, yes we know a great deal about viruses and the defenses against them. No, they don’t secrete toxins like bacteria; it’s generally the immune system that kills with viremia, not the viruses themselves. In COVID-19 it’s the florid inflammatory response that is fatal. For some this results in a system-wide coagulopathy. Immunity is a double-edged sword. Early in the disease it inhibits viremia, later in the course of the disease it kills. This is why dexamethasone given at the appropriate time saves lives. Give it too early and the virus replicates uncontrolled but give it later it can reduce the harmful inflammation. Ultimately what’s needed is a combination of an effective anti-viral together with an effective anti-inflammatory.

  26. Adrian says:

    Some outcomes can be excluded based on available data points.
    The US and France each had 1000 infections on an aircraft carrier.
    Nearly everyone on these ships is under 50, median age perhaps 30.
    General health likely above-average for their age groups.
    Hospitalization rate among infected people was 1-2%.
    Half of confirmed cases were asymptomatic.
    In the French case half the people on board tested positive, more than 75% asymptomatic would be mathematically impossible.

    The infections were 3 months ago, is anyone researching antibody persistence of recovered coronavirus patients in these groups?

  27. Joe B. says:

    Do the complications of (for the sake of argument) short-lived antibody response, cell-mediated response, and minimally-symptomatic or asymptomatic infection affect how you design a vaccine trial? Are there any insurmountable obstacles foreseen?

  28. David says:

    Yo, Adrian – ” is anyone researching antibody persistence of recovered coronavirus patients in these groups?”

    MMWR Morbidity Mortality Weekly Report 2020 Jun 12;69(23):714-721.

    sorry about the pun.

    1. Adrian says:

      If I am reading this correctly, in a group of young healthy adults 90% had antibodies 2-3 weeks after a positive PCR test.

  29. steve says:

    It’s really sad to have to post this in a forum like this one; if scientifically literate people don’t understand science then there’s little hope for the general public. Still, for those who eschew ideology and want to actually understand the science behind wearing masks these links may be useful. Note that they are from journals like Lancet, PNAS, Science, etc. Of course, some people will never be convinced by science but at least scientists should be.

  30. Ben says:

    What about memory B cells? Isn’t it true that even if the number of antibodies declines, memory B cells can produce them again in a future encounter with the same pathogen? Wouldn’t that mean that a current level of antibodies is not very important?

    1. Riah says:

      Hi Ben. Just picking up your very relevant question ( I always seem to dip into Derek’s great blogs too late 🙄). My understanding is that after differentiating (post encounter with antigen), B memory cells do the rounds circulating, but B plasma cells spew out antibodies for a few weeks then go and hide away in the bone marrow where they go into a sort of hibernation mode, ready to resurrect and go into AB production mode at a later date if and when the antigen returns. If that’s right then why the fuss that circulating AB levels reduce? Can’t this be tested by introducing say S protein( or other SARS-2 antigen) into some of these people who are no longer showing AB’s and seeing if AB production is then ramped up v quickly. If that happens, that means the plasma cells are still doing their job (given naive individuals will take much longer – over 5/7 days -to mount an AB response. Don’t understand why nobody is doing this challenge test. Anyone please correct me if my understanding is not quite right – I’ve still on L plates for immunology.

  31. Anon says:

    A big hydroxychloroquine study came out saying that it cuts deaths by about half. I wonder how many people had to die so arrogant liberal ” scientists ” could take a self serving sh** on the us president??

    1. Anon2 says:

      Not everyone here, and certainly not everyone in clinical trials is concerned with internal US politics. There is a whole other world out there, you know? Most of us arrogant, liberal “scientists” are just motivated to figure out what is going on and how we can improve things. Would you care to share this big study that shows HCQ cuts covid19 deaths in half? Because I can’t find it. And if data emerges that conclusively shows superiority of HCQ, then most certainly any decent scientist would follow that data. I yet have to see it.

      1. matt says:

        Not affiliated with the original poster, but here’s the paper, it’s an interesting non-randomized retrospective, but they did do a propensity-score-matched subset.

        1. steve says:

          There are multiple issues with that paper. For one thing, there is disproportionate use of steroids in the arm that got HCQ making it impossible to distinguish if it was HCQ causing the improvement or steroid use (which has independently been demonstrated to work). EVERY other clinical trial of HCQ has failed, this is an outlier and no scientist in the field accepts their results at face value.

          1. Daren Austin says:

            Just take the 20th trial results – after all at the 5% significance level, one is going to be positive. The confounding steroids is of course the bigger issue.

          2. Detroit Dan says:

            What about this finding:

            “hydroxychloroquine use was associated with decreased in-hospital mortality.”

            I’ve also seen quite a few other sources supporting HCQ effectiveness:



            “Govt expands Hydroxychloroquine as prophylactic for healthcare, other frontline workers
            Read more At:

            Here’s another interesting perspective:

            “Coincidentally or as a consequence, the countries with the highest mortality from COVID-19 are also the countries that have demonized chloroquine the most, i.e. Western Europe and part of the United States. There is therefore a geographical pro- or anti-chloroquine correlation, on the one hand North-South, on the other hand West-East, which is beyond scientific data. A total of 4.6 billions of people live in countries where chloroquine or hydroxychloroquine are recommended for COVID-19.”

          3. Derek Lowe says:

            For starters, you could try reading that first paper you cite, where it says “Due to the inherent limitations of our retrospective study design, there was no conclusive determination on the efficacy of hydroxychloroquine in patients with COVID-19.”

            Your second link is from over a month ago, and cites no data – just assertions of positive results.

            And your third link is an editorial from Didier Raoult and co-workers, who helped kick this whole thing off. Of course he supports the idea. He just doesn’t want to run any controlled trials to prove it.

          4. Tom says:

            ^^^ Yes Derek!

            Honestly, I can’t see why people continue with their assertions for using HCQ!

  32. matt says:

    I’ll do it two ways, since the first may be in moderation a while. Link to paper in handle.

  33. bacillus says:

    Aerosol infection was extensively studied by multiple countries during the “golden era” of biological warfare R&D ( 1940-1970). In fact much of what is being written about this issue with respect to SARsCoV2 is simple reinvention of the wheel by people who appear to have little clue about this vast literature. Among the issues with aerosol transmission is the dilution of the virus in the surrounding air. If I generate by coughing or sneezing a small particle aerosol containing 1000 PFU of the virus into a 800 cubic foot room, then I need to inhale an awful lot of that room’s air to expose myself to an infectious dose. Moreover, I’m inhaling very few viruses with each breath compared to inhaling the air of someone coughing directly in front of me. Then, there is the issue of survival of viruses in the form of small particle aerosols, and the survival criteria tend to vary from virus to virus and bacterium to bacterium. For instance, humidity has a huge effect of survival, and many viruses show a U-shaped survival vs humidity curve (high survival at very low and very high humidities, poor survival at 50% humidity). Additionally, pathogen virulence often drops the longer it stays in an aerosolized state. Outdoors, factors such as ozone, UV, dessication also affect survival. In the case of Mycobacterium tuberculosis one of the simplest demonstrations that it was transmissable via aerosol was to pump the air out of patients rooms into clean rooms containing cages of guinea pigs which are highly susceptible to TB. This should be an easy experiment to repeat with SARs CoV2 and hamsters. They don’t get very sick, but they do lose 10% body weight and show some scarring on their lungs early on after infection, and it should be possible to recover live virus from their upper respiratory tracts if colonization has occurred. Until then, I remain skeptical about this being a major route of infection for SARs2, but will willingly eat humble pie if proven wrong.

    1. steve says:

      Do you prefer your pie cold or warm? The simple fact is that aerosol transmission for SARS-CoV-2 is indisputable, see the multiple references I posted earlier.

      1. Charles H. says:

        Sorry, but it’s not indisputable. I believe that it happens and is *the* major mode of transmission, but I’m not convinced. WHO isn’t convinced enough to include it as *a* major mode of transmission. Yes, there’s a petition from 200 scientists in the field (I’m a programmer) to WHO to so include it, but WHO doesn’t find their evidence convincing.

        So it can certainly be disputed.

        1. steve says:

          You’re right; nowadays people will dispute that water is wet. I should have said it can’t be disputed based on the evidence.

  34. Joseph Nowoslawski says:

    Bias in thought slows advances in knowledge.

    A virus is not “alive” it is simply a pollutant that is “replicated” by the evolved “replication” molecular reactions of life forms.

    Bats have a long life span and therefore they aggregate pollutants.

    A virus is not a parasite as it would not kill the host over evolutionary time.

    Infected humans are killed by over stimulated immune responses not by the pollutant itself

    Public health approaches should follow pollution control measures ie respirators…

    We have to think differently to add to the viral knowledge base…

  35. Ronald Loggers says:

    Immuno-oncology has learned us that mounting an effective T-cell response is all about careful balance in the right context (pls check work of Prof Kees Melief, LUMC, ISA Pharmaceuticals on HPV16+ induced cancers).

    Too little CD8+ and CD4+ and there will be no therapeutic effect. Too much CD8+ and too little Tregs (n-Tregs CD4+FOXP3+CD25+ and subsequently antigen specific i-Tregs) seems to cause severe damage and might be leading cause of high observed COVID-19 fatalities.

    This balance is a function of the individuals adaptive immune system (MHC I and II repertoire) and of the specific viral strain (small mutation might trigger different immune responses). Besides, the context in which antigens are presented to the APC’s (DC’s) is important for the right polarization of the CD4+ response (preferable Th1 polarization).

    In my opinion, best approach might be to mount a (therapeutic) vaccine induced effective Treg-response in severe immune-overshoot cases and let the virus be cleared by the native immune response itself. I.e. threat the symptoms rather than the disease. This could be flanked with specific CD8+ responses targeting infected cells and immune (context) modulation such as the aIL-6 strategies pursued individually by Regeneron and Roche or possibly dexamethasone. I think it will be more targeted (no side-effect risks for the >95% of potentially infected that clear the virus without ending up on ICU) and more cost-effective (no need to produce vaccine for 7 billion people) than prophylactic vaccine approaches. Also, escape variants (a real risk for prophylaxis) likely to have less chance with such an approach.

    1. Agda says:

      There’s no turning back on finding a prophylactic vaccine. But given that it might not be very effective and probably will be slowly rolled out to the world population (hopefully starting with health care workers and most at risk groups), the approach you mention might also be a very interesting route.

  36. Theo Sanderson says:

    “Remember the paper discussed in that link in the first paragraph above, which found that 40% of asymptomatic patients went completely seronegative during their convalescence.”

    This would be very striking – but it looks like they only looked at IgG not IgM in convalescencee which seems a significant caveat? Apologies if I’m misreading.

    1. Given that IgG is sometimes showing up before IgM in SARS-CoV-2 (which is unusual), often showing up contemporaneously with IgM, and almost always up longer than IgM, it seems the better choice. IgG are the longer-term antibodies, and typically you’d have those long after IgM had sailed off into the sunset.

      E.g., these quotes from a large longitudinal preprint out of China:

      The level of total IgM was extremely low in the first week (median=5.34 AU/ML), and gradually increased until the 5th week (median=43.98 AU/ML), followed by a continuous decrease to the initial level. (p. 7)

      The level of total IgG was more detectable than IgM at the first week, and continuously increased to seventh week (median=154.54 AU/ML), and slightly decreased from the 8th week, but still kept considerably high level until the end of our observation (12th week, median=95.94 AU/ML) (Supplementary Figure S1A). (p. 7)

      While IgM was rarely detected (32.5%) during the early stage (SupplementaryFigure S1B). 97.4% of the confirmed patients have positive IgM or IgG at the first 1 week after symptom onset, indicating that the combination of IgM and IgG is necessary for auxiliary diagnosis. (p.8)

      1. Theo Sanderson says:

        Thanks for setting me straight on this!

  37. Erik Dienemann says:

    In case nobody posted this yet, a nice overview of the antibody/T-cell situation in recovering and unexposed patients and what this may or may not mean for immunity over time in these populations came out today in Nature Reviews Immunology. Reads a lot like Derek’s blog…

    By the way, one thing I’d love to see is following some of these “closed” populations with >80% testing positive by the PCR viral test (prisons, meatbpacking plants, etc.) to see how their antibodies and T-cell levels change over time. Would also be interesting to see if there is anyone who showed T-cell activity in their donated blood prior to COVID who then either did or did not become infected with the SARS-CoV-2. Not sure how many of these people exist. Alternatively, in any of these studies where they’ve looked at donated blood prior to COVID, were any of these people tracked down to see if any of them became infected?

    1. Marko says:

      Some of this debate about pre-existing immunity hinges on semantics. I think of “immunity” as sterilizing immunity – if you’re immune you don’t get a detectable infection. No PCR positives. Partial immunity way result in mild or asymptomatic disease , but a timely PCR test would still pick these up.

      The idea that pre-existing immunity one or more common cold coronavirus strains would provide sterilizing immunity to COV2 seems very unlikely to me , since repeat infections by those very common cold strains are well known to be common. There is a protective immunity there against the common cold , but it doesn’t appear to be sterilizing.

      The other argument against widespread pre-existing sterilizing immunity is that there have been cluster outbreaks where confined groups have shown PCR positivity at rates of 50% up to potentially 87% in the case of the Skagit , Wa. choir.

      This twitter thread goes into some of the misconceptions about this topic , and supplements the Nature article you posted by the same author:

    2. Riah says:

      Erik, yes I think that would be very very interesting to find out too. My recent reply to Geoff ( above or below?) and the new study it refers to might throw a little bit more light on the question but not answer it in full.

  38. Semi-Informed says:

    Interesting. It would make sense that a low level of “free floating” antibodies does now mean we are not protected against the virus as long as b-cell/t-cell response mechanism is somehow activated after first infection (sorry for likely super over-simplification). Was this response mechanism studied for older, better-known virus infections? What would be a typical “free” antibody level for a flue, ebola… etc, immediately after infection, after vaccination and over time?

  39. Sam Beyda says:

    I think that a solution to this problem could come from a possible human challenge trial (HCT). By exposing volunteers with antibodies to the virus we can learn more about reinfection rates. Among other benefits, an HCT would also be able to judge a vaccine’s efficacy quicker than a standard trial.

  40. David E. Young, MD says:

    Somewhat late to bring this up, so I might add this to a future blog post.

    Is there any scientific rational to get more than one vaccine? Is it reasonable to (eventually) consider a clinical trial where someone gets a combination of vaccines randomized to just one vaccine? (another huge, expensive endeavor, of course). Would even a small clinical trial, looking at covid neutralization as an endpoint, testing two vaccines vs each one alone. How about three vaccines? It gets pretty unwieldy about that time. But still, in principle, I would think that you could have better protection with more than one vaccine (or with boosters). The ultimate test of course, would involve 20,000 patients with the endpoints being mortality and contracting Covid and hospitalizations.

    There needs to first be verifying the current vaccines for safety and efficacy. Of course. But are researches / companies open to the idea of combining vaccines if their own vaccines just protect 60 percent?

    1. Marko says:

      It’s easy to imagine that the response to a COV2 vaccine may be similar to what was seen in this study involving H5N1 :

      “….Here we show that a two-dose immunization of humans with an inactivated, AS03-adjuvanted H5N1 avian influenza virus vaccine engaged both the preexisting memory and naive B cell compartments. Importantly, we show that the recruited memory B cells after first immunization were directed against conserved epitopes within the H5 HA stem region while the responses after the second immunization were mostly directed against strain-specific epitopes within the HA globular head. Taken together these findings have broad implications toward optimizing vaccination strategies for developing more effective vaccines against pandemic viruses.”

      A booster , even with the same vaccine , may be the way to go to generate the desired , strong COV2-specific response.

    2. Barry says:

      Adjuvants matter, and route of inoculation matters. Aerosol/nasal inoculation may prove better to evoke IgA to block the pneumonia, i.m. may prove better for evoking IgG to block the coagulopathies. And giving both may prove better than either alone. There’s a lot we need to learn about this novel virus.

      1. Derek Lowe says:

        Yes indeed. I would be fine with hitting a chord on the immunological piano, I think: more than one type of immunoglobin (for the reasons mentioned), as well as both CD4+ and CD8+ T cells.

      2. Marko says:

        ” There’s a lot we need to learn about this novel virus.”

        Yep. Especially regarding “correlates of protection” in the immune response. As near as I can tell, so far we know squat.

        In macaques , we know that primary infection provides “protection” ( NOT sterilizing ) against secondary challenge , for some time , at least :

        I’m more and more inclined to think that sterilizing immunity may not be an outcome of either infection or vaccines , and I’m OK with that. If we can relegate COVID-19 to the same category as the common cold , or even influenza , we can get back to some semblance of normalcy. Reducing severe disease and deaths by something like 70% or better , even as the virus continues to circulate and infect people , may end up being considered a major success for vaccines.

  41. Marko says:

    Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

    “For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk.”

    Selecting convalescent plasma donors with high titers of anti-spike IgG may not be such a good idea . Neutralizing abs are good when they inhibit viral entry , not so good when they generate deranged macrophages.

    1. Marko says:

      Similar , regarding the first SARS :

  42. Jennifer says:

    Could someone please breakdown the differences between T and B cells vs IgG and IgM?
    So Covid cells infect the body And:
    You could use a proven example for it like measles if that’s easier and more factual. I understand we don’t know much about how Covid behaves. I’m just trying to understand the typical process. Like: What makes the proteins? The B cells?
    I’m really interested in a simple analogy if possible.
    Thank you for your time and response.

    1. a grad student says:

      Excellent question! I’ll say first that I’m not an expert in immunology, but I think I can actually explain this fairly well.

      I will start with an analogy, and the details will come afterwards if you’re interested. Think of the immune system as an army. There are two types of T cells: helper T cells, which are like the generals of the army, and cytotoxic T cells, which are like the soldiers of the army. The generals (helper T cells) will direct the soldiers (cytotoxic T cells) towards invaders or infected cells that need to be killed. We’ll come back to B cells in a moment. First, IgG and IgM. These are different groupings of antibodies. Think of antibodies like bullets that the immune soldiers need to fight the virus. The catch is that each virus can only be killed by a specific kind of bullet. This brings us back to B cells, which are factories for those bullets. Each factory makes their own special bullet, so when the immune system finds a bullet that works, that B cell starts churning them out to get the infection under control.

      I hope that analogy worked on some level. If it didn’t, the more straightforward details are below.

      T and B cells are two different types of immune cells in the body. They are both born in bone marrow, although they mature in different locations (T cells in the thymus, B cells in bone marrow). Each of these cells has a different function.

      T cells have two types that are frequently mentioned with regard to covid: CD4+, or T helper cells, and CD8+, or cytotoxic T cells. Broadly speaking, T helper cells enable other immune cells to do their jobs, and cytotoxic T cells can kill infected cells that are producing viruses.

      B cells, on the other hand, are cells that make antibodies. They have antibodies sticking out of their surface, and once they encounter something those antibodies stick to, they’ll turn “on” and start making tons and tons of that same antibody.

      That brings us to IgG and IgM. These are types of immunoglobulins, which are essentially a bunch of antibodies stuck together in different ways. These are what those B cells I just mentioned produce once they’re activated. Immunoglobulins will then circulate through the body and stick to viral particles or infected cells, which marks them for destruction by the other parts of the immune system.

      A quick overview of an infection would be like this: first, a pathogen (disease-causing molecule or organism) gets into the body. It infects a couple cells and churns out copies of itself. Eventually, once they run into a B cell that has the right antibody on its surface, the B cell is activated and starts making more antibodies so your body can get the infection under control. T cells look for cells and particles marked by these antibodies and then kills them, thus (ideally) ending the infection.

      Hope that was clear enough!

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