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More Vaccine Data, in Advance of More Efficacy

I know that it’s been a run of vaccine posts around here, but the numbers just keep on coming. Today we have two more papers to look at, both published in The Lancet. –

The first is from the SinoVac inactivated virus effort (the CoronaVac vaccine). In this one, the virus is grown in Vero cell culture, harvested, and inactivated by treatment with beta-propiolactone. As mentioned in previous vaccine roundups, this is an older technique. Its advantages are that it’s a well-worked-out technology, but the disadvantages are that it’s also known to produce less active vaccines overall.

This paper is just safety, tolerability, and immunogenicity in the human trials; we don’t have actual efficacy data yet (although you’d figure that’s coming soon). And overall, it looks like the vaccine works, but not as strongly as some of the other data we’ve seen. This trial looked at 3-microgram and 6-microgram doses of the inactivated virus preparation (with an aluminum hydroxide adjuvant), in two rounds spaced either 14 or 28 days apart. The antibody response after the second dose was not impressive in the first trial – even after the second dose, only about 80% of the patients seroconverted with neutralizing antibodies. But the Phase II trial was more like it, with 95% to 99% of people seroconverting. The paper says:

The immune response in the phase 2 study was substantially higher than in the phase 1 study, which might be due to the difference in preparation process of vaccine batches used in phase 1 and 2 resulting in a higher proportion of intact spike protein on the purified inactivated SARS-CoV-2 virions in the vaccine used in phase 2 than that used in phase 1.

That’s interesting, to have changed things in mid-stream like that, but perhaps it was the unimpressive results the first time through that prompted it? But even with that change, the antibody titers seen after the second dose were (in all patients) lower than those seen in a panel of 117 recovered coronavirus patients. There is no detailed T-cell data, but the paper does mention that ELISpot assays “provided no clear evidence that the vaccine induced T-cell responses“. So that’s the big question here: is all this enough? It might be, but it might not (or not be enough compared to other vaccine options). We’re not going to know until we see actual efficacy numbers from the trials that are going on in Brazil, Indonesia, and Turkey. The Brazilian trial, you will have heard, has been turbulent and was suddenly halted last week on orders from Brazil’s turbulent president. What this will do to the statistics or timeliness of the overall results is not clear.

The other paper is from the AstraZeneca/Oxford adenovirus vector effort. It’s a look at safety and immunogenicity in a wider spectrum of patients than has been reported so far, and the main news from it is that older patients appear to respond very similarly to the younger ones, both in antibody titers and T cells. What’s more, the vaccine actually appears to be better tolerated in the older patients (both in local reactions at the site of injection and systemically). So that’s good news. The actual antibody and T-cell numbers are similar to the earlier report, and would appear to be what you’d need for an effective vaccine, but we’ll again have to wait for the real numbers. Those shouldn’t be long in coming – BioCentury has a graphic of the current advanced-trial vaccine landscape here, and they (and others) expect to hear from both the AZ/Oxford team and J&J’s single-dose trial in December. At that point, we will have a completely unprecedented look at the landscape: large nearly-simultaneous data sets for two different mRNA vaccines and two different adenovirus vector ones, all directed to the same pathogen, and neither technology ever having advanced into humans like this. Let’s hope we never see the like again, because you would only do it this way when your back is against the wall.

76 comments on “More Vaccine Data, in Advance of More Efficacy”

  1. Sunyilo says:

    I guess one has to wait for efficacy data in late phase clinical trials. Comparing antibody titers and T-cell responses for different – and simplified – models of antigens fall into apples-to-oranges category. So far, using the spike protein as the antigen seems to work out very well, but it’s too early to draw conclusions whether such cutting of corners will pay off for vaccination purposes (and just to be on record, it may well be the case for Covid-19 while not being generally valid for antiviral vaccine development).

  2. Dylan says:

    Idle speculation from someone that doesn’t know this space very well, but wondering if we can expect the rush of work that has been done on vaccines to spillover into other areas? Might this lead to a vaccine for the common cold (at least the ones caused by a coronavirus)? Could this spur a vaccine renaissance?

    1. Marko says:

      “….Could this spur a vaccine renaissance? ”

      I don’t know , but I think we’re fast approaching the point where the prospect of growing vaccines in chicken eggs will appear quaint.

    2. M says:

      What we’ve been able to learn from this effort is that their is tremendous potential for new vaccine technologies (e.g. mRNA) which should lead to more vaccine therapies and choices. As to more disease being targeted, I think this will *probably* happen, but it’s much harder to provide specifics (e.g. common cold), given the differing nature of many of the diseases for which vaccines are or can be beneficial.

      The other thing we’ve learned is how to quickly enable vaccine development in the event a new pathogen comes along. Hopefully this never happens again, but the odds are that it will.

    3. Daniel Barkalow says:

      The new technologies seem to be good at triggering an immune response to a specific protein, which is perfect for this coronavirus, where exactly one well-conserved strain is causing serious disease in lots of people. “If you get this vaccine, you have a 10% chance of needing a sick day, but you’ll almost certainly avoid one case of COVID-19 in your lifetime” is a good deal. On the other hand, “… but you’ll almost certainly have one fewer common cold in your lifetime” is not.

      It’s likely to be good against future novel viruses, and it is probably good for removing a barrier to getting immune system research into practical vaccines, but it’s probably not going to just remove the sole (or primary) barrier to vaccines for a lot of known diseases.

    4. Todd says:

      Generally, yes, because it’s not a lot easier to churn out targets and scale them up. It won’t be as fast as the COVID-19 vaccine, but you’ll see timelines in the 2-3 year range for vaccines as opposed to the standard 5-8 year range.

    5. Rich Stern says:

      Molecular biologist here, who specialized in virus pathogenesis (although one who has not been in the lab in nearly two decades).

      1. I think this is going to change how vaccines are made going forward. Not just the mRNA stuff, but also the overall process of identifying and modeling targets. While this vaccine appears to have gone very quickly, the necessary groundwork behind it has been going on for years.

      Interesting read on the background of how the vaccine came to be : Chemical & Engineering News, V. 89, Issue 38, September 29, 2020. Author is Cross. I think most non-scientists should be able to read and understand it.

      2. Re: Common cold. I wonder this too. The modeling of the spike protein was done using a spike protein from a coronavirus that causes the common cold. So, it does make one wonder if a vaccine against the common coronavirus could be made. One caveat, as you allude to, there are many things that cause the common cold. So, from a profit perspective, it may not be worth it.

      1. confused says:

        Yeah, for the common cold specifically, even if you could vaccinate against all four common cold coronaviruses, since the majority of colds are caused by something else, I don’t know how much demand there would be for “this vaccine reduces your risk of getting a cold by maybe 20%”.

        The technology in general seems extremely interesting though! If a “pan-coronavirus” vaccine turned out to be possible, could they develop vaccines against other virus types that are considered plausible sources of pandemics *beforehand*?

        1. ghyu says:

          A common cold coronavirus may be more severe in elderly people. I don’t believe we actually have numbers on how many people die from the 4 common strains. It’s clear influenza doesn’t cause all of the increase in winter deaths, so it’d be reasonable to assume that the elimination of cold coronaviruses could reduce winter deaths by something on the scale of 10-20%

          1. theasdgamer says:

            Kind of funny that URTI deaths mostly occur in winter. Almost makes one wonder if vitamin D deficiency has something to do with the deaths. Almost, but not quite.

            https://www.nature.com/articles/s41598-020-77093-z

      2. Dylan says:

        Thanks for the insightful feedback (this goes for everyone else that replied too).

    6. Jason says:

      There has been both scientific speculation and several preprints on the topic of pan-coronavirus vaccines.

    7. a s says:

      I believe there was some very promising research on cold vaccines happening just before the world dropped everything to focus on this one coronavirus. My girlfriend was signed up for an RSV vaccine clinical trial which was halted.

  3. Matthew says:

    Does anyone have a link to a table that shows population size and demographics of the vaccine phase 3 candidates?

  4. AE says:

    Hi Derek,

    J & J is adding a 2 dose trial to their ongoing single administration trial. Can we read between the lines that the single dose may not be meeting endpoints or are they just hedging?

    https://www.jnj.com/johnson-johnson-initiates-second-global-phase-3-clinical-trial-of-its-janssen-covid-19-vaccine-candidate

    1. OtherMichael says:

      It’s a hedge. No one knows the efficacy until the actual readout happens because of the blinding.

    2. Tony M says:

      More likely it is a response to Moderna’s 94.5% and Pfizer/BioNTech’s 95% efficacy results for there vaccines which require two doses. If J&J single dose vaccine came in less than those figures but the two dose came in around the same or better, you will not be able to say it is less efficient. If the data indicates, you then can always choose to give the 2 dose J&J vaccine and achieve the 2 dose efficancy.
      Regards

    3. Michael says:

      They’ve indicated in interviews that they want to see if the second dose will enhance durability of protection. As the press release noted, it’s to explore “long-term efficacy.”

  5. AE says:

    It looks like J & J is adding a second 2 dose trial. Can we read between the lines regarding efficacy of the single dose regime?

    https://www.jnj.com/johnson-johnson-initiates-second-global-phase-3-clinical-trial-of-its-janssen-covid-19-vaccine-candidate

  6. Some idiot says:

    Ok, stupid question for the day… I’m just a process chemist, but my overall feeling is that the science of adjuvants feels to me to be pretty well much a black box (or at least something black with a lot of weird tentacles and/or wings flapping their way around it). Yes, I know that they are supposed to increase the immune system’s activity (or awareness of) something new. But how do they work? And how on earth can good old aluminium hydroxide do anything useful? That one landed me somewhere between perplexed and bemused…

    Thanks again in advance!

    1. Some Other Idiot says:

      Part of the problem is that to the common man “adjuvants” ARE a black box and thus get treated in the earth, fire, air realm of science things. Read the antiVAXers stuff and one will see that the primary concern is in fact the adjuvants, so no Vaccine that uses one would be considered “safe!”

      Guess we need some common sense explanation of adjuvants to counteract the easily found Google info?

    2. Brian says:

      I once heard an immunologist giving a talk say something like- “Any time a cell dies badly, the immune system will sit up and take notice.” If that statement is accurate, you could expect that using aluminum hydroxide as an adjuvant would cause some cells to die in the area of the injection and make the immune system react to whatever is non-self in the area of the injury.

    3. Sc says:

      I really wonder how what they do relates to the tick enzymes or whatever that induce red meat allergies in some tick bite victims (like me). It certainly seems similar on a broad perspective. Guess we just need to wait for more research.

    4. Barry says:

      Some adjuvants (e.g. Levy’s CpG) are ligands for known TLRs that provoke vigorous innaate immune response

  7. rondi says:

    I’ll probably be banned for posting this here and clearly this is not on subject–it is a replay of a Senate hearing this morning on C-span2.org at 8pm est.
    spoiler—the Drs talk about using HCQ with other drugs for treatment within 5 days of symptoms. As you know–it keeps getting worse. IMHO–this may be the ONLY treatment to stop the surge. PLEASE–keep an open mind, with my previous sentence in mind 🙂
    one interesting reply by one of the Drs (Dr McCullough I think):
    01:29:33
    SENATORS, LISTENING TO THAT LAST EXCHANGE OF QUESTIONS AND ANSWERS, I WANT MY TESTIMONY TO BE CLEAR. THIS ENTIRE HEARING WAS ABOUT EARLY TREATMENT AND WHAT THOSE LAST SET OF EXCHANGES SHOWED, A COMPLETE LACK OF FOCUS, IT WENT OVER TO THE VACCINE, AND THEN IT WANDERED OVER TO WEARING MASKS AND EVEN WHAT’S BEING OFFERED AT THE THANKSGIVING DINNER. ONE OF THE REASONS WHY AMERICA IS FAILING COLOSSALLY IS A LACK OF FOCUS EXEMPLIFIED BY THE LAST SET OF EXCHANGES.

    1. Derek Lowe says:

      To be honest, I find this comment fairly worthless, but you also have to be a lot more worthless than this to get banned around here.

      1. theasdgamer says:

        My family contracted covid and we treated early with antivirals and symptoms resolved within 24 hours. Probably infected by my daughter who works in hospitals.

        Covid is everywhere now. My brother and his wife whom we haven’t seen in months and who live hundreds of miles away got it last weekend, we got it twice within the past month (recovered more quickly after the second go-round), a buddy and his wife living in town 20 miles away whom I haven’t seen in months got it two weeks ago.

        Covid is ubiquitous. 905 Mayo Clinic workers were infected in the last few weeks.

        The vaccine will shut the covid barn door after the covid horse is already three counties away.

        1. Robert says:

          Just clarifying – are you saying you got covid twice in a month?

  8. Jacky says:

    “Inactivated vaccines are not thought to induce CD8 T-cell responses”

    So does it mean inactivated vaccines is inferior than those vaccines which can induce T-cell responses?! As T-cell response may be important for long term protection too.

  9. Jason P says:

    Derek, thanks for the link to that table. Quick summary to the longer posts you made early on on the LARGE number of efforts out there.

    Now the question will become, which vaccine do I want to partake? The first two Pfizer & Moderna are mRNAs. On their heels are two Viral vector vaccines. Then later it looks like we might get a couple of protein vaccines.

    Have seen other ask before, why not get both of the early two? Seems like there would be no harm and perhaps the second one would boost the effects of the first? But how about mixing and matching: mRNA plus Viral Vector or mRNA plus Protein? Waste of time & resources or additive to immune system to be able to avoid other novel viruses as they develop?

    1. David says:

      Jason P: “why not get both of the early two? ”

      First, there’s no data to tell whether this is safe. Who knows how severe the immune response would be to the second vaccine?

      Second, there is a significant public health interest regarding distribution, so that the maximum number of people can be vaccinated, in order of some predetermined priority system. Vaccinating one person twice seems counterproductive, in terms of net result.

      1. Jason P says:

        @ David, I’m just thinking the “American way” or the ‘new age’ thinking! After all the world and society exists to serve my needs, no? Who cares if someone else doesn’t get a vaccine as long as I get mine and a second vaccine. I’ll take the dose the Anti-Vaxers don’t want. Shoot most of the under 25 crowd doesn’t need it anyway cause they’ll be asymptomatic. So get off my back, it’s a free country, I can do whatever I please regardless and I WANT WHAT I WANT!

        Now to the serious comment: This pandemic would have been over in 6-weeks had it occurred in the 1960s. Wonder if the needle ever swings back the other direction?

  10. Zambo says:

    Has anyone compared the phase 2 immune response data for the AstraZeneca and JNJ vaccines with the Moderna/Pfizer ones? Obviously pointless in the long run with more phase 3 data imminent but it would certainly help calm my worries that the vector vaccines may not be as effective as the mRNA ones if the neutralizing antibody/T cell counts were similar.

  11. GJ says:

    Derek,
    Very informative and timely coverage of important developments! It was rightly pointed out that Adjuvants is one of the main concerns for wide acceptance of vaccines. Can you please write a post addressing/explaining Adjuvants?

  12. Chris Phillips says:

    “BioCentury has a graphic of the current advanced-trial vaccine landscape here, and they (and others) expect to hear from both the AZ/Oxford team and J&J’s single-dose trial in December.”

    That is interesting. I think it’s worth noting that there will be other Phase III trials in the same timeframe outside the USA – for example an inactivated vaccine from Valneva – based in France and with support from the UK government – will reportedly start Phase III trials in December.

  13. Dan says:

    Could an immune response that high (Biontech – Moderna) trigger a cytokine storm in say 1 in 100.000 people? In other words: can a vaccine be too good?

  14. ghyu says:

    The inactivated virus vaccine may turn out to be less effective, but it has the huge advantage of containing all the proteins of SARS2. This may confer partial immunity against the 4 endemic human coronaviruses as well as a potential future pandemic virus. Maybe a combination of mRNA and inactivated virus, or an mRNA vaccine against a protein other than the spike would be useful.

    1. Marko says:

      If the long-term safety data pans out , I think there’s a future for mRNA cocktail vaccines , where multiple epitopes are targeted within a single injection.

  15. Douglas Wise says:

    I would like to comment from the perspective as a retired avian veterinarian. The modern poultry industry only exists today because of the success for over half a century in protecting poultry against disease associated with avian infectious bronchitis (corona) virus by use of a range of live and killed vaccines.

    High passage attenuated vaccines are typically used as primers and either lower passage or killed vaccines (with adjuvants) as boosters in situations in which longer lasting immunity is deemed necessary or desirable. Killed products, which of necessity have to be injected, contain much higher antigenic doses as they can’t self replicate in their hosts. They are thus considerably more expensive. Live vaccines are typically administered in drinking water, but occasionally as coarse nasal sprays. Given in this way (as opposed to by injection) they are supposed to provide more or less instant protection.

    By extrapolation, one would expect the SinoVac product to be a good booster but a poor primer.

    1. Mammalian scale-up person says:

      This is really interesting – I keep about a dozen backyard chickens and of course had given both the wing-poke and the drinking water vaccines to my flock, but didn’t pay much attention to why any of them were one way or another until I lost a couple of birds to a Marek’s vaccine failure. Thanks for the comment!

  16. Michael says:

    So this is an interesting study:

    https://www.medrxiv.org/content/10.1101/2020.11.18.20234369v1

    Over 12,000 health care workers tested for antibodies in April. 1,246 were seropositive. Then they were all followed for 30 weeks until earlier this month.

    89 cases of symptomatic disease among the seronegative, zero among the seropositive.

    But what is really interesting is that of the asymptomatic PCR positive cases, 76 of them were in the seronegative group and only 3 in the seropositive group. A hopeful sign that vaccines will indeed reduce asymptomatic cases too.

    1. theasdgamer says:

      Have there been any non-bogus studies of asymptomatic superspreaders? You could test such a theory on a lab full of exposed Vero cells.

      And have any papers been published on SARS-COV-2 cell exit mechanisms? I’m still looking for one if anyone has a link.

  17. luysii says:

    From today’s Science p. 895

    “Fauci says a COVID-19 vaccine always looked like a solid bet. The fact that many infected people clear the virus without de- veloping serious, if any, symptoms, shows that the immune system can beat it back. “I’ve been saying all along that when the body tells you that it’s capable of making an adequate immune response against natural infection, that tells you you have a pretty good chance to get a vaccine.”

    I don’t recall Fauci saying anything like this. Does anyone? If so, probably I missed it being too busy reading the deluge of papers on all things SARS-CoV-19

    1. Michael says:

      Yes, I recall him saying that convalescent patients clearing the virus was “proof of concept” for vaccines. I think he was comparing it to HIV.

      1. luysii says:

        Michael: Thanks — one of the more intriguing tidbits is that neuropilin1, a protein beloved by neuroscientists for its role in axon guidance, helps the virus get into cells. The chemistry is interesting, the pandemic virus has a polybasic sequence at the S1/S2 boundary which SRS-CoV-1 does NOT have. Furin cleaves it creating a binding site for neuropilin1. So this gives us an entirely different way to attack the virus. Science vol. 765 – 766, 856 – 860, 861 – 865 ’20

  18. Bill says:

    So the request for EUA has been submitted by Pfizer. I saw somewhere that it might take four weeks for approval. Four weeks equates to another 56,000 US deaths — maybe twice that depending on the holiday spike.

    What is that four weeks spent doing? Does everyone agree it’s import matches the anticipated extra death count which will result? I know it’s important. But are there ethical issues in the balance? What if it were your parents or grandparents? Just “oh well…”

    1. Dave says:

      If it takes 4 weeks, then there clearly would be a problem. I have to assume that all the mathematical analysis can take place in less than 10 minutes, assuming the programs are already written (And if they aren’t, then what were they doing in all the time since they knew this was coming?) If the EUA isn’t granted by Monday, I will be upset.

    2. David says:

      Bill: “What is that four weeks spent doing?”

      It’s really easy to underestimate the complexity and workload of people whose job you’ve never done. I’ve always been impressed that FDA reviewers work hard, work to deadline, and are thorough.

      I would guess (just a guess, though) that FDA will review records of every interaction with subjects to ensure that potential infection symptoms weren’t overlooked, trace individual datapoints through the databases to ensure that the sponsor company hasn’t dropped or mis-counted some data, look for patterns of adverse events that the sponsor company might have missed, and also review the vaccine manufacturing process, quality-control systems, and scale-up plans to ensure that consistent quality can be maintained after approval.

      That could easily take a while. For an ordinary review they generally schedule 10-12 months.

      1. David says:

        Several problems with this answer. They have had most of that data for quite some time and should have already started and nerely finished that analysis. Secondly the whole point of a third party review of the data is so the government does not have to do that. They only have to review the report from the third party. I have done this in another context for the govrnment so i know. Thorough review is necessary, but with lives in the balance and this good data.. i will be disappointed if we dont get an eua on Monday.

    3. Delph says:

      I would add on that Pfizer is already scaling up manufacturing now anyway in anticipation. Widescale vaccination isn’t yet possible because the doses aren’t there – the FDA approval step isn’t the rate limiting one at this point.

  19. Barry says:

    SinoVac changed the prep and then went to Phase II without a new safety trial??

    1. Derek Lowe says:

      That’s just what I was wondering, too. . .this was the first time I’d heard about the two different forms of their vaccine.

  20. DTX says:

    The key to the vaccines is production, not FDA’s time for review. It’s doubtful that Pfizer will wait for FDA’s approval until producing the vaccine. Pfizer is likely producing as much as possible. Once approved, demand will totally outweigh supply. This happens even in non-pandemic times. I know one big pharma that started manufacturing a vaccine 3 years ahead of anticipated FDA approval. We want FDA to do a thorough review so there is greater confidence in the vaccines and they’ve evaluated the risks & benefits thoroughly.

    Regarding inactivated vaccines being less effective; it depends on the adjuvant. GSK’s shingles inactivated vaccine gives far more short-term and long-lasting protection than Merck’s live attenuated one.

    On the question, does too effective of a vaccine create a cytokine storm? Unlikely. GSK’s shingles vaccine is ~98% effective, yet I’ve seen zero reports of cytokine storms. However, it does cause significant pain at site-of-injection and overall body malaise. However, most people would gladly take this instead of getting shingles.

    Similarly, I’d accept injection site pain and some body malaise to protect myself from Covid.

  21. Parade Drencher says:

    Sorry to cast doom and gloom on this discussion, but the fact, now verified by the CDC, is that the majority of COVID cases are transmitted by asymptomatic carriers. This means that unless these vaccines confer sterilizing immunity (unlikely), all they’re going to do is to create more unwitting vectors, many/most of whom will probably no longer think it necessary to wear masks and socially distance, because they themselves are not at [as much] risk. The result? More transmission, not less, and more serious cases among the 40% or so of the American population who will most likely refuse to get vaccinated, as well as many elderly and high-risk patients for whom the much-lauded 90-95% efficiency will not apply. Welcome to 2021, the “New” 2020.

    1. David says:

      Your claim that the vaccine will not confer sterilizing immunity seems very suspect. What do you base it on?

      1. Parade Drencher says:

        If I understand correctly, the original plan the primary and secondary endpoints for this first generation of vaccines are “virologically confirmed symptomatic SARS-CoV-2 infection regardless of the severity of symptoms (COVID-19) and virologically confirmed SARS-CoV-2 infection with symptoms classified as severe (severe COVID-19)” (Annals of Internal Medicine, 22 October 2020). In other words, disease, not infection, is the main focus, and it’s on this criterion that the current efficacy data are based.

        1. Marko says:

          Your doom-and-gloom parade is likely to be rained on shortly , as Moderna has announced they’re checking trial participants for antibodies that would detect asymptomatic infection. Just because the trial endpoints were focused on disease severity does not mean that a significant sterilizing immunity benefit will not be seen , at least for some period of time.

          At any rate , newer evidence suggests that true asymptomatics are a smaller fraction of those infected than once believed , now estimated at only ~20% , and that they are ~40% LESS likely to transmit disease than symptomatics:

          https://www.nature.com/articles/d41586-020-03141-3?utm_source=Nature+Briefing&utm_campaign=dfed4a7f39-briefing-dy-20201119&utm_medium=email&utm_term=0_c9dfd39373-dfed4a7f39-45171750

    2. Michael says:

      Parade Drencher, I would bet my life savings on Pfizer/Moderna vaccines reducing transmission rather than increasing it.

      Consider:

      1) Marko cites one stat from that article saying asymptomatics are 40% less likely to transmit. That same article refers to a Swiss study where they were 75% less likely to infect household contacts than symptomatics. The WHO estimates the secondary attack rate as being 65% lower among asymptomatics compared to symptomatics.

      2) Neutralizing antibodies have conferred protection from any infection as measured by mass PCR tests in outbreak settings such as the fishing boat and the Wisconsin summer camp.

      3) Neutralizing antibodies have conferred protection from reinfection in UK health care workers – zero symptomatic cases among the seropositive and very, very few asymptomatic positive PCR tests (which might, at that, be viral RNA rather than infectious virus upon asymptomatic reinfection).

      4) Pfizer and Moderna generate neutralizing antibodies more consistently than infection, and reinfection after natural infection is still extremely rare.

      5) There is every reason to think that even vaccinated people with asymptomatic infection would clear the virus with lower volume and shorter duration of shedding given their primed immune systems, and this has been true in animal challenge studies. Moreover, as the Nature article mentioned by Mario says, asymptomatics are not coughing on people.

      6) Derek pointed out a UK study recently showing that frontline workers with strong pre-existing T-cell responses to coronavirus proteins had zero infections.

      7) Given all this, I can’t imagine how it’s even reasonable to compare the transmission potential of a vaccinated person to a naive, susceptible person infected asymptomatically, who are not in any event principal drivers of transmission. The primary danger of “asymptomatic” transmission lies in *presymptomatic* transmission, which is why this is a uniquely difficult to control pandemic in so many ways.

      It is really frustrating to see mainstream media articles saying definitively that Pfizer and Moderna vaccines “do not prevent transmission.” That is not proven, highly pessimistic and wholly speculative. All available evidence (new but growing) is that the statement is far more false than true.

      The reason why the vaccine trials can’t assess this in real time is because it’s impossible to give tens of thousands of people PCR tests every day for months.

      1. Parade Drencher says:

        Thank you all for your replies. The fact is that I guess I’m confused. The CDC report that asymptomatic carriers are responsible for over 50% of new cases was just released. There have also been interviews recently (incl. one in the NYT) with epidemiologists who say they are worried about a possible “unintended consequence” of vaccination being more asymptomatic carriers/spreaders.

        On the other hand, the data cited here about the relative rarity of asymptomatic carriers spreading the disease (“asymptomatics are 40% less likely to transmit. That same article refers to a Swiss study where they were 75% less likely to infect household contacts than symptomatics. The WHO estimates the secondary attack rate as being 65% lower among asymptomatics compared to symptomatics”) also look reliable. Are these different reports contradictory, or am I misunderstanding something?

        1. David says:

          parade drencher: ” Are these different reports contradictory, …”

          No.

          The reports are looking at different phenomena, and the percentages reflect fractions of a different denominator.

          People are more likely to spread when symptomatic, as when asymptomatic (or pre-symptomatic). However, there are more asymptomatic (including pre-symptomatic) people than there are symptomatic, so even though each individually is less likely to spread virus, cummulatively they contribute a large fraction of new infections.

          Will the vaccine lead to more spread? As far as I can tell, we don’t have the evidence needed to provide an answer beyond theorizing. We simply don’t know if the immunity produced by any of these vaccines prevents colonization, shortens duration of infectivity, or reduces viral content (“dose”) in exhaled droplets. Even if we knew these factors, we might not be able to combine the knowledge into an accurate model of infection spread among a mix of vaccinated and non-vaccinated people (and the effect of the vaccine may be different as that mix varies). There is no feasible, ethical trial design that I can envision that will comprehensively answer this question. So we may never know.

          That doesn’t bother me too much.

      2. Michael says:

        I know I quote Deepta Bhattacharya fairly often these days, but this is yet another worthwhile thread. The math just doesn’t add up, based on what we know, for Pfizer and Moderna not to reduce transmission:

        https://mobile.twitter.com/deeptabhattacha

        He sets the over/under as 70% sterilizing and, in response to a comment, agreed that it might be even more beneficial than that re transmission, given likely reduced volume and duration of shedding among the vaccinated.

  22. Marko says:

    Convalescent plasma seems to have a beneficial effect in the elderly , if high-titer and used early enough :

    https://www.medrxiv.org/content/10.1101/2020.11.20.20234013v1

    A lesson for MAb usage : Use as early after infection as possible , or even prophylactically in high-risk cohorts.

    1. rondi says:

      I wonder how the distribution to hospitals will be in rural areas that are now are or almost filled to capacity. By the time most of us have symptoms @day5, get a Dr to prescribe a test, get a nasal swab test–wait 3 hours in line, get results probably 4-5 days (normally 2-3 days here), wait for the Plasma to arrive (how long??) AND be able to get in the hospital. By then “early” (early=days 1-5 after symptoms) has now passed and the Storm is building. Some hospitals are considering rationing care for non-elderly patients to care for non-maskers (I am assuming here you must be in the hospital to receive the Plasma. This is the same exact problem with discredited studies of HCQ (btw without Zinc)–given to folks too far past the early stages which is the only time HCQ & Zinc ALONG with the other drugs is effective.

  23. theasdgamer says:

    “‘No evidence’ that asymptomatic Covid-19 cases were infectious, analysis of post-lockdown Wuhan concludes”

    https://www.nature.com/articles/s41467-020-19802-w

    So much for the superspreader theory.

    1. Carl Sampson says:

      Funny, as that same Nature article also had this to say in the Discussions section:

      “Existing laboratory virus culture and genetic studies showed that the virulence of SARS-CoV-2 virus may be weakening over time, and the newly infected persons were more likely to be asymptomatic and with a lower viral load than earlier infected cases.

      Nonetheless, it is too early to be complacent, because of the existence of asymptomatic positive cases and high level of susceptibility in residents in Wuhan. Public health measures for the prevention and control of COVID-19 epidemic, including wearing masks, keeping safe social distancing in Wuhan should be sustained. Especially, vulnerable populations with weakened immunity or co-morbidities, or both, should continue to be appropriately shielded.”

      Translation: Even though the SARS-Cov-2 virus appears to be weakening, this is no time to let down our defenses concerning this pandemic.

  24. Julie8989 says:

    What is this new study that Sars2 deletions allow antibody escape?
    Are the vaccines doomed after all?

    https://www.biorxiv.org/content/10.1101/2020.11.19.389916v1

    1. Derek Lowe says:

      I don’t think so. The paper identified four regions that seem to throw deletion mutations a lot, but two of them don’t affect antibody binding at all. The other two affect some antibodies that attach to particular regions of the Spike protein, but does not affect the ones that recognized the receptor binding domain out on the end. So I might imagine that a really nasty deletion might make some of your antibodies moot, but definitely not all of them.

  25. Julie8989 says:

    Natural deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

  26. Shehla says:

    I came across this blog by Derek which I find so informative. Thank you Derek for these wonderful updates. I have a question about vaccines and I am hoping Derek or someone here may know the answer. Why did the scientists go with experimental vaccine platforms ( mRNA or adenovirus vectored vacvines) first and did not make a vaccine with traditional modality like inactivated whole sarscov2 virus vaccine like China ?

    1. Barry says:

      Around the world, there are at least 80 active vaccine projects on SARSCoV2. They include
      killed virus
      attenuated virus
      DNA
      mRNA
      recombinant antigen
      adenovirus displaying SPIKE protein
      https://www.nature.com/articles/d41586-020-01221-y

      stand by; these mRNA candidates are just the fastest to Phase III

    2. exGlaxoid says:

      Several groups were already working on vaccines for MERS based on mRNA, so they already had most of the technology ready. Making mRNA is quite quick, and can be done with only a sequence, not a live virus, so it was able to be started quite quickly. And mRNA synthesis can be scaled up readily, so that technology has the promise to allow us to create vaccines very quickly in the future. That is why nMRA is the first vaccine class to move forward, it is quickest. Plus there is little risk in making nRNA to only one or two proteins, as that cannot infect someone, so it can be done in most biochem labs.

      Creating and testing attenuated virus requires a safe lab plus quite a bit of time and effort, so while it may be a great way, it take a lot more time to find a good candidate. And making inactivated virus requires first growing live virus, which cannot be done in many smaller labs, plus a way to ensure that the virus has been fully inactivated, as you don’t want to screw that up.

      Making a viral vector vaccine is not triavial, but again, I think some groups were already working on this before Covid, so the technology was already in place, just needed to add a piece of RNA or DNA to the existing vectors to do it.

  27. Sc says:

    I guess the oxford/az one read out a bit sooner than predicted. Looking forward to hearing what the experts think!

    1. debinski says:

      Me too. The protocols are more complicated with various dosing arms, some of which they are not reporting data on (single shot). They are also single-blind. I’m not sure whether these results are definitive as far as the best dosing strategy.
      https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html

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