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More Pfizer Phase I Results: Antibodies, Viral Mutations, and T Cells

Recent posts here have gone into Moderna’s Phase I vaccine data, Pfizer’s Phase I vaccine data, what we don’t know yet about the relationship between T-cells, antibodies, and immunity to the coronavirus, and some new data that are starting to fill in those gaps. This morning comes a new preprint from the Pfizer/BioNTech team that lands squarely in this territory, and let me say up front that I think they have some very encouraging results. It’s a good way to start the day.

The previous Pfizer/BioNTech publication (a randomized double-blinded trial) focused on the antibody response (which looked pretty solid), but said nothing about T-cells, and as those two posts linked above make clear, I (and many others!) believe that that part of the immune response looks to be of great importance. This new paper makes up for that gap: it’s from a second study of the same mRNA vaccine candidate BNT162b1, this one non-randomized and open-label. I’m not as concerned about that in this case, since this same vaccine is being studied under controlled conditions at the same time – this work seems to be a “let’s get a read on T cells and dosing protocols”, and I’m fine with that, since those are not going to be very susceptible to placebo effects or investigator bias.

This work has five groups, with 12 patients each. One of them got a 60 µg dose of the mRNA formulation at Day a, and that’s all. The other groups got 1, 10, 30, and 50 µg doses, respectively, on Day 1 and again at Day 22, so this design provides a broader look at dose-response and at the effect of boosters versus a single injection. There were no serious adverse events – but remember, in the regulatory lingo, a serious event is a serious one indeed. What were observed were dose-responsive reactions (worst at the highest doses) of just the sort you’d expect: pain or soreness at the injection point, and overall feelings of fatigue, headache, muscle and joint pain, and some fever. It’s hard to do a head-to-head just yet, but these might be a bit less than Moderna’s Phase I results – at any rate, it seems clear that you’re definitely going to know that you’ve been vaccinated with these mRNA species. It will be interesting to compare the responses to the adenovirus vectors and others (word is expected on the Oxford/AstraZeneca work later today, in fact, and I’ll blog on that as soon as it appears as well).

There were changes in C-reactive protein and lymphocyte counts that are consistent with the “self-adjuvant-ing” nature of mRNA vaccines in general, but no other blood chemistry events. Consistent with the earlier trial data, there was a robust antibody response. What you find when you look at the paper’s Figure 1 and Figure 2 is that total antibody production kicked in somewhere between day 8 and day 22 (pre-booster shot), at all doses – and honestly, the doses don’t really look that different in that data. The 1 µg dose is weaker than the others (although not hugely so), and the 10, 30, 50, and 60 µg ones look quite similar. The booster shot (in those first four doses) raises things by about 10-fold.

When you look at neutralizing antibodies, the picture sharpens up (as it did in the Moderna data). There’s a more pronounced dose-response (the 1 µg dose is clearly inferior), and you can see, again as in the Moderna data, that the booster is really needed to get up to strong titers of neutralizing antibodies. The 60 µg-dosed-once data just can’t compete – the antibodies go up a bit and just stay there, and it’s clear that even 1 µg dosed twice is superior. The levels reached were in the upper range of those found in a convalescent serum panel for comparison, similar to what Moderna found with their candidate. Another very interesting point: I noted in the earlier post that Moderna’s neutralizing antibody data looked best at Day 43, and then went down a bit. These Pfizer/BioNTech numbers look best at Day 29, and have gone done a bit at Day 43. The effect is not huge, but it’s real. The text of the paper says “still increasing up to Day 43”, but that’s not what I see in Figure 2, and I don’t think I would have used that language, myself. More on this below,

On the other hand, there’s some valuable good news on the antibody front. Many people have been wondering about the effects of mutations in the Spike protein of the coronavirus – both on infectivity and severity of disease, and what these might mean for both monoclonal antibodies and for vaccines. Here’s a paper that just came out in Cell with a comprehensive look at the mutational landscape (100 variations), and it finds that the D614G mutant (which has been becoming more common, a post on that is here) does indeed appear to be more infectious. Moreover, it notes several variants that appear to be more resistant to neutralizing antibodies. This Pfizer/BioNTech manuscript (in Figure 2c) shows how well the neutralizing antibodies raised by this vaccine perform in a pseudovirus infection assay against 17 variations (including D614G), and they are all within error bars of each other, from what I can see. Moreover, one of the antibody-resistant variants from the Cell paper (V483A) is in this panel, and it’s also no different. So it looks like (from what we can see so far) that the neutralizing antibody response brought on by this vaccine candidate can handle a wide range of mutations in the Spike protein and its receptor-binding domain.

But (as I was going on about above), antibodies are not the whole story in the immune response to the coronavirus. Read those two posts linked on the subject if you haven’t, but the short form is that it appears that T-cell responses may be (1) longer-lasting, (2) important for some degree of protection against infection, and (3) perhaps already present (pre-COVID-19) in some fraction of the population due to exposure to as-yet-uncharacterized animal-derived coronavirus infections that we haven’t even noticed over the years. Moderna characterized their T-cell responses, and saw mostly CD4+ (as opposed to CD8+), and in those, mostly a Th1 response (see that earlier post for more on that). In this case, BNT162b1 produced CD4+ responses in 34 of 36 patients (one of these did have low levels of pre-existing reactive CD4+ cells, by the way – a lower percentage of people than found in the recent Nature paper, but it does confirm that such people are out there). The CD4+ responses correlated with the antibody titers raised in individual patients. And as with the Moderna results, these seemed to be almost entirely Th1 instead of Th2 – the authors believe that this is potentially a good thing, but as noted in the Moderna post, you can find arguments both ways about that point.

But as opposed to the Moderna candidate, there was also a robust CD8+ T-cell response (29/36 patients), which did not necessarily correlate with the antibody titers raised by the vaccine. Interestingly, neither of these T-cell effects were very dose-responsive. 6 out of 8 patients tested in the 1 µg dose cohort raised a T-cell response, and their CD4+ and CD8+ levels were almost the same as the 50 µg group! As a per cent of total circulating T cells, the levels seen after vaccination were significantly higher than those seen in the blood of convalescent patients, which could be a real difference. Recall that in the case of the 2003 SARS coronavirus, that antibodies disappeared from recovered patients, but that T-cell immunity has persisted for up to 17 years.

So while one would want to keep an eye on the antibody levels with this candidate (and believe me, you can be sure that Pfizer and BioNTech are doing that), the T cell response looks promising (and probably better than the Moderna candidate). We’ll have to keep all this in mind as the actual Phase II/III data hit, and we’ll see what difference all this makes in the real world!


36 comments on “More Pfizer Phase I Results: Antibodies, Viral Mutations, and T Cells”

  1. Roney says:

    Typo: have gone done ** (DOWN) a bit at Day 43

  2. theg9 says:

    It’s known that the thymus shrinks as we age and this can lead to reduced T cell production over time. Thus, any vaccines which stimulate T cell production as a response would probably be less effective in the elderly? This is known to happen with some flu vaccines, in which the doses for the elderly are tailored with much higher levels of antigens or adjuvants (which leads to other issues, but that’s a different conversation).

    1. cole says:

      ‘Any vaccines which stimulate T cell response’ is all vaccines. They are all generally less effective in the elderly for a host of mechanisms beyond just the thymus. For example, metabolism plays a huge role in lymphocyte viability, development, and diversity. Thus it’s very likely that the same issues will be seen with this vaccine. However, a vaccine effective in younger populations can get us to the point of herd immunity, and it would likely reduce the severity of disease even in e.g. elderly patients that do not demonstrate fully protective immunity (this is seen with influenza).

      1. Charles H. says:

        Didn’t I read a few months ago, WRT the Oxford vaccine, that in a test of apes the vaccine yielded not immunity, but rather a strong resistance to a severe case of COVID? In other words, how likely is it that the vaccine would increase the proportion of “silent spreaders” rather than producing herd immunity.

        This has bothered me considerably, but I haven’t seen anything further about the result. Except that “silent spreaders” seem to be a large proportion of human cases.

    2. Mike in Watertown says:

      As I read more about T-cell response, I am surprised not to hear more about thymosin for elderly patients. I see there is at least this Phase 2 trial:
      Is there more work that I am not hearing about? Or would there be a reason not to expect thymosin supplementation to be clearly beneficial?

  3. Dr. Manhattan says:

    Apropos thereunto, this was just released a few minutes ago on the Oxford/AZ vaccine. Both antibody & T cell responses observed. They claim that one dose elicited a good response. We will have to wait and see the published data.

  4. Carlos says:

    Great news. Nevertheless, I tend to be suspicious about ‘only’ good news about COVID-19 vaccine results. Are the bad results not published? Is it really going so fast precisely in the most-wanted-ever vaccine? We’ll see.

    1. Ken says:

      Derek’s last vaccine roundup post (July 7) listed 30 candidates, so perhaps it’s not that surprising that we’re hearing good results from one.

    2. Riah says:

      I would be far happier to see at least one of these candidates being tested against a true saline placebo instead of another vaccine. Is there one?

      1. Steve Scott says:

        They don’t want to use saline because the participants aren’t supposed to know if they’re getting the vaccine or a placebo. If they experienced no side effects from the shot, they would know they are in the placebo group. So, the placebo shot is a harmless off the shelf vaccine that will give you the same dragged down feeling.

        1. Riah says:

          that presupposes all of them know they are supposed to (and that in fact 100% of the vaccine recipients will) all experience side effects with the vaccine. Is this actually the case? I know that in the case of the Oxford vaccine, the “placebo” is a mengingitis vaccine with many known side efffects. What does it matter if they guess anyway- they still can’t be sure and it can’t influence whether they get covid or not, or how badly they get it – can it? It would give people more confidence if they used a harmless saline placebo – they could always put a minor irritant in it if recipients “knowing” concerns them.

          1. confused says:

            >>What does it matter if they guess anyway- they still can’t be sure and it can’t influence whether they get covid or not

            It could if knowing they got the real vaccine led them to be less careful about avoiding exposure.

  5. Matthew Gruner says:

    I’m curious about the genetic diversity of the test group and its effect on changes in the T cell response when things are scaled up to phase 3. Is there enough MHC diversity in these earlier phases to be predictive of the wider population. I’m reminded of the WEIRD (Western, educated, industrialized, rich and democratic) problem in psychology.

    1. A Nonny Mouse says:

      This is addressed as a concern in the Oxford study (90% white). I am sure that the Brazil and SA arms of the study will supply the necessary data.

    2. Barry says:

      I’m less concerned with the genetic diversity of the clinical population than with their age distribution. It is expected that younger patients will mount both humoral/B-cell and cell-mediaed/T-cell responses. That will be different in older subjects.
      Of course a vaccine maker would want to get FDA approval in all age-groups. But it may be that older subjects benefit more from herd immunity than from their own immune competence.

  6. Walter Sobchak says:

    Just released report on Phase I/II Oxford vaccine trials:

  7. Barry says:

    Very heartening that Pfizer is investing the effort to monitor more that circulating IgG

  8. Pete says:

    Derek: any thoughts on combination of mAB-evading/increased infectivity spike mutations and immune durability? Is there evidence to indicate whether we should worry about similar effects on cell immunity?

  9. George T Tenet says:

    Is the pfizer/biontech T-cell response including CD8+ specifically directed to the virus (eg, viral antigen and in in vitro assays), Or a generalized measure of T-cell CD8+ activity? Could this T-cell response be to just the (modified) nucleic acid component of the vaccine?

  10. Marko says:

    “…. a paper that just came out in Cell with a comprehensive look at the mutational landscape (100 variations), and it finds that the D614G mutant (which has been becoming more common, a post on that is here) does indeed appear to be more infectious. ”

    Never fear. The blue check-marked “experts” will continue to shout ” Founder effect ! Founder effect ! ” until their lungs collapse ( or they expire from D614G Covid-19 , whichever comes first. )

    1. Charles H. says:

      From various earlier reports, the variant is more infectious, but no more dangerous. It tends to lead to higher viral loads but not to sicker patients. (Take this with a grain or two of salt as I don’t remember my sources. Possibly Science News.)

      Also, apparently any immune reaction to one strain carries through to the other. And if you catch COVID in Europe or the US you likely caught the fast spreading variety.

  11. anon the II says:

    If Pfizer solves this problem, then I’ll forgive them for firing* me.

    *acquired biotech where I worked and let us all go..

  12. Lane Simonian says:

    As others have noted, many older individuals and/or those with co-morbidities are likely to have t-cell dysfunction to begin with. In the presence of this dysfunction, the body in many cases likely produces an overimmune response to the novel coronavirus. I am not sure to what degree any vaccine can overcome this. I am not even sure how much providing partial immunity to healthy individuals would slow down the spread of the virus.

    Probably a better approach would be to seek treatments that partially reverse t-cell dysfunction while at the same time tamping down further immune responses (curcumin, ebselen, ginseng, quercetin, etc.).

  13. Ignoramous says:

    Maybe this is a ridiculously silly question or perhaps it has been answered already….

    But how the heck are they testing for antibodies when there is no FDA approved test for serology testing?

    Ignorance can be cured…who has the cure?

    1. Nile says:

      A research group has access to tests that are performed in the research lab – complex, cumbersome, labour-intensive, and needing a lot of checking and re-testing – which will never be turned into a simple test that can be rolled-out commercially in a vial with a colour-change testing strip.

      Note, also, that the kind of mass-produced test that goes out with FDA approval is – usually – “Is it here or not? ”

      … And the vaccine development team’s testing lab won’t be simplifying and mass-producing their tests any time soon: they are asking “How much?”, and measuring several closely-related things separately, not the single, simple, “it” of a widely-released clinical test.

      1. Not so Ignorant Anymore says:

        OK got it! I think that first line about “labour intensive” says it all. Commercial labs need production line tests – fast & cheap. Now I see where the researchers have the incentive to do more cumbersome testing. Also see that a serology test would be a +/- proposition, while the vaccine producers are answering, how much and what types.

        Thanks for the clarification!

  14. GTT says:

    If known, which cell, tissues, organs pick up these nucleic acid based vaccines to express them?

  15. Excellent post and wonderful blog, this sort of interesting posts I really like, keep it up…

    1. Riah says:

      Derek, or anyone, please can you explain exactly how the mRNA ( Moderns, Pfizer etc, not Oxford which uses chimp Adenovirus) gets inside cells without being degraded? Do the different RNA vaccines have different strategies for this which would then affect their relative success in driving a response? Apologies if you already covered this somewhere – if so please point me to it. Thanks

  16. Kim says:

    I am in a trial study for the vaccine through Pfizer and have received two shots, 21 days apart. Of course since they do not tell you if you have had the vaccine, I decided to have an antibody test through Labcorp 14 days after my second shot and 36 days from the first shot. My results where as follows:

    This sample does not contain detectable SARS-CoV-2 IgG antibodies.
    This negative result does not rule out SARS-CoV-2 infection.
    Correlation with epidemiologic risk factors and other clinical and
    laboratory findings is recommended. Serologic results should not be
    used as the sole basis to diagnose or exclude recent SARS-CoV-2
    infection. This assay was performed using the Abbott SARS-CoV-2 IgG assay.

    Does it mean that I did not receive the vaccine or will this test performed by Labcorp not pick up the same antibodies that are in the vaccine?

    1. Marko says:

      “Does it mean that I did not receive the vaccine or will this test performed by Labcorp not pick up the same antibodies that are in the vaccine?”

      The latter , it looks like :

      “… The assay is a chemiluminescent microparticle immunoassay for qualitative detection of IgG in human serum or plasma against the SARS-CoV-2 nucleoprotein. ”

      What you wanted was an anti-spike antibody test , not anti-nucleoprotein.

  17. Nancy Iannelli says:

    Same here–thinking maybe a different test is required or an error. First injection pain at the injection site. After the second injection I had a fever (101) and mild body aches for 2 days, and pain at the injection site for 5 days. Had antibody test at labcorp 7 days after 2nd injection and received the same negative result.

  18. Dave Shabat says:

    I did the trial study for the vaccine through Pfizer and the result fro the SARS-CoV-2 IgG antibodies was Positive but some of my levels are low and I don’t know if it is because the Vaccine or something else:
    ABS Lymphocytes 698 cells
    RBC: 5.15
    HTC: 38.3%

    Any idea?


  19. Pam Barker says:

    How are the covid vaccines metabolize (what genes are involved) I have several mutations, and am trying to decide if the vaccine would be in my system long enough to do any good or would it be toxic as some drugs are for me.

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