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!