We’ve had some interesting vaccine news in the last few days, and it’s worth a closer look. A team from the NIAID, Emory, Moderna (and others) has reported results in a primate model for an Omicron-targeted mRNA booster shot that they’ve been working on, and the numbers are. . .a bit surprising. Macaque monkeys were dosed twice, four weeks apart, with the standard Moderna coronavirus vaccine, and then 41 weeks later one group of them got a booster of the same shot, while another got a booster of the new one with an Omicron variant sequence. Subsequent tests for neutralizing antibody levels, B-cell expansion, and response to a challenge with the Omicron virus itself showed that there was no difference between the two treatments at all.
It’s important to say right up front that both vaccine regimens did a strong job of protecting the test animals – strong enough that both groups of monkeys were pretty much completely protected in the lungs during the challenge study, which in its way makes comparison at that point a bit difficult (protection in the upper airway was strong, but less complete, as it is in humans). So I hope that people don’t get confused as this news gets out into thinking that the Omicron-focused booster did nothing. It worked fine; it’s just that it brought nothing extra compared to the regular booster. The animals showed waning antibody titers during the nine-month interval until the booster, and either one of the boosters brought those back up very strongly (and in fact to levels higher than they ever were). But that said, you’d have thought that there would have been some difference. After all, these vaccines are raising antibodies to a sequence of the viral spike protein, and Omicron has a whole list of mutations in that protein compared to Delta or the earlier variants, and these were incorporated into the sequence of this booster candidate. But with either booster, antibodies were raised with very similar specificities to the Spike protein’s receptor-binding domain.
The authors believe that this is most likely due to the phenomenon known (catchily) as “original antigenic sin”, or less rousingly, antibody imprinting. That’s been seen in many immune responses to many different antigens over the years. A person’s first exposure to a type of virus, for example, can have a noticeable effect on their later responses to similar ones. This is most easily demonstrated with flu viruses, which notoriously change from year to year within a couple of broad families (influenza A and B). The first flu you get as a child or infant can set you up for your ability to respond to various later varieties, but it should be noted that this can be either a less robust or a more robust response later on. Similarly, there’s some evidence of immunological imprinting having an effect in the current pandemic based on responses to earlier types of coronavirus infection. That’s one reason I don’t like the “original sin” phrasing, because it makes things sound like the consequences are always some sort of irreparable wound. In reality, it can go either way. The exact mechanisms behind this effect aren’t completely worked out – you can easily see how memory B and T cells could respond more quickly to a close-but-not-quite later infection, but there’s clearly more to it than that.
But this new preprint fits perfectly to an earlier result from the same team. The Beta variant was the previous champion at immune evasion among the coronavirus types, but (just as in this current work) a vaccine booster containing its sequence failed to protect macaques any differently than the regular vaccine+booster. It’s likely that we would not see any benefit from tailored booster shots unless we are dealing with a coronavirus variant that’s still further away in its sequence than Omicron. It’s impossible to say if we’ll ever get one of those – one hopes not – and it’s also impossible to say when we might have crossed the “New booster could be a good idea” line, either. You also would wonder what you’d get in either animal models or humans if you started with the Omicron-specific vaccine, rather than putting it on top of the original one as a booster. It’s possible that you might end up with a better response to Omicron per se, but as mentioned in the above paragraph, the subsequent effects on immunity to some future variant could go either way. Immunology! Such an experiment would at least control for any intrinsic differences in immunogenicity between the different Spike proteins, which is another possible effect that’s at work here.
I have been getting an increased number of questions about the whole original-antigenic-sin idea over the last few weeks, I have to say, so this paper is timely. But there’s a lot of confusion out there. Some people have been using this as a reason not to get a booster shot, for example, but what I take from this latest work is that that’s completely the wrong way to look at it. It’s the original vaccination that did the imprinting, if that’s what’s going on, and the booster is just not going to imprint you any more. The booster is still very beneficial for protection against severe illness from Omicron as compared to not getting boosted at all – and of course anything is preferable to not being vaccinated in the first place. You can look at this whole thing from glass-half-empty or glass-half-full perspectives. The former, in its most extreme Twitter-rific form, might be summed up as “We’re hosed. We vaccinated against an earlier coronavirus and now we can’t do any better no matter what comes along“, and the latter might come out as “Hey, those first vaccines were pretty damn good, maybe with protection about as powerful as we could have possibly have reached. We’re still showing strong effects all these variants later; nothing beats ’em“. My own take is that if a variant comes along that’s horrific enough to show major immune evasion, that very property will make it something that a new vaccine booster is likely to be able to target usefully. Omicron isn’t it, though. It’s different enough to be much faster-spreading, but it’s similar enough for the current vaccines to still provide a huge amount of protection.
By the way, this might be a good time to help dispose of a conspiracy theory that’s been going around for a while. You can find all sorts of people on social media who will try to convince you that the coronavirus vaccines (and particularly the mRNA ones) were somehow “never tested” in animals. That is of course wrong: the FDA will not even let you go into human trials without animal data for both efficacy and safety, much less approve a new therapy under an EUA or regular authorization. All of these vaccines have been through studies in mice and in primates (the regulatory authorities want two species as well, as they should). The second variant of this rumor is that animals were dosed, but (insert violin part from Bernard Herrmann’s score for the shower scene in Psycho). . .they all died. Also false. You’re not going to get very far with your application after that, either – and this study, along with many others in the literature, show that you can indeed dose animals with the mRNA vaccines. I don’t suppose it’ll do much good to take a whack at this one, but you have to try.
Let’s also take a moment to whack another conspiracy theory while we’re at it. You can find plenty of finger-wagging BS artists out there who will assure you that the “so-called variants” are nothing more than a plot to keep injecting people with vaccines over and over. This crowd differentiates a bit when you ask them why the evildoers want to keep doing that, with some of them muttering about 5G cell phone towers, others about dosages of the latest nanobots for tracking and crowd control, the really hard-core ones going on darkly about plots to weaken the population in order to kill off various targeted groups outright, and others just saying that it’s all a plot to keep making money. If any of this were the case, would you see an open discussion in the literature (with piles of data) about how an Omicron booster provided no extra benefit? You would not. So these people should buzz off, too, although they won’t. Decades from now they’ll be boring everyone around them in the rest home about the same stuff.
