Penny Moore, PhD, is research chair of Virus-Host Dynamics at the University of the Witwatersrand in Johannesburg, South Africa. A human immunodeficiency virus (HIV) researcher for about two decades, Moore redeployed much of her HIV research to measure humoral immune response to SARS-CoV-2 infection and vaccination. She recently participated in an audio interview about COVID-19 and the human immune response with the New England Journal of Medicine. Following is a transcription of the interview, which has been edited for length and clarity.1
Question: Antibody is only one component of the host response. Is there any way to judge how important it is as compared to T cell responses?
Moore: There’s a lot of redundancy that’s been built into the immune system. We know from lots of vaccine studies, and from work with monoclonal antibodies as well, that antibodies are really good at preventing infection, but in terms of prevention of severe disease, it’s probably a lot more complex than that. It seems most likely that prevention of severe disease is mediated by T cells and perhaps by non-neutralizing antibodies.
Neutralizing antibodies are just one small portion of the antibody response against SARS-CoV-2. Those are the antibodies that block infection, but non-neutralizing antibodies recruit Fc effector cells, and those may clear up infected cells after infection has happened.
The thing about T cells and about non-neutralizing antibodies is they have proven to be much more resilient against the variants of concern than the neutralizing antibodies. Neutralizing antibodies get knocked off by mutations quite easily, but the T cells and the non-neutralizing antibodies, they’ve managed to hold on, despite all the mutations that the various variants of concern have picked up. The problem with the T cells and with the non-neutralizing antibodies is we have very little sense of how much is enough to prevent severe disease.
We know quite a lot about antibodies, we have a good sense — a relatively good sense — of how much antibody is enough. But when we think about T cells, we actually don’t have a good way to measure that. It’s probably for two major reasons.
The first is that measuring T cell responses is much, much harder than measuring neutralizing antibody responses. And you need cells to be stored, and many times clinical trials don’t include those cells because it’s incredibly difficult and expensive to store them. And then the other problem with understanding how much is enough when it comes to T cells is that you need correlative [immune] protection from severe disease, and actually severe disease is becoming rarer and rarer, so it becomes increasingly difficult to actually design and conduct the experiments that we need to do to be able to understand how much is enough for T cells.
Question: Why is the T cell immune response less affected by SARS-CoV-2 mutations than circulating antibodies?
Moore: T cells recognize many more epitopes on the [virus] spike than most of the neutralizing antibodies. The neutralizing antibodies are kind of laser-focused on two or three specific areas of the spike, and so any mutation in those areas has a huge impact on neutralizing antibodies. But the binding antibodies or non-neutralizing antibodies are very specific, actually. They’re still very specific to the spike, but they recognize much larger chunks of the spike. In fact, they recognize almost the complete spike. And it’s the same with the T cell response, the CD8 responses, CD4 responses — they recognize large chunks of the spike.
A few scattered mutations, even as many mutations as we’re picking up in Omicron, has a huge impact on the neutralizing antibodies, but much less of an impact on binding antibodies and virtually no impact from what we’ve been able to see, fortunately, on the T cells. Even in Omicron, which had more than 30 mutations across the spike. So, it takes a lot more to knock those T cells off.
Question: Is there an “affinity maturation” or improving quality of the antibodies that an individual makes?
Moore: Yes, this is a really cool aspect of B cell biology, which is that antibodies essentially compete with one another in our bodies to become better and better. They re-enter a germinal center, which is a structure where they compete with one another. The antibody with the best binding potential outcompetes antibodies that are less good, and so those antibodies pick up more and more mutations, very much in the same way that the virus picks up mutations over time. And as those antibodies pick up beneficial mutations, they’re selected for.
Over time, in infections, you get antibodies that pick up more and more good mutations and that allows those antibodies to bind to the pathogen better and better. And we are seeing a lot of that in SARS-CoV-2. I think even more, perhaps, than we expected for an acute infection.
Question: Can you comment on the immune response to natural infection compared to vaccine-generated immunity?
Moore: Vaccination seems to trigger really, really good blood antibodies, but it’s infection that really triggers particularly good mucosal responses. People who’ve been infected most likely have better mucosal responses than people who’ve been vaccinated. And people who have hybrid immunity, a mixture of vaccination and infection, those people likely have very good mucosal responses.
The other major difference between people who’ve been infected compared to people who’ve been vaccinated is the fact that vaccines generally only contain the spike protein, whereas with infection, people’s immune systems are exposed to the entire virion, particularly from a T cell perspective. That’s really important because T cell epitopes span many more parts of the virion than just the spike protein.
It’s likely, at both the antibody level and the T cell level, that the responses are qualitatively different, depending on whether you’ve been vaccinated or infected. You get good antibodies and great T cells regardless, but there are probably some more subtle differences in quality between those two scenarios.
Question: Do you think that these constraints are going to ultimately limit the ability of a new highly virulent strain to develop in a population with lots of preexisting immunity?
Moore: One thing that we’ve learned in this epidemic is not to try to predict anything that this virus does, but I think a few things are certain.
With the number of transmissions that still occur across the world, with the fact that in many countries, particularly in Africa, vaccine rollouts have been poor, I think one thing that is certain is we’re going to see new variants. The virus is constantly trading things off. Mutations that occur in the virus occur randomly, but selection occurs. Although the mutations may be random, whether or not they persist in a viral population and come to dominate it kind of at population level, that depends on how they help the virus. And it’s always a tradeoff. This is what viruses do. They pick up mutations.
I think that the high levels of population immunity out there may mean that we’re getting fewer severe diseases, but we’re seeing huge numbers of transmissions. Every transmission comes with a risk that the virus is going to pick up more mutations.
I definitely don’t think that we can assume that all variants, looking forward, are going to be variants that are of lower virulence. I don’t think we can assume that at all. The mutations that give a virus an advantage in terms of transmissibility vs. immune-evasive properties, they’re often different.
What we do know from all viruses is that they are very good at circumventing our immune responses.
REFERENCE
- Rubin EJ, Baden LR, Moore PL, Morrissey S. Audio interview: Dissecting the host response to SARS-CoV-2. N Engl J Med 2022;386:e69.
Penny Moore, PhD, an HIV researcher for about two decades, has redeployed much of her research to measure humoral immune response to SARS-CoV-2 infection and vaccination.
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