It is now well known that SARS-CoV-2, the virus that causes COVID-19, can mutate to avoid vaccine protection against infection. The Omicron variants – BA.1, B1.1 and BA.2 – can infect those who were previously infected with other variants, even when vaccinated. A third booster shot provides some protection against an Omicron infection, but it decreases after three or four months, which leaves most people susceptible to re-infection. That said, immunity from previous infection or vaccination still dramatically reduces the incidence of hospitalization and death.
We have also come to realize that our main saviors against COVID-19 turn out to be not antibodies, but rather another part of the immune system: T cells. Studies show that the potency of our long-lived T cell response to the virus’ proteins – particularly of T cells that recognize the spike protein – is strongly correlated with the degree of protection.
There are two types of T cells, CD4 + and CD8 +, which are characterized by proteins on their surface. Because CD4 + T cells mostly help with the production of antibodies, the CD8 + T cells are the real heroes of history. Once they have identified an attacker they remember from a previous encounter, they act quickly to move in to kill, breaking down infected cells and shortening the virus’ life cycle.
Until Omicron, the differences in neutralization with vaccine-induced antibodies and of monoclonal antibodies were relatively small. However, the process by which T cells recognize viral proteins is very different from that of antibodies that recognize structures on the intact viral protein. We know that these critical structures, especially those of the outer peak protein, differ from variant to variant. It is precisely such a structural diversity that allows the virus to evade most antibodies that are formed in response to natural infection and vaccination.
In contrast, T cells do not recognize intact proteins. Rather, T cell recognition occurs when a viral protein in a cell is cut into short segments and rocked in the grip of a cellular protein called MHC type 1. MHC type 1 presents the viral fragment to the T cell on the cell surface where the T cell can recognize the combination of the viral fragment presented by the MHC type 1 protein.
T cells recognize and respond to a very wide range of viral protein fragments. For SARS-CoV-2, these fragments overlap very little with those regions of the virus that are sensitive to neutralization of antibodies. This is why T cell responses to viral infection are generally conserved across variants.
Until Omicron produced vaccines using one viral protein, almost the same T cell response to all variants. But now the situation has changed. Our MHC type 1 proteins are different, and each recognizes a unique set of viral protein fragments. Thus, our response to viral proteins depends on their sequence and on our own particular MHC type 1 set of proteins.
Consider a recent study by Gaurav D. Gaiha and his colleagues examining T cell responses to the Wuhan, Delta, and Omicron strains in humans who have either been infected, vaccinated, and boosted, or infected and vaccinated but not boosted. They found that most people infected after vaccination have strong and lasting CD4 + and CD8 + responses on all three variants.
But there was one worrying discovery. About 20% of those vaccinated showed one decrease of more than 50% in T cell response to Omicron compared to the Wuhan and Delta variants. These poor T cell responses were not correlated with gender or age, and follow-up experiments showed that the difference was due to lower CD8 + reactivity rather than the CD4 + T cell response.
The authors speculate that the inability of CD8 + T cells to respond to Omicron may be due to a lack of recognition of the mutated peptides. In fact, their theoretical calculations are consistent with the hypothesis that changes in the amino acid sequence of the Omicron spike protein underlie the observed blind spots in T cell recognition. Inherited differences in the ability to recognize specific protein fragments are likely to be the cause of some people’s inability to build anti-Omicron defenses. The authors offer presumption that “it is possible that these persons will have reduced protection against serious illness.”
A sober conclusion is that Omicron is driven so far from the original strain that 20% of the people in the study may not be fully protected, neither from infection nor from hospitalization and death. However, the study found that a third dose of vaccine increases T cell responses 20 times or more.
“While the Omicron spike protein was able to escape T cells in a subset of individuals,” Gaiha told me, “what we learned is that this deficiency in T cell recognition can be overcome by booster vaccination. In addition, we found that non-spike proteins could be attractive targets for second-generation vaccines to protect against future SARS-CoV-2 evolution. “
Gaiha is in favor of an optimistic interpretation. But Omicron is a warning that future variants could escape both antibodies and T-cell immunity. We can not predict whether a variant will emerge that evades the vaccines’ ability to protect against infection and serious illness, but we must be prepared for such a threat so that we do not remain unguarded from it.
William A. Haseltine, a scientist and entrepreneur, is the President and President of ACCESS Health International, a global health think tank.