From Alpha To Omicron: T cells hold up as SARS-CoV-2 evolves

Immune protection against SARS-CoV-2

If you’re one of the billions of people vaccinated against SARS-CoV-2, you may be wondering how well that protection is holding up as the virus continues to evolve and spawn new variants. You might have even experienced a breakthrough infection, or caught COVID-19 even after being fully vaccinated. These types of infections have unfortunately become more common as our immunity is less able to recognize mutated forms of the virus.

We now know the major parts of our immune system that are important in fighting SARS-CoV-2. Antibodies, which are produced by B cells, latch on to SARS-CoV-2 virus particles and prevent them from infecting our cells. Like base to acid, these “neutralizing” antibodies are especially important for counteracting a virus and preventing infection. Another major player known as T cells, help train B cells to produce these protective antibodies and also have important roles in eliminating cells that have already been infected. To remove infected cells, T cells first need to be able to recognize tiny pieces of the virus that stick out of infected cells. While T cells have important functions in limiting how sick you get after becoming infected, antibodies prevent you from becoming infected in the first place, which is why they have generally taken center stage in vaccine development efforts.

Variants disguise themselves from the immune system

However, the litany of SARS-CoV-2 variants that has emerged over the past two years shows just how cunning the virus can be. New variants donning unique sets of mutations have been able to slip past antibodies that are otherwise effective against earlier versions of SARS-CoV-2. Since parental forms of SARS-CoV-2 were used to develop most of the vaccines currently available, an important question going forward is how well the protection these vaccines provide will hold up against newer forms of the virus.

Some scientists think that T cells may provide an answer. While antibodies, which are key in preventing viral infection, have been thrown off by some variants that have popped up over the course of the pandemic, researchers have noticed that T cells are much less susceptible to virus shape-shifting. A recent study measured how well these different parts of the immune system in vaccinated individuals hold up against a wide variety of SARS-CoV-2 variants. 

Tarke and colleagues analyzed immune responses in people who received one of four COVID-19 vaccines: the mRNA vaccines produced by Pfizer or Moderna, the adenovirus-vectored vaccine developed by Johnson & Johnson, or the recombinant vaccine of Novavax. To address this question, the researchers recruited and collected blood from vaccinated individuals to measure how well their immune systems could recognize different SARS-CoV-2 variants. They focused on analyzing three main types of immune responses that we know are important in fighting SARS-CoV-2: T cells, B cells, and antibodies. First, the researchers measured T cell responses by mixing immune cells with synthetic pieces of SARS-CoV-2. The principle behind this type of experiment is that if the T cells have previously encountered the virus–or have been adequately trained by a vaccine–then they will respond to the artificial virus shards as if they were the real thing.

Not all parts of the immune system are easily fooled

For each of the vaccines, the researchers detected T cell responses capable of recognizing SARS-CoV-2 variants equally as well as the original form of the virus. T cell recognition of the ancestral virus remained consistent for a whole spectrum of diverse variants. In the vast majority of subjects, the T cells responded by producing cytokines, molecules important for orchestrating immune responses, and displaying proteins showing that they retained their virus-fighting capabilities against variants of SARS-CoV-2 they had not previously encountered. The researchers dove deeper and analyzed memory T cells, a specialized cell type whose job it is to remember viruses long-term. They made similar observations in these memory cells, which recognized major SARS-CoV-2 variants including Alpha, Beta, Gamma, and Delta.

The researchers then carried out a computational analysis of “epitopes,” or specific pieces of the virus that T cells recognize. They found that most T cell epitopes are identical across SARS-CoV-2 variants, which helps explain why T cells seem to recognize variants about as well as the original virus. When analyzing Omicron, the most recent variant, the researchers detected fewer fully identical epitopes compared to previous variants, but they noted that the majority of T cell epitopes in Omicron remained unimpaired, suggesting that evading T cells is likely not the primary reason the virus has been mutating at such a rapid pace.

Figure 1: Immune response to variants of SARS-CoV-2. Schematic depicting recognition of SARS-CoV-2 variants by different parts of the immune system. Top: T cells recognize SARS-CoV-2 variants nearly as well as the ancestral form of the virus. Bottom: B cells and antibodies have reduced activity against SARS-CoV-2 variants. Omicron is especially savvy at evading antibody responses.

Other parts of the immune system are thrown off as the virus mutates

Next, Tarke et al. analyzed antibodies and B cells, other parts of the immune system that are important in fighting SARS-CoV-2. In contrast to the promising observations they made for T cells, some SARS-CoV-2 variants were able to dodge these immune players. Memory B cells, which as their name implies, are supposed to be able to remember viruses for the long haul, could not recognize some of the variants to the same extent as the original SARS-CoV-2.

Similarly, the researchers found that antibody responses were compromised against several variants. Although it is well understood that SARS-CoV-2 variants are adept at disguising themselves from these immune molecules, the observation was concerning nonetheless. As SARS-CoV-2 evolves and variants continue to emerge, antibody responses from either vaccination or prior infection haven’t been able to hold up as well as T cell responses.

Reason for hope

While vaccine-induced antibody responses showed some decline against recent forms of the virus, the fact T cells are largely unimpaired is reason for hope. “The main takeaway is that T cells are still effective against the current SARS-CoV-2 variants, including omicron,” said Alison Tarke, lead author of the study. “The memory B cell and antibody response was more impacted by the variants, but we saw good T cell responses were maintained even at the later time points. We know that T cells cannot prevent infection but if you do get infected they can help you have a more mild case.”

Given that T cells are looking promising against SARS-CoV-2 variants, some scientists have called on regulators to consider T cell responses in assessing vaccine success in the long term. Antibody responses have so far been the star of the show in evaluating vaccines, but a broader assessment of vaccine-induced immunity may paint a more accurate picture of the protection these vaccines provide from severe disease.

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