How COVID-19 vaccines prime T cells to fight new coronavirus variants

• Some SARS-CoV-2 variants of concern can evade neutralizing antibodies in vaccinated individuals, raising concerns about the ability of vaccines to protect against them.
• COVID-19 vaccines also result in a T cell response that facilitates recovery from the disease.
• A recent study investigating variants of concern in individuals immunized with the Moderna and Pfizer COVID-19 vaccines found that the T cell response, unlike the antibody response, was not majorly disrupted.
• These results suggest that an intact T cell response to variants in vaccinated individuals may help prevent severe COVID-19.

The SARS-CoV-2 virus, like other viruses that have RNA as their genetic material, has a tendency to mutate constantly. Consequently, numerous SARS-CoV-2 variants have emerged as the COVID-19 pandemic has progressed.

A few SARS-CoV-2 variants have shown increased transmissibility, with the World Health Organization (WHO) designating them as “variants of concern (VOC).”

These VOCs include the alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2), and gamma (P.1) that originated in the United Kingdom, South Africa, India, and Brazil, respectively. The Centers for Disease Control and Prevention (CDC) recently downgraded the epsilon variant (B.1.427/429) that originated in the United States from a VOC to a variant of interest.

A prior SARS-CoV-2 infection or immunization with a COVID-19 vaccine results in the production of neutralizing antibodies by B lymphocytes, or B cells. They bind to the spike protein of the virus and inhibit its ability to infect the host cells.

VOCs carry mutations on the spike protein that neutralizing antibodies recognize, potentially reducing vaccinated individuals’ immunity to these variants.

For example, the AstraZeneca vaccine is effective against the alpha variant but shows a drastic decline in efficacy against the beta variant. Furthermore, the beta variant also exhibited reduced susceptibility to neutralizing antibodies in clinical trials involving the same vaccine.

How new variants can escape neutralizing antibodies has raised concerns about the ability of vaccines to protect against current and future variants.

However, there is another component of the immune system that involves T lymphocytes or T cells. There are two major subtypes of T cells: CD4⁺ T cells and CD8⁺ T cells.

CD4⁺ T cells, also known as helper T cells, release proteins called cytokines that help mount an immune response by activating other immune cells.

On the other hand, CD8⁺ T cells, or cytotoxic T cells, directly kill virus-infected cells.

Both CD4⁺ and CD8⁺ T cell responses have links with reduced disease severity, meaning they may play a vital role in recovery from COVID-19. Furthermore, COVID-19 vaccines are known to elicit a reaction from these T cells.

Therefore, vaccinated individuals and those who have previously contracted the virus would have T cells that recognize the original SARS-CoV-2 variant isolated in Wuhan. However, scientists did not know whether these T cells would also respond to the SARS-CoV-2 VOCs.

In other words, while some VOCs can evade neutralizing antibodies produced by B cells after vaccination, their effect on T cell response was not known.

A recent study investigated the effect of VOCs on T cell response in individuals immunized with the Moderna or Pfizer/BioNTech COVID-19 vaccines or who previously contracted a SARS-CoV-2 infection.

The research found that the response of CD4⁺ and CD8⁺ T cells obtained from vaccinated individuals to most VOCs was similar to the original variant isolated in Wuhan.

Although the magnitude of T cell response to some VOCs was lower than that of the original variant, the decline was modest.

The study’s results suggest that activation of T cells upon vaccination may offer protection against VOCs, despite their ability to escape neutralization by antibodies.

The study appears in the journal Cell Reports Medicine.

Measuring T cell responses to SARS-CoV-2 variants

To assess the response of CD4⁺ and CD8⁺ T cells to VOCs, the researchers first obtained blood samples from three donor groups.

These groups included individuals without prior exposure to SARS-CoV-2, those recovering or having already recovered from a SARS-CoV-2 infection, and people vaccinated with either the Moderna or Pfizer/BioNTech vaccines.

Donors in the recovering group included those exposed to the original SARS-CoV-2 variant before the VOCs became prevalent in the U.S.

The researchers used the blood samples to isolate peripheral blood mononuclear cells (PBMCs), a subpopulation of blood cells that includes T lymphocytes.

Unlike the activation of B cells that occurs upon recognizing proteins on the surface of a virus or other pathogen, T cells recognize viral proteins digested and broken down into peptides.

Therefore, the researchers used peptides synthesized from the genetic material of the original SARS-CoV-2 and the VOCs. These peptides represented all the proteins produced by these variants.

The PBMCs obtained from a particular donor group were incubated with peptides from a specific SARS-CoV-2 variant for 20–24 hours. The exposure to the viral peptides results in the activation of T cells, which involves a change in the expression of proteins on the surface of T cells.

After the incubation period, the researchers quantified the number of CD4⁺ and CD8⁺ T cells activated in response to the peptides using flow cytometry. Flow cytometry is a technique to identify and quantify different subgroups of cells based on the expression of unique proteins — in this case, T cells activated in response to the SARS-CoV-2 peptides.

The researchers measured the percentage of CD4⁺ and CD8⁺ T cells in vaccinated individuals that activated in response to peptides from a specific SARS-CoV-2 variant.

They found that the magnitude of CD4⁺ and CD8⁺ T cell responses in vaccinated individuals to peptides from the alpha and gamma variant were similar to the ancestral variant peptides.

However, they noticed a 14% and 22% decrease in the magnitude of CD4⁺ and CD8⁺ T cell response, respectively, to beta variant peptides. Similarly, the CD8⁺ T cell response to peptides from the epsilon variant was lower (10%) than the ancestral variants.

These results show that the T cell response to VOCs in vaccinated individuals was largely unaffected.

T cell response to spike protein peptides

The VOCs often carry mutations in genes that code for the spike protein. The spike protein mediates the entry of SARS-CoV-2 into human cells, while spike mutations can increase transmissibility or prevent binding to neutralizing antibodies.

The researchers compared the T cell response to spike protein peptides from the different SARS-CoV-2 variants using flow cytometry. They also measured the T cell response by detecting the secretion of the cytokines IFNγ and IL-5 after peptide exposure.

The team found that T cells from vaccinated individuals produced similar responses to the spike protein peptides from the VOCs and the original variant.

However, T cells from recovering donors showed a lower response to the alpha, beta, and epsilon variants than the original variant in the cytokine assay.

Bioinformatic analysis

The researchers then wanted to understand why the mutations in the VOCs did not significantly affect T cell response.

T cells recognize specific sections on the SARS-CoV-2 peptides called “epitopes,” resulting in T cell activation.

Therefore, the scientists investigated if the mutations in the VOCs affected the T cell epitopes. They studied this by adopting a bioinformatics approach, using an algorithm to make predictions based on experimental data from a previous study.

The analysis predicted that over 90% of the CD4⁺ and CD8⁺ T cell epitopes characterized in the original variant were likely to remain unchanged or conserved in the VOCs.

Similarly, the analysis showed that mutations in the VOCs were not likely to disrupt the ability of these cells to recognize the epitopes and produce an immune response.

Therefore, the bioinformatic analyses showed that the mutations present in the VOCs have a minor effect on T cell response. These results support and complement the data obtained from the experiments described above.

These findings highlight the importance of considering T cell response while designing vaccines. The study’s co-author, Dr. Shane Crotty, noted, “T cell epitopes are well conserved among SARS-CoV-2 variants, so incorporating T cell targets into future COVID vaccines could be a clever way to make sure future variants cannot escape the vaccines.”

Conclusions

The absence of a major disruption of T cell response to the VOCs in individuals exposed to the ancestral variant through vaccination or prior infection shows the crossreactivity of T cells to these variants.

Speaking to Medical News Today, the study’s co-author, Dr. Alba Grifoni, Ph.D., noted: “Our study suggests that at the population level, the majority of the T cell responses are conserved and are able to recognize the variants.”

“While the T cells are not able to prevent infections, they can limit the spread of the infection and consequently limit the disease severity induced by variants that partially escape the antibodies’ responses induced by natural infection or vaccination.”

However, Dr. Grifoni cautioned that their findings were not comprehensive. She said, “Our study did not address differences across all the currently available vaccines. We did focus on mRNA-based vaccination; however, a recent study from Barouch lab showed the same conclusion for the adenoviral vector vaccine Ad26.COV2.S. We have not examined whether responses induced by an infection with a variant sequence will be able to cross-recognize the ancestral reference sequence present in the currently approved vaccines.”

“In our study, a pressing question remains on how T cells behave with the new upcoming variants, particularly delta,” added Dr. Grifoli.

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