COVID-19: Are T cell vaccines the future?

• Current vaccines target the spike protein of SARS-CoV-2. This protein mutates frequently, which could make currently available vaccines less effective.
• Researchers in the United States recently investigated the effects of T cells that recognize a different protein in the virus — one that does not mutate as quickly as the spike protein.
• T cells are a type of white blood cell that can ‘remember’ antigens for decades. Vaccines developed using this new approach may provide more lasting protection.

All current COVID-19 vaccines encourage the body to generate antibodies that target the spike protein of SARS-CoV-2, the virus that causes COVID-19. But variants of the virus often have mutations in this protein.

Researchers warn that as the virus continues to mutate, variants may resist these antibodies and thus escape the protection of currently available vaccines.

In an effort to develop second-generation COVID-19 vaccines, some scientists are looking at parts of the virus that do not mutate as quickly. Among them are scientists from the Broad Stem Cell Research Center, at the University of California, Los Angeles.

A team from the center recently completed a study showing that rare T cells, a type of white blood cell, can target a different protein in SARS-CoV-2 and a range of other coronaviruses. Part of this protein is an enzyme called viral polymerase (RdRp).

Theoretically, vaccines based on RdRp could trigger a longer-lasting immune response, as well as greater protection against future variants.

But, as Martin Hibberd, a professor of emerging disease at the London School of Hygiene and Tropical Medicine, noted in an interview with Medical News Today, “It is worth pointing out that so far, universal vaccines are not required, as we have not yet had a variant of SARS-CoV-2 that can escape the current vaccines.”

The new study appears in the journal Cell Reports.

How T cells function

T cells are white bloods cells that help fight infections. Each has a unique protein called a T cell receptor on its surface that can recognize fragments of foreign proteins, such as those of viruses. These foreign proteins are called antigens.

When one receptor recognizes an antigen, T cells start replicating quickly and destroy the cells that the virus has infected. Many of the T cells die off once the infection is gone, but some become memory cells and remain in the body, ready to fight the virus if it ever returns.

Identifying the T cells with receptors of particular interest can be time consuming and expensive because they are often present in very low numbers.

Investigating T cell receptors

The authors of the recent study conducted a series of laboratory experiments involving RdRp. To investigate whether the human immune system has T cell receptors that recognize RdRp, the team took blood samples from healthy participants and exposed the samples to RdRp. Some of the receptors in the blood samples did recognize the protein.

Using a newly developed technique, the scientists identified the genetic sequence of the receptors. Next, they engineered T cells to carry the receptors that targeted RdRp.

The team then set out to learn whether these modified T cells could successfully bind to and kill coronaviruses, including SARS-CoV-2.

What did they find?

The authors discovered that RdRp was “highly conserved,” meaning that the RNA that codes for it is less likely to mutate, within SARS-CoV-2 and other human coronaviruses.

The authors explain that this stability is “likely due to its critical role in the virus life cycle.”

T cell receptors from people who had never contracted SARS-CoV-2 did recognize part of RdRp. As hoped, receptors isolated in the laboratory recognized and killed cells containing this enzyme.

Dr. Owen Witte, a co-author of the study and the center’s founding director, told MNT, “We were pleasantly surprised that specific T cells could be identified, as the anticipated frequency of such cells would be expected to be low.”

“This might complement current vaccine designs targeting the spike protein to produce neutralizing antibodies. Our direct demonstration of T cells in the blood of [healthy] individuals […] says that the repertoire of human T cells contains specificities reactive with peptides derived from the highly conserved polymerase/replication complex,” he continued.

“Very recently, in independent work from another group, it has been reported that post [SARS-CoV-2] infection, T cells reactive to the polymerase/replication complex could be defined. Their findings are highly complementary to ours. Such T cell responses would not neutralize the virus and prevent infection but could target the virus-infected cells to limit virus production and spread within the host to lessen the severity of disease.”

Pavlo Nesterenko, a Ph.D. student and the study’s lead author, told MNT:

“The polymerase could be a good next-generation vaccine candidate because it is highly conserved. High conservation means that multiple variants, as well as multiple coronaviruses, can be targeted by one vaccine.“

Limitations and future work

Though the study showed that RdRp-specific receptors could recognize processed parts of RdRp in the laboratory, the team did not show direct control of live SARS-CoV-2. They are now evaluating the viral polymerase as a potential new vaccine component.

Dr. Witte told MNT: “Much more analysis of T cells […] needs to be done and is in progress in my group. Follow-up studies to evaluate the potential of vaccine strategies based on sequences derived from replication complex proteins are also initiated.”

Prof. Hibberd concluded, “There is plenty of work, including my own, suggesting that there are multiple conserved T cell epitopes across the SARS-CoV-2 genome and that these may match other coronaviruses, so the results are not unexpected.”

“Work is required to see if any T cell responses can be protective against infection. Currently, we know that a history of infection by other coronaviruses does not offer protection against COVID-19, so the shared T cell epitopes between them do not appear to be protective.”

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