Researchers are finding a potential pathway to a widely protective T-cell COVID-19 vaccine.


3D printing of a peak protein of SARS-CoV-2, the virus that causes COVID-19, in front of a 3D printing of a particle of SARS-CoV-2 virus. Spike protein (foreground) allows the virus to enter and infect human cells. In the virus model, the surface of the virus (blue) is covered with spike proteins (red) that allow the virus to enter and infect human cells. Credit: NIH

Gaurav Gaiha, MD, DPhil, a member of the Ragon Institute of MGH, MIT, and Harvard, studies HIV, one of the most mutated viruses known to mankind. But the ability of HIV to mutate is not unique among RNA viruses: most viruses develop mutations or changes in their genetic code over time. If a virus is causing disease, the proper mutation can allow the virus to escape the immune response by changing the viral pieces that the immune system uses to recognize the virus as a threat, pieces that scientists call epitopes.

To combat the high rate of HIV mutation, Gaiha and Elizabeth Rossin, MD, Ph.D., Retina Fellow at Massachusetts Eye and Ear, a member of the mass general Brigham, developed an approach known as structure . With this, they can identify viral pieces restricted or restricted to mutation. Changes in epitopes with mutational restraints are rare, as they can cause the virus to lose its ability to become infected and replicate, essentially preventing it from spreading.

When the pandemic began, Gaiha immediately recognized the opportunity to apply the principles of network analysis based on the structure of HIV to SARS-CoV-2, the virus that causes COVID-19. He and his team reasoned that the virus would probably mutate, potentially in ways that would allow him to escape the natural, vaccine-induced immunity. Using this approach, the team identified SARS-CoV-2 epitopes with mutational restrictions that can be recognized by known as T cells. These epitopes could be used in a vaccine to train T cells, providing protective immunity. Recently published in Cell, this work highlights the possibility of a T cell vaccine that can offer broad protection against new and emerging variants of SARS-CoV-2 and other SARS-like coronaviruses.

From the earliest stages of the COVID-19 pandemic, the team knew it was imperative to prepare for future mutations. Other laboratories had already published the protein structures (plans) of about 40% of the SARS-CoV-2 virus, and studies indicated that patients with a robust T cell response, specifically a cell response. T CD8 +, were more likely to survive COVID 19 infection.

Gaiha’s team knew these ideas could be combined with their unique approach: the network analysis platform to identify mutation-restricted epitopes and a newly developed trial, a report that is currently in the press. . Cell reports, to identify epitopes successfully targeted by CD8 + T cells in HIV-infected individuals. Applying these advances to SARS-CoV-2 virus, they identified 311 highly networked epitopes in SARS-CoV-2 that were likely to be mutationally restricted and recognized by CD8 + T. .

“These network-connected viral epitopes are connected to many other viral parts, which probably provides some form of stability to the virus,” says Anusha Nathan, a medical student in Harvard-MIT’s health science and technology program. and co-author of the study. “Therefore, the virus is unlikely to tolerate structural changes in these highly connected areas, making them resistant to mutations.”

One can think of the structure of a virus as the design of a house, Nathan explains. The stability of a house depends on some vital elements, such as the supporting beams and a foundation, which connect and support the rest of the structure of the house. Therefore, it is possible to change the shape or size of items such as doors and windows without endangering the house. However, changes in structural elements, such as support beams, are much riskier. In biological terms, these support beams would be mutationally restricted; any significant change in size or shape would jeopardize the structural integrity of the house and could easily lead to its collapse.

Very connected epitopes in a virus function as support bundles, connecting to many other parts of the virus. Mutations in these epitopes can be risky the ability to infect, replicate, and ultimately survive. Therefore, these highly connected epitopes are often identical, or nearly identical, in different viral variants and even in close relationships. in the same family, making them an ideal vaccine.

The team studied the 311 epitopes identified to find the two present in large quantities and likely to be recognized by the vast majority of human immune systems. They ended with 53 epitopes, each of which represents a potential target for a broadly protective T-cell vaccine. Since patients who have recovered from COVID-19 infection have a T-cell response. , the team was able to verify their work by seeing if their epitopes were the same ones that had elicited a T cell response in patients who had recovered from COVID-19. . Half of the patients recovered with COVID-19 studied had T-cell responses to highly networked epitopes identified by the research team. This confirmed that the identified epitopes were able to induce an immune reaction, making them promising candidates for use in vaccines.

“The AT cell vaccine that effectively targets these highly networked epitopes,” says Rossin, who is also co-lead author of the study, “would potentially be able to provide lasting protection against multiple variants of SARS-CoV-2, including future variants “.

At that time, it was February 2021, more than a year after the pandemic, and worrying new variants were popping up all over the world. If the team’s predictions about SARS-CoV-2 were correct, these variants of concerns should have had little or no mutation in the highly connected epitopes they had identified.

The team obtained sequences from the newly released B.1.1.7 Alpha, B.1.351 Beta, P1 Gamma and B.1.617.2 Delta SARS-CoV-2 versions. They compared these sequences with the original SARS-CoV-2 genome, checking for genetic changes against their highly connected epitopes. Surprisingly, of all the mutations they identified, only three mutations were found to affect the highly networked epitope sequences, and none of the changes affected the ability of these epitopes to interact with the immune system.

“Initially, it was all prediction,” says Gaiha, a researcher in the MGH Gastroenterology Division and lead author of the study. “But when we compared our network scores with sequences of worrying variants and the compound of circulating variants, it was as if nature confirmed our predictions.”

Over the same time period, mRNA vaccines were being deployed and immune responses to these vaccines were being studied. Although vaccines induce a strong and effective antibody response, the Gaiha group determined that they had a much smaller T cell response against highly connected epitopes compared to patients who had recovered from COVID-19 infections.

While current vaccines offer strong protection against COVID-19, Gaiha explains, it is unclear whether they will continue to provide equally strong protection as more variants of concern begin to circulate. This study, however, shows that it is possible to develop a broadly protective T cell vaccine that can protect against worrisome variants, such as the Delta variant, and may even extend protection to future SARS-CoV-2 variants and coronavirus similars. which may arise.

SARS-CoV-2 infections can trigger antibody responses against multiple virus proteins

More information:
Anusha Nathan et al, Design of structure-guided T cell vaccines for SARS-CoV-2 and sarbecovirus variants, Cell (2021). DOI: 10.1016 / j.cell.2021.06.029

Citation: Researchers Find Potential Pathway to a Widely Protective COVID-19 T-Cell Vaccine (2021, July 2) Retrieved July 2, 2021 at potential-path-broadly-covid-vaccine .html

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