Explore the potential pathway of a large-scale protective COVID-19 vaccine using T cells

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Using a method developed for HIV, researchers have identified stable T-cell vaccine targets in SARS-CoV-2. These stable targets, known as highly network-bound epitopes, are very likely to be stable in different types of virus. The findings provide a path forward for a large-scale protective COVID-19 T-cell vaccine.

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

To combat the high mutation rate of HIV, Jaeha and Elizabeth Rosin, MD, PhD, a Massachusetts Eye and Ear Retina Fellow, a member of Mass General Brigham, developed an approach known as structure-based network analysis. Using this, they can identify restricted or restricted viral pieces of mutants. Changes in mutationally restricted episodes are rare, as they can cause the virus to lose its ability to infect and reproduce, essentially rendering it unable to reproduce.

When the pandemic began, Gaiha immediately recognized an 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 have concluded that the virus is likely to mutate, possibly in ways that allow it to escape both natural and vaccine-induced immunity. Using this approach, the team identified mutationally restricted SARS-CoV-2 epitopes that can be recognized by immune cells known as T cells. These epitopes can then be used in a vaccine to train T cells, providing protective immunity. This work, recently published in Cell, highlights the possibility of a T-cell vaccine that could provide broad protection against novel and emerging variants of SARS-CoV-2 and other SARS-like coronaviruses.

From the early stages of the COVID-19 pandemic, the team recognized that it was essential to prepare against potential future mutations. Other laboratories have already published the protein structures (schemes) of nearly 40% of SARS-CoV-2, and studies have indicated that patients with a strong T-cell response, specifically a CD8+ T-cell response, were more likely to survive COVID. 19 infections.

Gaiha’s team knew these ideas could be combined with their unique approach: a network analysis platform to identify mutationally restricted epitopes and an assay they had just developed, a report currently in publication in Cell Reports, to identify epitopes successfully targeted by CD8+ T cells in HIV-infected individuals. Humanity. Applying these developments to SARS-CoV-2, they identified 311 highly retinal epitopes in SARS-CoV-2 that are likely to be mutationally restricted and recognized by CD8+ T cells.

says Anusha Nathan, a medical student in the Harvard Health Sciences and Technology Program and co-first author of the study. “Therefore, the virus is unlikely to tolerate any structural changes in these highly interconnected regions, making them resistant to mutations.”

Nathan explains that you can think of the architecture of the virus like the design of the house. The stability of the house depends on certain vital elements, such as the support beams and the foundation, that connect and support the rest of the house’s structure. So it is possible to change the shape or size of elements such as doors and windows without endangering the house itself. However, changes in structural elements, such as supporting beams, are much more serious. Biologically, these support beams would be mutationally restricted – any major changes in size or shape would compromise the structural integrity of the house and could easily lead to its collapse.

The highly intertwined loops of the virus act as supportive bundles, connected to many other parts of the virus. Mutations in such epitopes can jeopardize the virus’ ability to infect, reproduce, and eventually survive. Therefore, these retinal epitopes are often identical, or nearly identical, across different viral variants and even across closely related viruses in the same family, making them an ideal target for a vaccine.

The team studied 311 identified epitopes to find both are present in large quantities and likely recognized by the vast majority of human immune systems. They ended up with 53 epitopes, each representing a potential target for a large-scale 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 that triggered the T-cell response in patients who had recovered from COVID-19. Half of the recovered COVID-19 patients studied had T-cell responses to the highly reticular loops identified by the research team. This confirmed that the identified epitopes were able to induce an immune reaction, making them a promising candidate for use in vaccines.

“An AT-cell vaccine that effectively targets these highly interconnected epitopes is likely to be able to provide long-term protection against multiple variants of SARS-CoV-2, including future variants,” says Rosin, who is also the study’s first co-author. .

By this time, it was February 2021, more than a year into the onset of the pandemic, and worrying new variables had emerged around the world. If the team’s predictions about SARS-CoV-2 are correct, these variants of the concerns should contain few or no mutations in the very retinal epitopes they identified.

The team obtained sequences from the newly circulated B.1.1.7 Alpha, B.1.351 Beta, P1 Gamma and B.1.617.2 Delta SARS-CoV-2 variants of concern. They compared these sequences to the original SARS-CoV-2 genome, and examined the genetic changes against their high reticular epitopes. Remarkably, among all the mutations identified, only three were found to affect high retinal epitope sequences, and none of the changes affected the ability of these epitopes to interact with the immune system.

“Initially, it was all a prediction,” says Gaiha, a researcher in the MGH Division of Gastroenterology and senior author of the study. “But when we compared our network’s results to the sequences of the variants of concern and the complex of circulating variants, it was as if nature confirmed our predictions.”

In the same time period, mRNA vaccines were published and the immune responses to those vaccines were studied. While the vaccines induce a strong and effective antibody response, the Gaiha group determined that they had a much lower T-cell response against highly reticular epitopes compared to patients who had recovered from COVID-19 infection.

While current vaccines offer powerful protection against COVID-19, Gaiha explains, it is unclear whether they will continue to provide equally strong protection as more and more worrisome variables begin to spread. However, this study shows that it may be possible to develop a broad-spectrum protective T-cell vaccine that can protect against variants of concern, such as the delta variant, and possibly even extend protection to future SARS-CoV-2 variants and similar coronaviruses. that may appear.

Reference: “Structure-guided T-cell Vaccine Design for SARS-CoV-2 Variants and Sarpic Viruses” By Anusha Nathan, Elizabeth J Rosin, Clariti Kasiki, Ryan J Park, Ashok Khatri, Dylan Kondakjian, Jonathan M Orbach, Nishant K Singh, Arman Bashirova, Rhoda Tanu Mensengop, Verna, Verna Michael T. Waring, Alija Bechuca-Trusha, Wilfredo F. Garcia Beltran, A. John Everett, Vivek Naranby, Mary Carrington, Bruce De Walker, Gaurav D. Cell Gaiha, accepted, DOI number: 10.1016/j.cell.2021.06.029

Gaiha is an assistant professor of medicine at Harvard Medical School. Additional authors include Clarity Kasiki, Ryan J. Park, Dylan Kondakjian, Jonathan M. Auerbach, Ph.D., and Chant K. Singh, Ph.D., Ruda Tanu Minka, Fernando Senjubi, Michael T. Waring, Alija Pechuka-Trucha, Ph.D., Wilfredo F. Garcia Beltran, MD, and Bruce D. Walker, RD, Ragon Institute; A. John Iafrate, MD, Vivek Naranbhai and Ashok Khatri of MGH; Mary Carrington, Ph.D., of the National Institutes of Health; and Arman Bashirova, NCI.

This study was supported by the National Institutes of Health and the Massachusetts Pathogen Preparedness Association (MassCPR). Additional support was provided by the Howard Hughes Medical Institute, the Ragon Institute, the Mark and Lisa Schwartz Foundation, Enid Schwartz (BDW), Sandy and Paul Edgerley. Roider is supported by the Heed Ophthalmic Foundation. Gaiha is supported by the Bill and Melinda Gates Foundation, the Burroughs Wellcome Career Award for Medical Scientists and the Gilead Program for HIV Research. This project was funded in whole or in part with federal funding from the Frederick National Cancer Research Laboratory.

Conflicts of interest: Roider and Gaiha filed PCT/US2021/028245 patent application.

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