Potential Path Discovered to a Broadly Protective COVID-19 Vaccine Using T Cells

Using a method developed for HIV, researchers have identified stable T-cell vaccine targets in SARS-CoV-2. These stable targets, known as highly networked epitopes, are most likely stable across different variants of the virus. The results provide a path forward for a broadly protective COVID-19 T-cell vaccine.

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

To combat HIV’s high mutation rate, Gaiha and Elizabeth Rossin, MD, PhD, a Retina Fellow at Massachusetts Eye and Ear, a member of Mass General Brigham, developed an approach known as structure-based network analysis. This allows them to identify viral stretches that are restricted or restricted by mutation. Changes in mutation-linked epitopes are rare, as they can cause the virus to lose its ability to infect and replicate, rendering it essentially unable to propagate itself.

When the pandemic started, Gaiha immediately saw an opportunity to apply the principles of HIV structure-based network analysis to SARS-CoV-2, the virus that causes COVID-19. He and his team reasoned that the virus would likely mutate, possibly in ways that would allow it to escape both natural and vaccine-induced immunity. Using this approach, the team identified mutation-restricted SARS-CoV-2 epitopes that can be recognized by immune cells known as T cells. These epitopes could then 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 could provide 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 possible future mutations. Other labs had already published the protein structures (blueprints) of about 40% of the SARS-CoV-2 virus, and studies indicated that patients with a robust T-cell response, especially a CD8+ T-cell response, were more likely to have COVID – to survive. 19 infection.

Gaiha’s team knew these insights could be combined with their unique approach: the network analysis platform to identify mutation-restricted epitopes and an assay they had just developed, a report currently in print at Cell Reports, to identify epitopes that were successfully identified. targeted by CD8+ T cells in HIV-infected individuals. Applying these advances to the SARS-CoV-2 virus, they identified 311 highly networked epitopes in SARS-CoV-2 that are likely both mutationally restricted and recognized by CD8+ T cells.

“These highly networked viral epitopes are connected to many other viral parts, which probably provides some form of stability to the virus,” said Anusha Nathan, a medical student in the Harvard-MIT Health Sciences and Technology program and co-first author of the study. “Therefore, the virus is unlikely to tolerate structural changes in these highly networked regions, making them resistant to mutations.”

You can think of the structure of a virus as the design of a house, Nathan explains. The stability of a house depends on a few essential elements, such as support beams and a foundation, which connect to and support the rest of the house’s structure. It is therefore possible to change the shape or size of elements such as doors and windows without endangering the house itself. However, changes to structural elements, such as support beams, are much more risky. In biological terms, these girders would be limited by mutation – any significant change in size or shape would compromise the structural integrity of the house and could easily lead to collapse.

Highly networked epitopes in a virus act as struts and connect to many other parts of the virus. Mutations in such epitopes can compromise the virus’ ability to infect, replicate and ultimately survive. These highly networked epitopes are therefore often identical, or nearly identical, across different viral variants and even across closely related viruses in the same family, making them an ideal vaccine target.

The team studied the identified 311 epitopes to find that both were present in large quantities and likely recognized by the vast majority of the human immune system. They ended up with 53 epitopes, each representing 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 as those that elicited a T-cell response in patients who had recovered from COVID-19 . Half of the recovered COVID-19 patients 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 response, making them promising candidates for use in vaccines.

“AT cell vaccine that effectively targets these highly networked epitopes,” said Rossin, who is also a co-first author of the study, “could potentially provide long-term protection against multiple variants of SARS-CoV-2, including future variants.” .”

By then, it was February 2021, more than a year into the pandemic, and new worrisome variants appeared around the world. If the team’s predictions about SARS-CoV-2 were correct, these variants of concern should have had little to no mutations in the highly networked epitopes they identified.

The team has obtained sequences of the newly circulating 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, comparing the genetic changes to their highly networked epitopes. Remarkably, of all the mutations they identified, only three mutations were found affecting 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,” said Gaiha, a researcher in the HGH division of gastroenterology and senior author of the study. “But when we compared our network scores with sequences of the variants of concern and the composition of circulating variants, it was as if nature confirmed our predictions.”

During the same period, mRNA vaccines were deployed and immune responses to those vaccines were studied. Although the vaccines induce a strong and effective antibody response, Gaiha’s group found that they had a much smaller T-cell response against highly networked epitopes compared to patients who had recovered from COVID-19 infections.

While current vaccines offer strong protection against COVID-19, Gaiha explains, it’s unclear whether they will continue to provide as strong protection as more and more variants of care begin to circulate. However, this study demonstrates that it may be possible to develop a broadly protective T-cell vaccine that can protect against the variants of concern, such as the Delta variant, and possibly even extend protection to future SARS-CoV infections. 2 variants and similar coronaviruses. that can arise.

Reference: “Structural Guided T Cell Vaccine Design for SARS-CoV-2 Variants and Sarbecoviruses” by Anusha Nathan, Elizabeth J. Rossin, Clarety Kaseke, Ryan J. Park, Ashok Khatri, Dylan Koundakjian, Jonathan M. Urbach, Nishant K Singh, Arman Bashirova, Rhoda Tano-Menka, Fernando Senjobe, Michael T. Waring, Alicja Piechocka-Trocha,
Wilfredo F. Garcia-Beltran, A. John Iafrate, Vivek Naranbhai, Mary Carrington, Bruce D. Walker, Gaurav D. Gaiha, Accepted, Cell.
DOI: 10.116/j.cell.2021.06.029

Gaiha is an assistant professor of medicine at Harvard Medical School. Other authors include Clarety Kaseke, Ryan J. Park, Dylan Koundakjian, Jonathan M. Urbach, PhD, Nishant K. Singh, PhD, Rhoda Tano-Menka, Fernando Senjobe, Michael T. Waring, Alicja Piecocka-Trocha, PhD, Wilfredo F Garcia-Beltran, MD, and Bruce D. Walker, MD, of the Ragon Institute; A. John Iafrate, MD, Vivek Naranbhai and Ashok Khatri of MGH; Mary Carrington, PhD, of NIH; and Arman Bashirova, NCI.

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

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