Gaurav Gaiha MD, DPhil is a member at the Ragon Institute of MGH MIT and Harvard who studies HIV, one the most rapidly-mutating viruses known. HIV's ability mutate isn’t unique to RNA viruses. Most viruses experience mutations over time. The right mutation, which scientists call epitopes, can enable a virus to escape from the immune system if it is disease-causing.Gaiha and Elizabeth Rossin (MD, PhD), a Retina Fellow at Massachusetts Eye and Ear and a member Mass General Brigham, devised a structure-based network analysis approach to combat HIV's high mutation rate. This allows them to identify viruses that are restricted or constrained from mutation. Mutationally constrained epitopes can be changed, but they are very rare. They can make the virus unable to replicate and infect others, thus preventing it from spreading.Gaiha saw an opportunity to apply HIV structure-based network analysis principles to SARS-CoV-2 (the virus that causes COVID-19), as soon as the pandemic started. His team believed that the virus would likely evolve, possibly in ways that would enable it to escape natural and vaccine-induced immune systems. The team discovered mutationally constrained SARS-2 epitopes, which can be recognized and used by immune cells called T cells. These epitopes can then be used to create a vaccine that trains T cells and provides protective immunity. This work was recently published in Cell. It highlights the possibility for a T-cell vaccine that could provide broad protection against emerging SARS-CoV-2 variants and other SARS-like coronaviruses.The team was aware of the importance of preparing for future mutations from the very beginning stages the COVID-19 pandemic. Similar blueprints had been published by other labs. Studies showed that patients who had a strong T cell response (CD8+) were more likely to survive COVID-19.Gaiha's team realized that these insights could be combined together with their unique approach: the network analytics platform to identify mutationally constrained Epitopes. They also developed an assay to identify Epitopes that were successfully targeted in HIV-infected individuals by CD8+ T cell. Cell Reports is publishing a report on it. These advances were applied to the SARS-2 virus and they found 311 highly networked epitopes that are likely to be both genetically constrained but also recognized by CD8+ cells.Anusha Nathan is a Harvard-MIT Health Sciences and Technology student and co-first author. She says that these highly networked viral epitopes provide stability for the virus. The virus will not tolerate structural changes in these highly connected areas. This makes them resistant to mutations.Nathan explains that a virus's structure can be compared to a house's design. A few essential elements are required to ensure a house is stable. These include support beams and foundations that connect to the rest of the structure. You can change the size or shape of windows and doors without putting the house at risk. However, structural changes like beams and support beams are more dangerous. These support beams are biologically constrained. Any significant change in size or shape could compromise the structural integrity and lead to the house's collapse.AdvertisementHighly networked epitopes within a virus act as support beams connecting to other parts. Mutations in these epitopes could compromise the virus's ability infect, reproduce, and survive. These epitopes are highly networked and can be found across many viruses, as well as within closely related viruses. This makes them a great vaccine target.To find the 311 epitopes that were most likely to be recognized and present in large numbers, the team examined them. Each epitope could be a target for a broad protective T cell vaccine. They came up with 53. The team was able verify their work because patients who have recovered from COVID-19 have a T-cell response. They also checked if the epitopes they had created a T-cell response in patients who had recovered. The research team found that half of the COVID-19 patients had T cell responses to the highly networked epitopes. These results confirmed that epitopes could induce an immune reaction and make them potential candidates for vaccines.Rossin, who is also co-first author, said that a T cell vaccine that targets these highly networked epitopes "would potentially be in able to provide long-lasting defense against multiple variants SARS-CoV-2," including future ones.It was February 2021. This was more than a full year after the pandemic began and new variants were appearing all over the world. These variants of concern should not have been affected by mutations in highly networked epitopes, as the team predicted about SARS-CoV-2.The sequences were obtained from the B.1.1.7 Alpha and B.1.351 Beta variants of concern. These sequences were compared with the original SARS/CoV-2 genome and cross-checked the genetic changes against the highly networked epitopes. Surprisingly, only three of the mutations that they found affected highly networked epitope sequences and none of them had an effect on the immune system's ability to interact with these epitopes.AdvertisementGaiha, a senior author of the study and an investigator at the MGH Division of Gastroenterology, said that it was initially all prediction. "But, when we compared our network score with sequences from variants of concern as well as the composite of circulating variants it was almost like nature was confirming what we had predicted."During the same period, mRNA vaccinations were being developed and tested. The vaccines produce a strong and powerful antibody response. However, Gaiha's team found that patients with COVID-19 infection had a smaller T cell response to highly networked epitopes than those who received the vaccines.Gaiha says that the current vaccines offer strong protection against COVID-19. However, it is not clear if they will continue providing strong protection once more variants of concern become available. However, this study shows that it is possible to create a broad protective T cell vaccine that can protect against all variants of COVID-19. It may also be possible to extend protection to any future SARS-CoV-2 or similar coronaviruses.Gaiha is an assistant professor at Harvard Medical School in Medicine. Clarety Kaseke and Ryan J. are additional authors. Park, Dylan Koundakjian and Jonathan M. Urbach are PhDs, Nishant K.Sing, Ph.D., Fernando Senjobe and Rhoda Tano–Menka, Dr. Michael T. Waring, Alicja Pichocka-Trocha; Wilfredo F. Garbtran, MD, and Bruce D. Walker from the Ragon Institute; A. John Iafrate; MD, Vivek Naranbhai, Ashok Khatri from MGH, Mary Carrington, NIH; and Arman Bashirova from NCI; and Arman Bashirova from NCI; and Arman Bashirova from NCI; and Arman Bashirova of the NCI; and Arman Bashirova from NCI; and Arman Bashirova from NCI; and Arman Bashirova from NCI; and Arman Bashirova from NIH; Mary Carrington, PhD; and Mary Carrington, Mary Carrington, NIH; and Arman Bashirova from NCI; and Arman Bashirova from NCI.The National Institutes of Health (NIH) and the Massachusetts Consortium of Pathogen Readiness, (MassCPR) supported this study. The Ragon Institute, Howard Hughes Medical Institute and the Mark and Lisa Schwartz Foundation provided additional support. Enid Schwartz (B.D.W.) also contributed. Sandy Edgerly and Paul Edgerly. The Heed Ophthalmic Foundation supports Roider. Gaiha is supported in part by the Bill and Melinda Gates Foundation. The Frederick National Laboratory for Cancer Research has funded this project in whole or in part.Conflicts of Interest: Roider, Gaiha filed patent application PCT/US2021/028245.
