Development of a T-cell-inducing vaccine against SARS-CoV-2 infection

Abstract

he emergence of betacoronavirus SARS-CoV-2 at the end of 2019 in China lasts for almost a year and has already resulted in more than 30 million infections and 1 million deaths worldwide. Vaccines are essential and urgently needed to control the pandemic and the strategies under development are mostly aimed at inducing antibodies against the viral protein spike, responsible for binding to the ECA-2 cell receptor (ACE-2). However, the antibody response against natural coronavirus infection, in general, tends to be short-lived, which would indicate an inadequate protection correlate if considered in isolation. Epidemiological observations of the SARS-CoV-1 outbreak in China in 2005, the in vitro demonstration that antibodies against variants of the spike protein can increase infection, as well as the induction of harmful effects by two vaccines targeting that protein, suggest a dual role between protection and pathology mediated by antibodies directed at the spike. On the other hand, previous studies using SARS-CoV-1 have shown that CD8 T cells promote viral load reduction, clinical recovery and protection under experimental conditions, as well as promoting survival for years after primary infection even in animals that have not developed responses antibody-mediated. In addition, cytotoxic responses mediated by CD8 T lymphocytes are responsive after restimulating in vitro, resulting in high production of cytokines and antiviral molecules, showing that they play a critical role in protection against SARS-CoV. ImunoTera, in turn, developed two products that use as a base a technology totally focused on the induction of T cells. Its first product, in the form of DNA vaccine, was able to induce high frequencies of specific CD8 T lymphocytes that were correlated to the regression and permanent cure of tumors induced by human papilloma virus (HPV) infection in a murine model. The hypothesis we anticipate to demonstrate is based on the premise that a combined CD8 T cell response, in addition to the humoral response, is critical for a successful anti-COVID-19 vaccine. The main objective of this proposal is to develop a DNA vaccine capable of inducing cellular immune responses against SARS-CoV-2 appropriate to the genetics of the population of Brazil, through the design of target sequences that include better SARS-CoV-2 epitopes recognized by T lymphocytes. The use of these regions as antigens in a vaccine formulation should be able to induce a robust cytotoxic cellular response in the Brazilian population, previously or not exposed to the virus, and, thus, contribute to the assembly of lasting immune protection against COVID -19. (AU)