SUMMARY:
UCLA researchers in the Department of Microbiology, Immunology, and Molecular Genetics have developed a novel way to use the sequencing information from T cell mediated immune responses to profile TCR alpha/beta sequences against SARS-CoV-2 virus. This invention has potential to help develop therapeutics or characterize and produce a long-term immunity vaccine for SARS-CoV-2 and other coronaviruses.
BACKGROUND:
As of March, 2022, current estimates report that there have been over 435 million cases of SARS-CoV-2 worldwide and about 5.9 million total reported deaths. To combat this virus, several vaccines have been developed and administered. In the United States alone, the Center for Disease Control reports that over 553 million vaccines have been administered. Despite the efficacy of the current SARS-CoV-2 vaccines at reducing the number of severe infections in the short period of time following vaccination, there is a need for significant improvement to achieve eradication of the virus. This is in part because of the frequency of breakthrough infections, especially of new variants of the virus, in individuals who are fully vaccinated for SARS-CoV-2. Therapeutics for active COVID-19 infections are also limited in number and efficacy. New therapeutics are needed to control the spread of COVID-19.
T cell-based approaches to the development of therapeutics and vaccines have recently been developed targeting infections by bacteria, parasites, and viruses. During a typical immune response, T cells continuously surveil for infection using T cell receptors (TCRs) that recognize peptides from pathogens. Identification of TCRs directed against a known pathogen could enable development of highly effective therapeutics or vaccines against conserved epitope targets required for control of infection. This could aid in the development of therapeutics and vaccines that maintain functionality even as a pathogen mutates. However, the development of strategies to design or discover TCRs that are reactive towards desired epitopes is challenging due to the low number of cells expressing any given TCR and the difficulty in producing diverse populations of T cells with variable TCRs.
INNOVATION:
Researchers at UCLA led by Dr. Owen Witte have discovered novel TCRs that recognize conserved epitopes on SARS-CoV-2 and other coronaviruses for use in the development of cellular therapeutics and novel vaccine development strategies. T cell reactivity was profiled by mRNA sequencings via cross-linker regulated intracellular phenotype (CLInt-seq). The authors generated a peptide pool of HLA-A*02:01 restricted epitopes through the use of several algorithm reduction tools and sequence homology to SARS-CoV-2 virus. Using CLINT-seq, the peptide pool was profiled in stimulation experiments using human normal peripheral blood mononuclear cells (PBMCs). The UCLA researchers discovered that their donor PBMCs has CD8+T cells with a detectable T cell response to a SARS-CoV-2 epitope pool. The TCR alpha/beta sequences were reconstructed in overexpression vectors and subsequently tested in human lymphocytes to profile recognition. The research team identified TCRs that recognize the highly conserved SARS-CoV-2 RNA polymerase. The TCR alpha/beta sequences provide valuable cognate epitope information that can be used to develop novel cellular therapeutic interventions and aid in vaccine development.
POTENTIAL APPLICATIONS:
● Vaccine development for SARS-CoV-2 virus
● TCRs can be used directly as cell therapy
● Profiling of SARS-CoV-2 T cell immune responses
ADVANTAGES:
● CD8+ T cell epitopes are highly conserved, which can help in targeting of diverse SARS-CoV-2 variants and new coronaviruses
DEVELOPMENT-TO-DATE:
Researchers identified TCRs that recognized highly conserved regions of SARS-CoV-2, which can now be explored as vaccine targets.
Related Papers (from the inventors only):
1. Nesterenko, P.V., McLaughlin, Tsai, B.L., Sojo, G.B., Cheng, D., Zhao, D., Mao, Z., Bangayan, N.J., Obusan, M.B., Su, Y., Ng, R.H., Chour, W., Xie, J., Li, Y.R., Lee, D., Noguchi, M., Carmona, C., Phillips, J.W., Kim, J.T., Yang, L., Heath, J.R., Boutros, P.C., Witte, O.N. HLA-A*02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses. Cell Reports. 2021.
2. Nesterenko, P.V., McLaughlin, J., Cheng, D., Bangayan, N.J., Sojo, G.B., Seet, C.S., Qin, Y.,Mao, Z., Obusan, M.B., Phillips, J.W., Witte, O.N. Droplet-based mRNA sequencing of fixed and permeabilized cells by CLInt-seq allows for antigen-specific TCR cloning. Proceedings of the National Academy of Sciences. 2021.