As of early May 2020, there have been approximately 3.7 million confirmed cases of COVID-19 infection worldwide, and approximately 260,000 deaths.1 A retrospective cohort study of patients from Wuhan, China demonstrated that although both survivors and non-survivors initially follow similar clinical courses, developing sepsis and acute respiratory distress syndrome (ARDS) at similar time points, non-survivors progress on to multi-organ failure (MOF), secondary infection, and death.2 Additionally, pediatric cases have been shown to have a much milder disease course than adults, and the reasons for this are not clear.3These differences in clinical courses could in part be explained by the patients? pre-existing T cell repertoire, phenotype, and HLA- specificity, which may influence downstream T cell phenotype and cytokine responses. Using in silico approaches, we identified multiple potential T cell epitopes which can be divided into 3 broad categories: 1) Epitopes with homology to the original SARS virus 2) Epitopes with homology to other viruses/bacteria 3) Epitopes with homology to self-antigens. We have developed aAPC constructs to interrogate both HLA class I and HLA class II CD8+ and CD4+ T cell responses, respectively. As such, we will be able to obtain a broad understanding of the role these 3 different types of virus-specific epitopes play in the development of COVID- 19 specific responses. A better understanding of how T cells contribute to progression of disease severity is especially pertinent to patients who are on long-term immunosuppressive therapies because of malignancies, bone marrow transplant, or organ transplant. Patients with cancer were found to have higher probabilities of having more severe disease and worse outcomes in China than both patients without cancer and cancer survivors.4This proposal builds upon previously published work to screen patients for virus-specific T cells using only 100 ?L of whole blood, and with a turn-around time of less than 24 hours.5 In addition, we have also developed an enrichment and expansion (E+E) technology to rapidly expand virus and tumor-specific T cells within a 7 day time frame.6?12Combining these two approaches, we will identify clinically important T cell epitopes and demonstrate that functional T cells can be expanded to large numbers over a brief period-of-time in otherwise healthy donors and patients with cancer.
A critical unmet need in the current COVID-19 pandemic is an understanding of how cellular immunity, T cells, contributes to disease progression and convalescence. The routine study of the T cell responses to disease is technically challenging, requiring multiple steps, reagents, and time. We have developed novel artificial Antigen Presenting Cell, aAPC, technology to study T-cell responses on a large scale in a multiplexed, high-throughput fashion, which is essential given the rapidly evolving nature of the pandemic. As such, we will be able to obtain a broad understanding of the role that cytotoxic CD8+ T cells and CD4+ helper T cells play in COVID-19 infections in healthy cohorts as well as in patients with cancer. Additionally, our approach can also be used as an alternative diagnostic modality complementary to nucleic amplification tests (NAT) and ELISA-based antibody assays, neither of which address COVID-19-specific T cell responses.
