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Antibodies in Infectious Diseases: HIV Biomarker Discoveries, Complement Enhanced SARS-CoV-2 Neutralization and Vaccine Generation
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Dissertation
Antibodies in Infectious Diseases: HIV Biomarker Discoveries, Complement Enhanced SARS-CoV-2 Neutralization and Vaccine Generation
2024
Overview
The main barrier towards an HIV cure is the presence of latently HIV-infected cells that make up the viral reservoir which persists through antiretroviral therapy. Although there is some leaky protein transcription in these latent cells, they evade immune surveillance and through homeostatic proliferation, maintain the viral reservoir. To eradicate the viral reservoir, one must be able to target it through the use of a biomarker. In the first part of this thesis, sea lamprey were immunized with latently HIV-infected T cells to generate a library of lamprey antibodies. 1273 antibodies were isolated and screened against HIV infected and non-infected primary cells. 25 antibodies were found to be specific to HIV infected cells which are currently being classified further.Due to the COVID pandemic, HIV research was placed on ‘hold’ in order to develop SARS-CoV-2 neutralization assays and COVID vaccine development efforts. In chapter 3 we report the SARS-CoV-2 neutralization titers of human convalescent sera were consistent across all disease states except for severe COVID-19, which yielded significantly higher neutralization titers. Heat inactivation of human convalescent serum was shown to inactivate complement proteins, and the contribution of the complement system in SARS-CoV-2 neutralization was often over 50% and mainly driven through the classical pathway. In some cases, heat inactivation completely abolished neutralization levels to undetectable levels. This effect was also observed in COVID-19 vaccines and could be abolished in individuals who were being treated with anti-complement antibodies for other diseases.Safe and effective vaccines are needed to end the COVID-19 pandemic. In the final chapter we report the preclinical development of a lipid nanoparticle formulated SARS-CoV-2 mRNA vaccine. Tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Mouse immune sera elicited by PTX-COVID19-B vaccination neutralized SARS-CoV-2 variants of concern, including the Alpha, Beta, Gamma and Delta lineages. No adverse effects were induced by PTX-COVID19-B in either mice or hamsters. Based on these results, PTX-COVID19-B was authorized by Health Canada and had passed a phase 2 clinical trial.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798342759953
