Characterizing Protective Antibody Responses to Recombinant Ebola Virus Subunit Vaccines in Non-Human Primates
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2023
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Ebola virus (EBOV) causes lethal hemorrhagic fevers with case fatality rates of up to 90%. Outbreaks are sporadic and unpredictable, and vaccination has been key to controlling disease. The establishment of correlates of protection is a critical step in vaccine development and assessment and are an asset to outbreak control and robust public health strategies. Although approved vaccines for EBOV are available, limited stock, low durability, and requirement of ultra-cold-chain storage highlight the need for improved vaccine technology. We have developed a recombinant subunit vaccine that shows improved safety and thermostability profiles, allowing easier deployment in endemic regions. Our vaccine has shown high efficacy in the gold standard non-human primate model of cynomolgus macaques; However, we have yet to fully characterize the immune responses that are elicited. This dissertation aims to establish humoral correlates of protection for EBOV by determining antibody characteristics associated with protection as well as important glycoprotein targets and the timing at which various antibody functions control infection. We find that a combination of protective antibody qualities including GP targets, neutralization, and effector function can be used to predict vaccine efficacy. Ability of antibodies to bind virus despite the presence of the mucin-like domain was also correlated with higher vaccine induced protection against EBOV with the majority of neutralizing and Fc effector functioning antibodies binding regions beneath the mucin-like domain. Post-challenge kinetics are also a relatively unexplored aspect of vaccine induced protection. Here we find that rapid antibody recall responses are needed to confer protection in sensitive NHP models and increases in antibody function later after infection, likely stemming from IgM, are not sufficient for protection in non-survivors. Our research highlights the importance of EBOV GP epitopes beneath the mucin-like domain as well as rapid memory recall responses. These findings can be used in the assessment and development of next generation vaccine candidates.
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Immunology, Molecular biology, Microbiology, antibody, correlates of protection, Ebola, glycoprotein, immune response, vaccine
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167 pages
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