Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Lucas, Carolina

Abstract

Emerging infectious diseases like SARS-CoV-2 and re-emergent pathogens such asmpox (formally known as monkeypox) have posed substantial challenges to global health, often due to immune escape and antigenic variability. My research addresses these challenges by evaluating and designing vaccine strategies to enhance immune responses and cross-protection, focusing on SARS-CoV-2 variants and members of the Orthopoxvirus family. The central aim of my research is to understand and overcome limitations in immune responses to antigenically variable pathogens. My studies focus on humoral responses to SARS-CoV-2 variants through targeted booster regimens, exploring cross-protective immunity in Orthopoxvirus vaccines, and testing new mRNA vaccines to effectively target MPXV. For SARS CoV-2 variants, the research shows that a heterologous BNT162b2 mRNA booster following a primary CoronaVac regimen significantly boosts neutralizing antibody levels, especially against the Delta and Omicron variants, although neutralization of Omicron remains challenging. Age emerged as a critical factor, with older adults showing notably lower antibody responses after a homologous CoronaVac booster, underscoring the importance of heterologous regimens for vulnerable populations. With the global emergence of the MPXV clade IIb, we expanded our focus to study immunity induced from Orthopoxvirus vaccines. This research revealed that antigenic distance between viruses substantially impacts vaccine effectiveness. Vaccinia-based vaccines were shown to provide durable immunity to smallpox, although the degree of cross-protection across orthopoxviruses varies. Notably, smallpox vaccines induce higher cross-neutralization against vaccinia and cowpox viruses compared to MPXV, suggesting that closer antigenic matches result in stronger immune protection. We also observed lasting T-cell reactivity to VACV and MPXV epitopes, indicating that long-lasting cross-reactive T-cell memory may play a significant role in sustaining vaccine efficacy. In addition, I have been actively involved in evaluating vaccine immunity for new vaccine technologies and therapeutics strategies. We tested two novel polyvalent mRNA vaccines targeting MPXV, both of which demonstrated promising immune responses, including robust T-cell reactivity, cross-neutralization potential for related orthopoxviruses, and effective protection following challenge in mouse models. Moreover, we identify a new monoclonal antibody, isolated from an mpox infected patient, targeting the MPXV EV A35 protein. This monoclonal antibody demonstrated the ability to inhibit in vitro and in vivo viral spread. These findings provide valuable insights into vaccine-induced immunity, which can help address immune evasion mechanisms in both SARS-CoV-2 and orthopoxviruses. By enhancing our understanding of immune responses across diverse viral pathogens, this research may inform the development of more effective vaccines and therapeutics, ultimately improving preparedness for future emerging infectious threats.

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