Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Scott E. Hensley

Abstract

Infants are particularly vulnerable to infection and severe disease, yet we lack effective vaccines for this population. While maternal antibodies can provide protection, they also inhibit the infant’s de novo antibody response. Furthermore, maternal antibodies can exacerbate disease in some contexts. Thus we need better vaccination strategies to protect infants. Here, we establish mouse models of influenza virus- and flavivirus-specific maternal antibody transfer. We show that influenza virus-specific maternal antibodies protect infant mice from influenza disease and that Zika virus-specific maternal antibodies protect infants from Zika virus-mediated disease. Dengue virus-specific maternal antibodies neither protect from nor exacerbate disease during Zika virus infection of infant mice. We further demonstrate that influenza virus-specific maternal antibodies inhibit infants’ responses to conventional influenza vaccines. To solve this problem, we show that a novel vaccine, nucleoside-modified mRNA encapsulated in lipid nanoparticles (mRNA-LNP) encoding influenza hemagglutinin, overcomes maternal antibody inhibition by prolonged establishment of germinal centers. mRNA-LNP vaccination offers a promising means of eliciting protective immune responses in infants in the presence of maternal antibodies. These results have important implications for the design of vaccines for use in mothers and infants.

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