The influenza virus continues to cause significant morbidity and mortality in humans, resulting in up to 50,000 deaths per year in the United States. Annual vaccination remains the recommended prophylaxis for influenza. However, vaccines must be reformulated to account for antigenic drift and, even when vaccines contain strains that antigenically match circulating strains, they display suboptimal efficacies. Two glycoproteins coat the surface of the influenza virus – the more abundant and immunodominant hemagglutinin (HA), which serves as the receptor-binding protein, and the neuraminidase (NA), an enzyme that functions to free budding viruses from infected cells. Current influenza virus vaccine strategies aim to elicit neutralizing antibodies against the HA, but past studies have demonstrated that neuraminidase inhibition titers are correlated with reduced illness and viral shedding in humans. Despite the accumulated evidence that an anti-NA immune response is beneficial, the NA content in vaccines is not standardized.
Here, the potential breadth of protection afforded by NA antibodies was investigated by studying the use of NA as a vaccine antigen and by characterizing broadly cross-reactive murine monoclonal antibodies against the NA. Using baculovirus-expressed, purified protein, it was demonstrated that vaccination with adjuvanted NA was sufficient to induce protection against lethal influenza virus challenge in mice. In the same study, the N1 NA content of inactivated influenza virus vaccines from different companies was found to be highly variable. Furthermore, in humans vaccinated with standard inactivated influenza virus vaccine, the induction of serum NA titers was significantly lower than that of HA titers. In the second part of this dissertation, panels of monoclonal antibodies were generated against the N8 NA of an emerging H10N8 influenza virus strain and against the NA of influenza B virus. Monoclonal antibodies against the influenza B virus NA displayed in vivo prophylactic and therapeutic protection in mice, robustly activated antibody-dependent cellular cytotoxicity (ADCC) in vitro, and displayed neuraminidase inhibition against an oseltamivir-resistant influenza B virus. As a whole, our data strongly suggest that targeting the influenza virus NA may be beneficial when designing novel influenza virus vaccines or antibody-based therapeutics.
|Advisor:||Palese, Peter, Krammer, Florian|
|Commitee:||Eichelberger, Maryna C., Fernandez-Sesma, Ana, Garcia-Sastre, Adolfo, Moran, Thomas M., Simon, Viviana A.|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 79/09(E), Dissertation Abstracts International|
|Keywords:||Antibodies, Antigen, Cross-protection, Influenza, Neuraminidase, Vaccination|
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