Influenza neuraminidase antibodies and immunogen design

About This Grant

PROJECT SUMMARY Influenza viruses pose a continuous global health threat due to seasonal epidemics and pandemic risks. While seasonal influenza vaccines are currently the most effective preventative measure, they are prone to antigenic drift of the circulating strains and lack cross-protection against zoonotic strains. Consequently, there is an urgent need for vaccines capable of eliciting broad immunity against diverse influenza strains and subtypes. Influenza viruses have two surface antigens, hemagglutinin (HA) and neuraminidase (NA). Most efforts in vaccine development against influenza viruses have been focusing on eliciting HA antibodies. As a result, seasonal influenza vaccines are very poor at inducing NA antibody responses. Nevertheless, NA is increasingly recognized as a promising vaccine target due to the recent discovery of broadly protective NA antibodies as well as the demonstration of NA antibodies as an independent correlate of protection. However, significant knowledge gaps hinder the development of effective NA-based vaccines. For example, the number of known NA antibodies is considerably lower than that of HA antibodies, limiting our understanding of NA antigenicity as well as the immunodominant hierarchy among NA epitopes. Furthermore, the mechanisms underlying the development of broadly neutralizing NA antibodies remain largely unknown. To address these knowledge gaps, this proposed study aims to systematically analyze the structure-function relationships of a large panel of NA monoclonal antibodies. We also aim to map the affinity maturation pathways leading to the evolution of breadth in broadly protective NA antibodies, and engineer a broadly protective NA-based immunogen. This proposed study will leverage unique clinical samples from individuals who have received seasonal influenza vaccine candidates that contain NA as a component, as well as state-of-the-art structural biology and high-throughput experimental approaches. Our results will significantly enhance the fundamental understanding of NA antibody responses and offer unprecedented insights into NA-based vaccine design, which will be instrumental in developing universal influenza vaccines.