CEIRR Researchers Identify New Antibodies That Could Aid in the Development of a Broadly Protective Influenza Vaccine

Publication CommentaryFebruary 15, 2024

A recently published study has taken us one step closer to creating a universal flu vaccine, a widely sought after solution to the ever-changing nature of influenza antigens. Dr. Ruipeng Lei and CRIPT researchers, Dr. Florian Krammer and Dr. Ali H. Ellebedy, contributed to this study published in Immunity. The authors characterized three protective antibodies that cross react with neuraminidases from various seasonal H3N2 strains.

Influenza virion with hemagglutinin (red) and neuraminidase (blue), falsely colored.

The influenza virus has two main antigens on its surface: hemagglutinin (HA) and neuraminidase (NA). Historically, seasonal influenza vaccine development focused on targeting the hemagglutinin antigen, but the current vaccine’s suboptimal protection has led researchers to investigate the less characterized NA. Compared to HA, the molecular characterization of the antibody response to NA is still lacking even though the NA antibody response does make up a correlate of protection independent of the HA response.

Using electron microscopy, the researchers characterized the structure of three NA antibodies isolated from a recently vaccinated individual. All three of these antibodies bound to overlapping conserved epitopes on the underside of the NA head domain, distant from the NA active site where antibodies typically bind. All three antibodies could bind across multiple seasonal influenza H3N2 subtypes, with one antibody, binding to an H9N2 subtype, a non-seasonal N2 strain. The authors speculate that these antibodies may have broad reactivity across influenza subtypes due to their binding at conserved regions, but further testing beyond N2 subtypes is required.

Though these antibodies bound far from the NA active site, two of the three antibodies inhibited viral growth in vitro, likely via steric hindrance dependent on the positioning of the antibody. Other in vitro experiments demonstrated that all three antibodies could provide both therapeutic and prophylactic protection, indicating the importance of cell-mediated immunity. When assessed in vivo, all antibodies conferred protection, indicating that partial inhibition of viral growth is still sufficient for in vivo protection.

Overall, Lei et al. indicate that targeting regions outside of the normal antigenic regions can provide a cross-strain, broadly protective immunity that might outlast the antigenic changes of seasonal influenza. These antibodies represent new candidate targets for a universal flu vaccine, a much sought after replacement for the yearly influenza vaccine.

Lei R. et al. (2023) Leveraging vaccination-induced protective antibodies to define conserved epitopes on influenza N2 neuraminidase. Immunity. 56(11): 2621–2634.