NAction! How Can Neuraminidase-Based Immunity Contribute to Better Influenza Virus Vaccines?

Abstract

Neuraminidase is one of the two surface glycoproteins of influenza A and B viruses. It has enzymatic activity that cleaves terminal sialic acid from glycans, and that activity is essential at several points in the virus life cycle. While neuraminidase is a major target for influenza antivirals, it is largely ignored in vaccine development. Current inactivated influenza virus vaccines might contain neuraminidase, but the antigen quantity and quality are varied and not standardized. While there are data that show a protective role of anti-neuraminidase immunity, many questions remain unanswered. These questions, among others, concern the targeted epitopes or antigenic sites, the potential for antigenic drift, and, connected to that, the breadth of protection, differences in induction of immune responses by vaccination versus infection, mechanisms of protection, the role of mucosal antineuraminidase antibodies, stability, and the immunogenicity of neuraminidase in vaccine formulations. Reagents for analysis of neuraminidase-based immunity are scarce, and assays are not widely used for clinical studies evaluating vaccines. However, efforts to better understand neuraminidase-based immunity have been made recently. A neuraminidase focus group, NAction!, was formed at a Centers of Excellence for Influenza Research and Surveillance meeting at the National Institutes of Health in Bethesda, MD, to promote research that helps to understand neuraminidase-based immunity and how it can contribute to the design of better and broadly protective influenza virus vaccines. Here, we review open questions and knowledge gaps that have been identified by this group and discuss how the gaps can be addressed, with the ultimate goal of designing better influenza virus vaccines.

Meeting report and review: Immunological assays and correlates of protection for next‐generation influenza vaccines

“…Examples of these alternative immune correlates include the serum virus neutralization antibody titer, 18,19 which often, but not always, aligns with the serum HI antibody titer. In addition, serum neuraminidase inhibition (NI) antibody titers have been identified as independent correlates of protection in field studies by Monto et al and Couch et al 9,10,20 Furthermore, this is supported by recent data from an H1N1 human challenge model. 21 Of note, anti-HA stalk antibodies can interfere with H6NX-based NI assays which have to be taken into account in their interpretation.…”

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

“…Monoclonal antibodies (mAbs) administered either prophylactically or therapeutically have been proposed as a strategy to provide immediate immunity and augment existing vaccines and drugs in combatting seasonal and pandemic influenza infection. Broadly neutralizing antibodies against conserved epitopes of the haemagglutinin (HA) stem and head, and antibodies against the neuraminidase (NA) are candidates for human treatment 1, 2 . Both prophylactic and therapeutic administration of these antibodies have been shown to be effective in the mouse and ferret 3–10 .…”

Neuraminidase antigenic drift of Influenza A virus H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

“…Neuraminidase inhibitory antibodies have previously been shown to inhibit virus replication by inhibiting enzymatic activity of the protein or by inducing a cellular immune response through antibody dependent cellular cytotoxicity (ADCC) [12, 20, 30, 33] or a combination of both. With two recombinant viruses only differing in the 245 NA glycosylation sequence, we sought to understand how this glycan would impact the ability of 229-1G03 and 235-1C02 to neutralize virus infectivity.…”

“…In recent years the NA protein has had renewed interest as a relatively conserved protein that’s an attractive vaccine target[12, 22, 41]. In some respects, the NA protein is an excellent candidate for a universal vaccine.…”

“…Antibody response to NA are not induced effectively in all age groups by current influenza vaccines because the amount of NA is not standardized in vaccine preparations and the NA protein conformation is more sensitive to the current vaccine production methods than the HA protein[12, 20, 43, 44]. While other methods for inducing NA immunity are being developed, our data show that two amino acid changes in N2 NA can lead to escape from antibodies that bind to one of the most universal antigenic sites of the protein.…”