Influenza Neuraminidase as a Vaccine Antigen

Abstract

Neuraminidase (NA) is the second most abundant influenza surface glycoprotein and contributes to virus replication in several ways, most notably by removing sialic acids from the host and viral glycoproteins, releasing newly formed virus particles from infected cells. Antibodies that block this enzyme activity restrict virus replication in vitro. This chapter describes foundational epidemiologic and human influenza challenge studies that provide evidence of an association between NA inhibiting antibodies and resistance to disease. Mouse challenge studies show that while NA immunity is infection-permissive, NA-specific antibodies attenuate infection and prevent severe disease. NA immunity is most effective against homologous viruses but there is substantial protection against viruses with a heterologous NA (different lineage within a NA subtype). Monoclonal antibodies specific for conserved antigenic domains of subtype N1 protect against seasonal and pandemic H1N1 as well as H5N1 virus challenge. Clinical studies demonstrate that licensed seasonal vaccines contain immunogenic amounts of NA, but the contribution of this immunity to vaccine efficacy is currently not known. New types of influenza vaccines could be designed to elicit NA immunity. Because NA induces heterologous immunity, it could be an important constituent of universal influenza vaccines that aim to protect against unexpected emerging viruses.

Comparison of the Efficacy of N9 Neuraminidase-Specific Monoclonal Antibodies against Influenza A(H7N9) Virus Infection

“…NA-specific antibodies against N1 and N2 subtypes protect against lethal influenza virus challenge in mice and ferrets (23,(34)(35)(36)(37)(38). Consistent with what is known about NA function (12,39) and previous findings with N1 MAbs (23), the present study shows that N9 MAbs do not interfere with initial virus entry but inhibit virus release from infected cells. SEM observation provided direct evidence that N9 MAbs inhibited virus spread by blocking the release of virions from infected cells.…”

“…Antibodies that inhibit NA activity correlate with reduced clinical signs of influenza and shortened duration of virus replication (10). Although current influenza vaccines do not contain a standard amount of NA, there are many examples demonstrating increased NA inhibition (NI) antibody titers following vaccination (11,12) and a correlation between NI titers and vaccine effectiveness (13)(14)(15)(16). While a recombinant HA-based A(H7N9) vaccine has been developed and clinically evaluated (4), the contribution of NA immunity against A(H7N9) infection has been less explored.…”

Cross-Reactive Neuraminidase-Inhibiting Antibodies Elicited by Immunization with Recombinant Neuraminidase Proteins of H5N1 and Pandemic H1N1 Influenza A Viruses

“…NA-based influenza vaccines are attractive because of the relatively smaller number of changes in NA antigens compared to the changes in HA antigens in host immune systems (31,32). For this study, we constructed and purified H5N1 rNA and pH1N1 rNA proteins from Sf9 insect cells and found that mice immunized with H5N1 rNA and pH1N1 rNA proteins exhibited higher quantities of NA-specific total IgG, IgG1, IgG2a subclass, and NI antibodies, increased numbers of ASCs in the spleen, and better protective immunity against live-virus challenges.…”

Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase

“…Immunity to NA contributes to resistance against influenza virus (9)(10)(11). NA-inhibiting antibodies do not inhibit virus attachment and entry but, rather, reduce virus replication by preventing the release of newly formed viral particles from infected cells, resulting in mild disease symptoms (12)(13)(14)(15).…”