Antibody to Influenza Virus Neuraminidase: An Independent Correlate of Protection

J Infect Dis. 2015 Oct 15;212(8):1191-9. doi: 10.1093/infdis/jiv195. Epub 2015 Apr 8.


Background: Laboratory correlates of influenza vaccine protection can best be identified by examining people who are infected despite vaccination. While the importance of antibody to viral hemagglutinin (HA) has long been recognized, the level of protection contributed independently by antibody to viral neuraminidase (NA) has not been determined.

Methods: Sera from a controlled trial of the efficacies of inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) were tested by hemagglutination inhibition (HAI) assay, microneutralization (MN) assay, and a newly standardized lectin-based neuraminidase inhibition (NAI) assay.

Results: The NAI assay detected a vaccine response in 37% of IIV recipients, compared with 77% and 67% of participants in whom responses were detected by the HAI and MN assays, respectively. For LAIV recipients, the NAI, HAI, and MN assays detected responses in 6%, 21%, and 17%, respectively. In IIV recipients, as NAI assay titers rose, the frequency of infection fell, similar to patterns seen with HAI and MN assays. HAI and MN assay titers were highly correlated, but NAI assay titers exhibited less of a correlation. Analyses suggested an independent role for NAI antibody in protection, which was similar in the IIV, LAIV, and placebo groups.

Conclusions: While NAI antibody is not produced to a large extent in response to current IIV, it appears to have an independent role in protection. As new influenza vaccines are developed, NA content should be considered.

Clinical trials registration: NCT00538512.

Keywords: clinical trial; hemagglutinin; immune correlates; influenza; influenza vaccine; neuraminidase; serologic assays; vaccine response.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Viral / biosynthesis
  • Antibodies, Viral / blood*
  • Female
  • Hemagglutination Inhibition Tests
  • Hemagglutinins, Viral / immunology
  • Humans
  • Immunoglobulins / blood
  • Influenza Vaccines / immunology*
  • Influenza, Human / immunology
  • Influenza, Human / prevention & control*
  • Male
  • Middle Aged
  • Neuraminidase / antagonists & inhibitors
  • Neuraminidase / immunology*
  • Neutralization Tests
  • Orthomyxoviridae / enzymology
  • Orthomyxoviridae / immunology*
  • Vaccination
  • Vaccines, Attenuated / immunology
  • Vaccines, Inactivated / immunology
  • Young Adult


  • Antibodies, Viral
  • Hemagglutinins, Viral
  • Immunoglobulins
  • Influenza Vaccines
  • Vaccines, Attenuated
  • Vaccines, Inactivated
  • Neuraminidase

Associated data