Please cite this paper as: Easterbrook et al. (2011) Immunization with 1976 swine H1N1‐ or 2009 pandemic H1N1‐inactivated vaccines protects mice from a lethal 1918 influenza infection. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2010.00191.x.

Background  Zoonotic infections with H1N1 influenza viruses that evolved initially from the 1918 virus (1918) and adapted to swine threatened a pandemic in 1976 (1976 swH1N1) and a novel reassortant H1N1 virus caused a pandemic in 2009–2010 (2009 pH1N1). Epidemiological and laboratory animal studies show that protection from severe 2009 pH1N1 infection is conferred by vaccination or prior infection with 1976 swH1N1 or 1918.

Objectives  Our aim was to demonstrate cross‐protection by immunization with 2009 pH1N1 or 1976 swH1N1 vaccines following a lethal challenge with 1918. Further, the mechanisms of cross‐protective antibody responses were evaluated.

Methods  Mice were immunized with 1976 swH1N1, 2009 pH1N1, 2009 seasonal trivalent, or 1918 vaccines and challenged with 1918. Cross‐reactive antibody responses were assessed and protection monitored by survival, weight loss, and pathology in mice.

Results and Conclusions  Vaccination with the 1976 swH1N1 or 2009 pH1N1 vaccines protected mice from a lethal challenge with 1918, and these mice lost no weight and had significantly reduced viral load and pathology in the lungs. Protection was likely due to cross‐reactive antibodies detected by microneutralization assay. Our data suggest that the general population may be protected from a future 1918‐like pandemic because of prior infection or immunization with 1976 swH1N1 or 2009 pH1N1. Also, influenza protection studies generally focus on cross‐reactive hemagglutination‐inhibiting antibodies; while hemagglutinin is the primary surface antigen, this fails to account for other influenza viral antigens. Neutralizing antibody may be a better correlate of human protection against pathogenic influenza strains and should be considered for vaccine efficacy.