Boosting Heterosubtypic Neutralization Antibodies In Recipients Of 2009 Pandemic H1N1 Influenza Vaccine

In 2009, a new emerging pandemic H1N1 influenza virus with a combination of gene segments derived from North American and Eurasian swine lineages was identified. A mass vaccination has been implemented to prevent the spread of 2009 pandemic influenza virus in China. However, highly limited information is available on whether this vaccine induces cross-reactive neutralization antibodies against other subtypes of influenza viruses. We employed pseudovirus based assays to analyze heterosubtypic neutralization responses to those concomitant seasonal or highly pathogenic avian influenza viruses that also have posed considerable threads to public health in serum samples of 23 recipients of 2009 pandemic influenza vaccine. Our data demonstrated that one dose of unadjuvanted inactivated split pandemic vaccine not only stimulated neutralization antibodies against the cognate 2009 pandemic H1N1 influenza A virus, but also raised broad cross-reactive neutralization activities against the seasonal H3N2 influenza A virus and the highly pathogenic avian H5N1 influenza A virus, but lesser to the seasonal H2N2 influenza A virus. Interestingly, significant neutralization activities against 2009 pandemic H1N1 influenza A virus were already found in the baseline serum samples of 20 subjects collected before vaccination. The pandemic H1N1 influenza vaccine is immunogenic, and is able to elicit both hemagglutination-inhibition (HAI) and homologous neutralization antibodies in parallel.2009 pandemic influenza vaccine could boost individual pattern of cross-reactive neutralization responses to other subtypes of influenza viruses. These cross-reactive neutralization activities were near-completely abolished after the depletion of immunoglobin G (IgG) from the serum samples. In contrast, H1N1 vaccination alone in influenza-naive mice elicited only vigorous homologous neutralizing activities but not cross-reactive neutralization activities against other subtypes of influenza viruses. Together, these data suggest that the hemagglutin of 2009 pandemic H1N1 influenza vaccine contains cross-reactive neutralization epitopes which could elicit significant cross-reactive neutralizing IgG antibodies. The observational discrepancy between humans and mice may be explained by the different neutralization activities at baseline:vigorous cross-reactive neutralization activities were identified in human samples at baseline, whereas no activities were detected in mouse samples in the absence of vaccination, as shown in mock-control-immunized mice. The preexisting immunity, as observed in our study, plays an important role in finalizing the composition of immunity, and that the inoculation of the 2009 pandemic H1N1 influenza vaccine served as a boost is able to enhance the preexisting cross-reactive neutralization activities but not for eliciting the de novo cross-reactive neutralization activities. The exposure to 2009 pandemic H1N1 influenza vaccine is likely to modify the hierarchical order of preexisting immune responses to influenza A viruses. These findings provide insights into the evolution of human immunity to influenza viruses after experiencing multiple influenza virus infections and vaccinations.