Cross-reactive immunity to clade 2 strains of influenza virus A subtype H5N1 induced in adults and elderly patients by Fluval, a prototype pandemic influenza virus vaccine derived by reverse genetics, formulated with a phosphate adjuvant, and directed to clade 1 strains

Abstract

High fatality rates and multiple cases of transmission of avian H5N1 influenza viruses to humans illustrate the urgent need for an efficacious, cross-protective vaccine against H5N1 strains. Extensive genetic characterization of H5N1 strains has elucidated the natural evolutionary relationship of these strains, linking groups known as clades to a common ancestor. Although the clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines, there is some evidence that cross-reactive immunity can be afforded. We aimed to assess the immunogenicity of a clade 1 H5N1 (NIBRG-14) whole-virus vaccine with an aluminum phosphate adjuvant and to determine whether it can induce cross-reactive immunity against antigenically drifted clade 2 H5N1 strains, both those derived by reverse genetics and wild-type isolates. A total of 88 (44 adult and 44 elderly) subjects, who received one dose (6 microg) of the vaccine, were studied. As judged by U.S. and European licensing criteria based on hemagglutination inhibition, the subjects developed cross-reactive immunity against all studied H5N1 strains belonging to a clade different from that of the strain utilized to produce the vaccine. Our findings highlight the importance of stockpiling, since cross-immune reactions induced by prepandemic vaccines will likely reduce morbidity and mortality in case of a pandemic.

FIG. 1.

Evolution of the H5N1 hemagglutinin gene. The arrows indicate the vaccine strain (Vietnam/1194/2004) and the strains against which cross-reactive immunity was tested.

FIG. 2.

Seroconversion rates (percentages of subjects) for adult and elderly subjects by hemagglutination inhibition.

FIG. 3.

Postvaccination/prevaccination GMT ratios for adult and elderly subjects by hemagglutination inhibition.

FIG. 4.

Seropositivity rates (percentages of subjects) for adult and elderly subjects by hemagglutination inhibition.

FIG. 5.

Seroconversion rates (percentages of subjects) for adult and elderly subjects by microneutralization.

FIG. 6.

Postvaccination/prevaccination GMT ratios for adult and elderly subjects by microneutralization.

FIG. 7.

Total antibody levels measured by ELISA. The difference between the titers for NIBRG-14 on day 21 and day 0 was taken as 100% for purposes of comparison.