Protection against H5N1 by multiple immunizations with seasonal influenza vaccine in mice is correlated with H5 cross-reactive antibodies.

BACKGROUND: Current seasonal influenza vaccines are believed to confer protection against a narrow range of virus strains. However, their protective ability is commonly estimated based on an in vitro correlate of protection that only considers a subset of anti-influenza antibodies that are typically strain specific, i.e., hemagglutination inhibiting antibodies. Here, we evaluate the breadth of protection induced with a seasonal trivalent influenza vaccine (composition H1N1 A/California/07/09, H3N2 A/Victoria/210/08, B/Brisbane/60/08) against influenza challenge in mice. METHODS: Balb/c mice were immunized once, twice, or three times with seasonal influenza vaccine to assess protection against heterosubtypic H5N1 influenza challenge, or homologous H1N1 influenza virus as a control. Passive transfer of immune serum was used to determine the contribution of humoral immunity to protection. RESULTS: Multiple immunizations with seasonal influenza vaccine induced up to 80% protection against heterosubtypic H5N1 influenza challenge in mice without eliciting detectable H5N1 neutralizing antibodies. Comparable levels of protection were reached by passive transfer of immune serum, and protection was correlated with the titer of vaccine-induced, H5 cross-reactive, non-neutralizing antibodies that are at least in part directed against conserved HA epitopes. CONCLUSIONS: Here, we demonstrate that seasonal vaccine has the ability to induce broad serum-mediated protection, and that the mechanism of this protection is different from the vaccine-induced homologous protection.

Transient humoral protection against H5N1 challenge after seasonal influenza vaccination of humans.

Current influenza vaccines are believed to confer protection against a narrow range of virus strains. The identification of broadly influenza neutralizing antibodies (bnAbs) has triggered efforts to develop vaccines providing 'universal' protection against influenza. Several bnAbs were isolated from humans recently vaccinated with conventional influenza vaccines, suggesting that such vaccines could, in principle, be broadly protective. Assessing the breadth-of-protection conferred to humans by influenza vaccines is hampered by the lack of in vitro correlates for broad protection. We designed and employed a novel human-to-mouse serum transfer and challenge model to analyze protective responses in serum samples from clinical trial subjects. One dose of seasonal vaccine induces humoral protection not only against vaccine-homologous H1N1 challenge, but also against H5N1 challenge. This heterosubtypic protection is neither detected, nor accurately predicted by in vitro immunogenicity assays. Moreover, heterosubtypic protection is transient and not boosted by repeated inoculations. Strategies to increase the breadth and duration of the protective response against influenza are required to obtain 'universal' protection against influenza by vaccination. In the absence of known correlates of protection for broadly protective vaccines, the human-to-mouse serum transfer and challenge model described here may aid the development of such vaccines.