Induction of broadly-reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans

ABSTRACT

Influenza virus infections are a major public health concern and cause significant morbidity and mortality worldwide. Current vaccines are effective but strain specific due to their focus on the immunodominant globular head domain of the hemagglutinin. It has been hypothesized that sequential exposure of humans to hemagglutinins with divergent globular head domains but conserved stalk domains could refocus the immune response to broadly neutralizing epitopes in the stalk. Humans have pre-existing immunity against H1 (group 1 hemagglutinin) and vaccination with H5 HA (also group 1) – which has a divergent globular head domain but a similar stalk domain – represents one such sequential exposure scenario. To test this hypothesis, we used novel reagents based on chimeric hemagglutinins to screen sera from an H5N1 clinical trial for induction of stalk-specific antibodies by quantitative ELISA and neutralization assays. Importantly, we also investigated the biological activity of these antibodies in a passive transfer in a mouse challenge model. We found that the H5N1 vaccine induced high titers of stalk-reactive antibodies which were biologically active and protective in the passive transfer experiment. The induced response showed exceptional breadth towards divergent group 1 hemagglutinins but did not extend to group 2 hemagglutinins. This data provides evidence for the hypothesis that sequential exposure to hemagglutinins with divergent globular head domains but conserved stalk domains can refocus the immune response towards the conserved stalk domain. Furthermore, the results support the concept of a chimeric hemagglutinin universal influenza virus vaccine strategy that is based on the same principle.

Significance Influenza virus vaccines have to be re-formulated and re-administered on an annual basis. The development of a universal influenza virus vaccine could abolish the need for this cumbersome and costly process and would also enhance our pandemic preparedness. This study addressed the following questions that are essential for the development of a hemagglutinin stalk based universal influenza virus vaccine: 1) Can stalk-reactive antibodies be boosted by vaccination with divergent HAs that share conserved epitopes? 2) How long-lived are these vaccine induced stalk-reactive antibody responses? 3) What is the breadth of this reactivity. 4) Are these antibodies functional and protective? Our results further strengthen the concept of induction of stalk-reactive antibodies by sequential exposure to hemagglutinin immunogens with conserved stalk and divergent head domains. A universal influenza virus vaccine based on the same principles seems possible and might have a significant impact on global human health.