Abstract
Annual immunization against influenza virus is a large international public health effort. Accumulating evidence suggests that antibody mediated cross-reactive immunity against influenza hemagglutinin (HA) strongly correlates with long-lasting cross-protection against influenza virus strains that differ from the primary infection or vaccination strain. However, the optimal strategies for achieving highly cross-reactive antibodies to the influenza virus HA have not yet to be defined. In the current study, using Luminex-based mPlex-Flu assay, developed by our laboratory, to quantitatively measure influenza specific IgG antibody mediated cross-reactivity, we found that prime-boost-boost vaccination of ferrets with rHA proteins admixed with adjuvant elicited higher magnitude and broader cross-reactive antibody responses than that induced by actual influenza viral infection, and this cross-reactive response likely correlated with increased anti-stalk reactive antibodies. We observed a similar phenomenon in mice receiving three sequential vaccinations with rHA proteins from either A/California/07/2009 (H1N1) or A/Hong Kong/1/1968 (H3N2) viruses admixed with Addavax, an MF59-like adjuvant. Using this same mouse vaccination model, we determined that Addavax plays a more significant role in the initial priming event than in subsequent boosts. We also characterized the generation of cross-reactive antibody secreting cells (ASCs) and memory B cells (MBCs) when comparing vaccination to viral infection. We have also found that adjuvant plays a critical role in the generation of long-lived ASCs and MBCs cross-reactive to influenza viruses as a result of vaccination with rHA of influenza virus, and the observed increase in stalk-reactive antibodies likely contributes to this IgG mediated broad cross-reactivity.
Highlights
Seasonal influenza virus infection is one of the largest recurring global public health threats [1]
We tested post-vaccination and post-infection ferret sera against a panel of 16 rHAs that included major H1(group 1) and H3 circulating or vaccine influenza strain subtypes. Details of those purified rHAs (S1 Fig) and control experiments with strain specific monoclonal antibodies are provided in S2 Fig. The results (Fig 2) showed that sera collected from 9 different H1 or H5 influenza virus infections had very specific antibody reactions against homologous or similar strains within the same subtype, but minimal cross-reactivity against other influenza rHAs within the same phylogenic group
Adjuvanted influenza vaccine induces broadly cross-reactive IgG responses to influenza hemagglutinins reactivity within the H1 subtype, and to H5N1 influenza strains of the same phylogenetic subtype
Summary
Seasonal influenza virus infection is one of the largest recurring global public health threats [1]. Antibody mediated protection against infection by influenza A and B viruses arises from prior infection and vaccination. Infection induces adaptive immunity mediated by both antibodies and virus reactive T cells, while vaccination primarily elicits a T cell dependent IgG response directed against influenza virus hemagglutinin (HA) and neuraminidase (NA) proteins[2, 3]. HA is responsible for viral binding to host cell surface sialic acid residues and for viral fusion. Most neutralizing anti-influenza virus antibodies target the HA protein head region, which contains the sialic acid receptor-binding site. Antibodies targeting this region can neutralize the virus by blocking binding to sialic acid residues on the surface of target cells [4]
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