Chimeric Hemagglutinin-Based Influenza Virus Vaccines Induce Protective Stalk-Specific Humoral Immunity and Cellular Responses in Mice

Abstract

The high variation of the influenza virus hemagglutinin (HA), particularly of its immunodominant head epitopes, makes it necessary to reformulate seasonal influenza virus vaccines every year. Novel influenza virus vaccines that redirect the immune response toward conserved epitopes of the HA stalk domain should afford broad and durable protection. Sequential immunization with chimeric HAs (cHAs) that express the same conserved HA stalk and distinct exotic HA heads has been shown to elicit high levels of broadly cross-reactive Abs. In the current mouse immunization studies, we tested this strategy using inactivated split virion cHA influenza virus vaccines (IIV) without adjuvant or adjuvanted with AS01 or AS03 to measure the impact of adjuvant on the Ab response. The vaccines elicited high levels of cross-reactive Abs that showed activity in an Ab-dependent, cell-mediated cytotoxicity reporter assay and were protective in a mouse viral challenge model after serum transfer. In addition, T cell responses to adjuvanted IIV were compared with responses to a cHA-expressing live attenuated influenza virus vaccine (LAIV). A strong but transient induction of Ag-specific T cells was observed in the spleens of mice vaccinated with LAIV. Interestingly, IIV also induced T cells, which were successfully recalled upon viral challenge. Groups that received AS01-adjuvanted IIV or LAIV 4 wk before the challenge showed the lowest level of viral replication (i.e., the highest level of protection). These studies provide evidence that broadly cross-reactive Abs elicited by cHA vaccination demonstrate Fc-mediated activity. In addition, cHA vaccination induced Ag-specific cellular responses that can contribute to protection upon infection.

Pandemic influenza virus vaccines boost hemagglutinin stalk-specific antibody responses in primed adult and pediatric cohorts

“…In preclinical studies, priming with inactivated seasonal influenza virus vaccines has shown some promise. 19,38 It might be possible Fig. 2 GMTs and MGIs for anti-H2 full-length antibodies measured by ELISA following vaccination with adjuvanted pandemic vaccines and seasonal vaccine.…”

Immune Pressure on Polymorphous Influenza B Populations Results in Diverse Hemagglutinin Escape Mutants and Lineage Switching

“…However, it is not clear what effect polyclonal and cross-reactive antibodies generated after multiple vaccinations or exposures have on IBV evolution. There is evidence to suggest that receiving vaccines with the same HA stalk region and different head regions may increase the antibodies that target the more conserved regions of the HA protein [33]. Other work indicates that antibodies generated towards viruses encountered early in life may be expanded and comprise a large portion of the influenza-specific antibodies [34].…”

Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection

“…Our review also considers the generation and expansion of MBCs at different points in the response to both maintain OAS response patterns and adapt to emerging HAs. Our increasing understanding of MBC competition, immunodominance hierarchies, and Ab regulation of B cell responses will continue to guide development of vaccine composition and administration strategies to optimize B cell-mediated protection generated against IAV infection [63][64][65][66][67].…”