Evaluation of mismatched immunity against influenza viruses

Prior immunity against influenza A viruses generates sterilizing immunity against matched (homologous) viruses and varying levels of protection against mismatched (heterologous) viruses of the same or different subtypes. Natural immunity carries the risk of high morbidity and mortality, therefore immunization offers the best preventative measure. Antibody responses against the viral hemagglutinin protein correlate with protection in humans and evidence increasingly supports a role for robust cellular immune responses. By exploiting mismatched immunity, current conventional and experimental vaccine candidates can improve the generation of cross-protective immune responses against heterologous viruses. Experimental vaccines such as virus-like particles, DNA vectors, viral vectors and broadly neutralizing antibodies are able to expand cross-protection through mismatched B- and T-cell responses. However, the generation of mismatched immune responses can also have the opposite effect and impair protective immunity. This review discusses mismatched immunity in the context of natural infection and immunization. Additionally, we discuss strategies to exploit mismatched immunity in order to improve current conventional and experimental influenza A virus vaccines.