Immunogenicity of Enhanced Influenza Vaccines Against Mismatched Influenza Strains in Older Adults: A Review of Randomized Controlled Trials

Antigenic drift is a major driver of viral evolution and a primary reason why influenza vaccines must be reformulated annually. Mismatch between vaccine and circulating viral strains negatively affects vaccine effectiveness and often contributes to higher rates of influenza-related hospitalizations and deaths, particularly in years dominated by A(H3N2). Several countries recommend enhanced influenza vaccines for older adults, who are at the highest risk of severe influenza complications and mortality. The immunogenicity of enhanced vaccines against heterologous A(H3N2) strains has been examined in nine studies to date. In six studies, an enhanced, licensed MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) consistently increased heterologous antibody titers relative to standard influenza vaccine, with evidence of a broad heterologous immune response across multiple genetic clades. In one study, licensed high-dose trivalent inactivated influenza vaccine (HD-IIV3) also induced higher heterologous antibody titers than standard influenza vaccine. In a study comparing a higher dose licensed quadrivalent recombinant influenza vaccine (RIV4) with HD-IIV3 and aIIV3, no significant differences in antibody titers against a heterologous strain were observed, although seroconversion rates were higher with RIV4 versus comparators. With the unmet medical need for improved influenza vaccines, the paucity of studies especially with enhanced vaccines covering mismatched strains highlights a need for further investigation of cross-protection in older adults.