A multi-valent vaccine approach that elicits broad immunity within an influenza subtype.

Vaccines directed toward individual strains of highly variable viruses like influenza lose efficacy when the circulating viruses no longer resemble the vaccine isolate. Historically, inclusion of more than one isolate per subtype of influenza has been limited by the need to include large doses of antigen with typical protein-based vaccine approaches and by concerns that an immunodominant response to one antigen will limit the response to closely related antigens. Here we provide proof of principle demonstrating that a multi-valent vaccine directed against multiple influenza A virus hemagglutinins (HAs) can elicit broad, neutralizing immunity against multiple strains within a single influenza subtype (H3). We employed a DNA vaccine to direct immunity toward the HA component alone, and a live attenuated influenza virus (LAIV) to assess immunity against the whole virus. Delivery of either HA-DNA or LAIV yielded broad protective immunity across multiple antigenic clusters, including heterologous strains, that was similar to the combined immunity of each antigen assessed separately. Priming with HA-DNA followed by an LAIV boost strengthened and broadened the antibody response toward all three H3 HAs. This prime:boost multi-valent approach was thus able to elicit immunity against multiple strains within the H3 subtype without evidence of immune interference between closely related antigens. Although the trivalent vaccine described here is not a universal vaccine, since protection was limited to circulating viruses from about a two-decade period, these data suggest that full protection within a subtype is possible using this approach with multiple antigens from current and predicted future influenza strains.