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

Abstract

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.

Response of BALB/c mice to a monovalent influenza A (H1N1) 2009 split vaccine

“…Adjuvants are therefore required to elicit protective immune responses at antigen doses equal to or lower than those used in current seasonal influenza vaccines. [5][6][7] Aluminum salts are the most widely used adjuvants in licensed vaccines with an excellent safety profile.…”

EDiP: the Epitope Dilution Phenomenon. Lessons learnt from a malaria vaccine antigen and its applicability to polymorphic antigens

“…AMA1 Natural [31] versus DiCo [16], influenza HA Historical versus Modern H1N1 [41]). This is supported by influenza studies where exposure to only three components yielded broadly neutralizing responses within an influenza subtype [41,43]. Of note here is that the immune dominance of the HA head epitopes differs significantly following infection or vaccination [78], which may have repercussions for the number of vaccine components required to induce broadly neutralizing responses.…”

“…When comparing maximal amino acid distances between AMA1 and influenza H1 HA (Figures 2 and 3), it is evident that influenza HA is more variable than AMA1 [41,[43][44][45]. Huber et al have shown that a prime with DNA followed by a live-attenuated virus boost with a mixture of three H3N2 viruses (Hong Kong 1968, Victoria 1975, and Leningrad 1986) covers 20 years of antigenic drift in mice [43].…”

“…Huber et al have shown that a prime with DNA followed by a live-attenuated virus boost with a mixture of three H3N2 viruses (Hong Kong 1968, Victoria 1975, and Leningrad 1986) covers 20 years of antigenic drift in mice [43]. Carter et al show that sequential infection in ferrets with three seasonal H1N1 strains (either historical or modern) confers protection against H1N1pdm challenge (not contained in infection series) [41].…”

Correlates of vaccine protection from influenza and its complications

“…49 In pre-clinical models, a balanced immune response with induction of both neutralizing IgG1 and Fc-interacting IgG2a has proven to be ideal. 45,50,51 The contribution of the corresponding human Fc-interacting isotypes (i.e., IgG1) toward protective immunity is not as clear as it is in mice, and the majority of vaccine approaches target neutralizing antibodies preferentially without regard to isotype. Interestingly, however, the IgG1 isotype is preferentially induced in humans during natural infection, which may have implications for protective immunity.…”