Combined CpG and MPL as vaccine adjuvants improve immunity and heterosubtypic protection against lethal viral challenge in single dose and prime/boost regimens

Abstract

Abstract Current Influenza A virus (IAV) vaccines show poor efficacy, often 40–60%. A strategy to improve effectiveness of IAV vaccines is to include adjuvants to activate innate immunity. We examined the potential of combined pattern recognition receptor agonists CpG and MPL to increase IAV vaccine induced protection. When administered in a single, low dose intramuscular hemagglutinin (HA) protein vaccine, mice receiving MPL + CpG experienced less morbidity after homologous challenge compared to mice receiving single agonists. In experiments analyzing heterosubtypic protection, vaccines containing MPL delivered intramuscularly (i.m.) showed increased protection against weight loss while the addition of CpG enhanced antibody responses but not survival. To determine if MPL and CpG have combinatory effects at different sites, HA and NP were delivered with MPL i.m. while HA and NP were simultaneously delivered with CpG intranasally (i.n.). Data demonstrate that combination MPL i.m. + CpG i.n. abrogated morbidity, but did not improve survival compared to MPL + CpG i.m. Further, mice given MPL + CpG produced IgG antibodies that were cross-reactive to H1N1 virus, yet magnitude of antibody responses did not correlate with protective efficacy. Finally, comparison of MPL i.m. + CpG i.n. in a prime/boost regimen, followed by heterosubtypic challenge, showed that weight loss was significantly lowered in mice that received prime/boost vaccination compared to mice that received prime only. Higher antibody responses induced by a second dose of vaccine did not correlate with protective capacity, suggesting that antibody levels, while indicators of vaccine immunogenicity, do not directly correlate with ability to protect mice from severe disease. Supported by Trudeau Institute and Clarkson University.