Combination CpG and MPL agonists heighten vaccine-induced protection against Influenza A virus challenge

Abstract

Abstract Current strategies for Influenza A Virus (IAV) vaccination result in antibodies against strain specific viral coat proteins. These antibodies do not provide protection against heterologous IAV strains and leave the population vulnerable to pandemics of highly pathogenic IAV. Vaccines may be improved by targeting T cells, which unlike B cells, are able to recognize inner, conserved IAV antigens, such as nucleoprotein (NP), increasing the potential for protection against different IAV stains. During live IAV infection multiple pattern recognition receptors (PRRs) on innate immune cells are activated; therefore vaccines triggering multiple PRRs may elicit better protection. As dendritic cells are the most potent antigen presenting cells for T cells, bone marrow derived dendritic cells (BMDCs) were activated by combined agonists that trigger separate, yet complementary PRR signaling pathways. Here we show that combined PRR agonists MPL and CpG, which activate TLR4 and TLR9 respectively, increased in vitro cytokine and chemokine expression by BMDCs. Further, intramuscular vaccination of mice with IAV pdm09 H1N1 hemagglutinin (HA) protein plus combined CpG and MPL, as adjuvants, induced the formation of pdm09 HA specific IgG2c antibodies. Combined CpG and MPL recipient mice experienced less weight loss and lower mortality after lethal challenge with pdm09 H1N1 compared to mice receiving lone agonists, suggesting that combined agonists improve protection. T cell activation in response to combined CpG and MPL is currently being investigated, as well as responses generated via mucosal, intranasal vaccination. Thus combined agonists that promote B and T cell mediated immunity could be incorporated into next generation IAV vaccines.