TH17-Based Vaccine Design For Prevention Of Nontypeable Haemophilus Influenzae Infection

BACKGROUD AND PURPOSE:Nontypeable Haemophilus influenzae(NTHi),an opportunistic pathogen,often causes acute otitis media(AOM),sinusitis,conjunctivitis and community acquired pneumonia.It has been reported that recurrent NTHi infection was strongly associated with exacerbation of chronic obstructive pulmonary disease(COPD)and cystic fibrosis.In addition,NTHi can co-operate with influenza virus and cuases excessive mortality of flu patients.Current available Hib conjugate vaccines are only effective to prevent serotype b infection rather than NTHi.Thus,there is an urgent need for NTHi vaccine.Till now most studies have focused on antibody-based vaccine development,and encountered enomous challenges to identify ideal vaccine candidates due to extensive sequence and antigenic variation among clinical strains.Recently,T cells have been shown to provide serotype-independent protection by recognizing antigens conserved cross species,implying that they are promising vaccine targets.Here,we identified 2 novel NTHi vaccine candidates,characterized NTHi specific T cell responses in immune host and accessed the capacilities of T-cell-based vaccination strategies in protecting in vivo against NTHi infection,trying to find a different way to develop NTHi vaccine.METHODS:Establish murine pulmonary NTHi infection model,we characterized the NTHi specific adaptive immune response and investigated the antigens aoursing specific T cell responses and antibodies.Contributions of antibodies and T cells in the vaccine-induced immunity were evaluated by adoptive transfer experiments.Based on bioinformatics results,we selected several candidate antigens and determined their antigenities.The protective efficacy of screened vaccine candidates against NTHi infection was acessed by challenge experiments.RESULTS:Intranasal instillation of NTHi into the lungs of mice induced robust Th17 responses in the lung.Unlike the humoral response,which was highly strain specific,antigen specific Th17 cells recognized both homologous and heterologous Hi strains and mediated cross-protection.Moreover,membrane associated proteins were recognized by Th17 cells in NTHi infectied mice.Immunization with the subset of membrane proteins that elicited the strongest Th17 response protected mice against single NTHi and IAV/NTHi co-infectionCONCLUSIONS:Our results demonstrate that NTHi infection induces both cellular and humoral immune responses.Unlike the restricted protection against NTHi infection mediated by specific antibodies,membrane-associated protein specific Th17 cells provided broad protection against NTHi infection,which strongly suggests the promising candidate vaccine development based on Th17 immune responses.