Haemophilus influenzae lipoprotein fusion vaccine and lipoprotein vaccine platform development

Rochester General Hospital (Ny), Rochester NY

Investigators

Abstract

Abstract: A vaccine to prevent Nontypeable Haemophilus influenzae (NTHi) infections is a major unmet need. NTHi causes respiratory infections in children and adults including acute otitis media (AOM), acute sinusitis, conjunctivitis, acute exacerbations of chronic obstructive pulmonary disease (COPD), neutrophilic asthma and invasive disease that leads to high morbidity and mortality worldwide. Previously we have shown lipidation of proteins P6 and OMP26 of NTHi enhances antibody and Th17 immunity and provides protection against nasopharyngeal (NP) colonization and ear infection caused by NTHi compared to non-lipidated constructs. In this project, we will evaluate immunogenicity and protective efficacy of NTHi lipidated protein D and protein F and their fusion constructs versus their non-lipidated constructs after systemic vaccination in a mouse model of NP colonization, ear and lung infection. We expect our novel lipidated and fusion constructs to enhance serum and mucosal IgG antibody and activate Th17- mediated immunity in nasal associated lymphoid tissue (NALT) along with generating T-cell resident memory (TRM) against NTHi. Differential effects of diacyl vs triacyl variation of a lipid moiety in stimulation of TLR2/TLR1 vs. TLR2/TLR6 will be determined. We have synthesized and will test a quadrivalent (L-OMP26φNL-P6φNL-PDφNL-PF) fusion (truncated version of each proteins based on their functional epitopes) making only one protein lipidated anticipating enhanced immunogenicity for all 4 proteins. Overall the project will expand our understanding of immune mechanisms activated by novel lipoprotein NTHi fusion vaccine constructs and identify any differences in immune response associated with diacyl vs. triacyl lipidation (TLR2/TLR1 vs. TLR2/TLR6 activation) on protective efficacy against NTHi NP colonization, ear and lung infection. This project will more broadly innovate with a novel lipoprotein vaccine platform that may be applied to other pathogens and vaccine candidate proteins (including those that are not naturally lipidated) where mucosal colonization is the first step of pathogenesis.