Single Antigen Strategy for Prevention of Recurrent and Chronic Suppurative Otitis

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 DESCRIPTION (provided by applicant): The goal of this proposal is to evaluate the prophylactic potential of antibodies to the conserved bacterial surface polysaccharide poly-N-acetyl glucosamine (PNAG) for prevention of recurrent and chronic suppurative otitis media (CSOM) specifically caused by the two most common pathogens of otitis media (OM), Streptococcus pneumoniae (SP) and non-typeable Haemophilus influenzae (NTHi). Both of these organisms produce surface PNAG, a molecule recognized to be essential for several bacterial biofilms. Drs. Pier and Pelton and collaborators have already published evidence that PNAG is expressed as a capsule-like antigen, intercalated within the known capsules of SP and NTHi on isolates obtained directly from the middle ear in children and in chinchillas. The unique aspect of this proposal will be targeting one antigen, present on both pathogens that could impact the reduced quality of life associated with recurrent OM and the profound deafness and suppurative complications associated with CSOM. As PNAG is produced by many commensal organisms (E. coli, S. epidermidis, B. fragilis), natural antibody to PNAG is commonly found in humans5. However, natural antibodies bind to the highly acetylated glycoform of PNAG (>60% acetylation) and are of low efficiency for mediating opsonic or bactericidal killing and show littl protective efficacy against infection5. Pier and colleagues have reported that by reducing the levels of acetylation to <30%, the glycoform of PNAG produced, called deacetylated PNAG (dPNAG), induces opsonic and/or bactericidal antibodies when conjugated to carrier proteins against both SP and NTHi. Importantly, these antibodies appear to have no effect on normal flora as evidenced by results from a phase 1 clinical trial of a MAb to PNAG in humans and multiple other lines of evidence including long-term animal studies. This project will evaluate the in vivo efficacy of passively transferred polyclonal and monoclonal antibody to PNAG for protection against pneumococcal and nontypable haemophilus influenzae middle ear disease in a well-established chinchilla model of bacterial otitis media, define a protective antibody concentration of anti- PNAG antibody for future studies of PNAG-conjugate vaccine efficacy, and evaluate immunogenicity of a 9GlcNH2-TT conjugate vaccine to demonstrate the potential of a passive-active strategy for reducing the burden of middle ear disease in children.