New vaccines against pneumonia: Investigating protein-specific immune responses to Streptococcus pneumoniae using Experimental Human Pneumococcal Carriage

Abstract

Infections caused by Streptococcus pneumoniae are a major cause of morbidity and mortality globally: S. pneumoniae is the primary bacterial agent of pneumonia, the leading cause of death in children under 5 years of age and a major cause of invasive disease in the elderly. Currently licensed vaccination strategies target pneumococcal capsular polysaccharides of which there are 94 known types (serotypes). Antibodies against vaccine serotypes effectively protect against invasive pneumococcal disease, but less so against mucosal infections including pneumonia. New vaccine development efforts aim to overcome these hurdles by targeting conserved and immunogenic pneumococcal proteins. The Pneumococcal Surface Protein A (PspA) is a leading candidate due to its expression across all known clinically relevant pneumococcal strains, and ability to protect against infection across serotypes. However, PspA sequence heterogeneity necessitates identification of cross-protective protein constructs. In this doctoral research project, I investigated pneumococcal protein-specific humoral and CD4+ T-lymphocyte immune responses to S. pneumoniae utilising the platform of Experimental Human Pneumococcal Carriage (EHPC). With an emphasis on PspA, immune responses to nasopharyngeal carriage - the prerequisite to pneumococcal disease and proxy for infection - were evaluated. I present the first evidence of CD4+ T-cell responses specific to an individual pneumococcal purified protein in the blood of healthy adults both before and after carriage. PspA-specific CD4+ T-cell responses to S. pneumoniae in bronchoalveolar lavage of healthy adults after EHPC were detected at lower levels than in blood, indicating non-immunodominance of PspA as a T-cell antigen in the lung, and compartmentalisation of immune response. I also describe from preliminary data, a potential role of PspA in protection from pneumococcal carriage re- acquisition, and optimise an assay for the identification of linear pneumococcal protein epitopes with potential for inclusion in a multiple epitope protein. Unveiling protein-specific immune responses to S.pneumoniae using controlled and reproducible EHPC, may aid in our understanding of immunity towards selection of protein vaccine candidates for protection against human pneumococcal infection and disease.