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

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

'Birthing a Better Future': A mixed-methods evaluation of an exhibition on the early years of life

BACKGROUND: Our study aimed to evaluate to what extent Zero2 Expo's 'Birthing a Better Future', a co-created multimedia exhibition, was effective in raising awareness on the importance of the first 1001 days of life and explore what refinements would help to optimize the impact of future exhibitions. METHODS: We conducted a mixed-methods evaluation of the exhibition delivered in the John Radcliffe Hospital, Oxford. Through convenience sampling, 14 participants were selected to participate in 12 structured interviews and 19 participants completed a questionnaire. Interviews were thematically analysed alongside quantitative analysis of questionnaire responses through Likert scales. RESULTS: The majority (78.6%, n = 11/14) of participants who completed the questionnaire either agreed or strongly agreed that the exhibition raised their awareness about the first 1001 days of life. This was supported by the analysis of interviews. The use of art was found to provoke an emotional engagement from participants. Participants felt that the length of the written pieces and location of the exhibition were important factors for designers to consider in future exhibitions. CONCLUSION: This study demonstrated that multimedia exhibitions, combining science with art, may be an effective way to raise awareness of public health messages. Engaging with key stakeholders will be an essential step in order to improve future public health exhibitions. PUBLIC CONTRIBUTION: When designing the study, the public reviewed the study tools, which were refined based on their feedback. At every phase of the study, members of the public who are artists co-created the exhibition content

Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage

Item does not contain fulltextThe ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal immunoglobulin G (IgG) to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating. Passive immunization with this antiserum was ineffective to block acquisition of colonization compared to agglutinating antisera raised against the encapsulated parent strain. In the human challenge model, samples were collected from PCV and control-vaccinated adults. In PCV-vaccinated subjects, IgG levels to CPS were increased in serum and nasal wash (NW). IgG to the inoculated strain CPS dropped in NW samples after inoculation suggesting its sequestration by colonizing pneumococci. In post-vaccination NW samples pneumococci were heavily agglutinated compared with pre-vaccination samples in subjects protected against carriage. Our results indicate that pneumococcal agglutination mediated by CPS-specific antibodies is a key mechanism of protection against acquisition of carriage. Capsule may be the only vaccine target that can elicit strong agglutinating antibody responses, leading to protection against carriage acquisition and generation of herd immunity