MRC/FAPESP - bilateral agreement: Multiple-epitope vaccine to confer serotype-independent protection against pneumonia

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Pneumococcal infections account for 11% of all deaths in children under 5 years of age and in older adults, Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Pneumococcal infections in both children and adults are potentially preventable by vaccination but current vaccines do not offer the level of protection needed. Furthermore, the use of polysaccharide conjugate vaccine is associated with disease caused by non-vaccine types, a phenomenon known as serotype replacement. The existence of >90 different pneumococcal types implies that serotype replacement will be a persistent problem for anti-capsular vaccines. The development of a vaccine based on pneumococcal proteins common to all strains offers the potential for serotype-independent protection and the complete eradication of carriage. Pneumococcal surface proteins A (PspA) and Pneumococcal surface protein C (PspC) among the most promising candidates for a protein-based vaccine. Although these proteins are variable among different clinical isolates, we have found some variants that are able to induce antibodies with broad reactivity, recognizing different PspA and PspC variants. We have also shown that fusion of PspA protein fragments is an efficient strategy to extend protection provided by a protein, but the ideal epitopes (parts of the protein) to be included in the vaccine has yet to be defined. The selection of epitopes capable of inducing antibodies with broad cross-reactivity (able to recognize all variants of PspA and PspC) is of clinical importance to the successful development of a vaccine using this approach. We will use peptide array techniques to describe the entire range of cross-reactive epitopes target by sera that are known to be cross-reactive (murine immunized and human sera) and determine the optimal epitopes to be included in the vaccine. The approach of using peptide arrays has been successful used to identify immunogenic epitopes of candidates for Plasmodium and Leptospira vaccine but not yet for S. pneumoniae. Our group at LSTM has successful established an Experimental Human Pneumococcal Carriage (EHPC) model and has established pneumonia patient cohorts. We will use a unique set of pre- and post-pneumococcal intranasal inoculation samples to dissect responses to PspA and PspC epitopes to a known carriage event. We will use samples from pneumonia patients to compare healthy and susceptible antibody function. Results obtained in a previous experimental human carriage study showed that presence of serum antibodies against PspA correlated with failure to establish carriage. We have observed increased antibody responses to PspA and PspC in serum, nasal wash and bronchoalveolar lavage following carriage. Immunoglobulin reponses to exposure, carriage and disease are different and show compartmentalization. There is an urgent need for a pneumonia vaccine that is effective in childhood and in old age. We propose that an optimal vaccine will protect both age groups against pneumonia caused by all serotypes of pneumococci. We will achieve this by identifying epitopes of PspA and PspC to produce a multiple-epitope vaccine, test this vaccine in murine models of invasive disease and confirm cross-reactivity of antibodies using a wide panel of pneumococcal clinical isolates. Further we will use the effective acquired immunity that protects healthy adults against carriage and the deficient response of pneumonia patients to determine the effective levels and function of antibodies to this vaccine candidate. Finally, we will confirm induction of cellular responses elicited by immunisation in mice and the presence of multiple-epitope antigen specific CD4 T cells in healthy adults and pneumonia patients.