ICF: Pneumococcal vaccine to prevent transmission of serotype 3 pneumococcus

Pneumococcal vaccine to prevent transmission of serotype 3 pneumococcus Serotype 3 pneumococcus (SPN3) has increased not only in carriage prevalence but also as a cause of severe invasive pneumococcal disease, both meningitis and pneumonia, world-wide following the introduction of pneumococcal conjugate vaccines (PCV). This emergence of SPN3 disease is most likely due to suboptimal protection confered by PCV against this capsular type. Further, SPN3 strains have a high rate of antimicrobial resistance which is itself an emerging global threat. There are both murine and human data to support the hypothesis that pneumococcal protein vaccines may show efficacy against SPN3 disease and also prevent nasopharyngeal carriage. Human nasopharyngeal carriage of pneumococci is not only the pre-requisite for disease but also the reservoir and means of transmission of these bacteria in the community. Prevention of pneumococcal carriage therefore results in reduction of both transmission and disease. We have developed safe experimental human pneumococcal carriage models of several pneumococcal types in both the UK and Malawi over the last 15 years. These human challenge experiments allow direct testing of vaccine efficacy in the prevention of pneumococcal carriage. We have tested conjugate and protein vaccines using serotype 6B pneumococci and showed comparable efficacy to subsequent phase 3 studies and post-licensure surveillance (for conjugate). We now wish to test the effect of PnuBioVax vaccine in reduction of SPN3 carriage in an experimental human pneumococcal carriage model in Malawi. SPN3 is the most prevalent pneumococcal serotype in Malawi, particularly in children and adults living with HIV, and an important cause of disease across Africa. We have recently established an SPN3 carriage model using a Malawi strain in both the UK and Malawi. PnuBioVax (PBV) is an immunogenic and low-cost protein vaccine candidate which demonstrated a good safety profile in a published phase 1 trial. PBV formulation has a pool of well characterized pneumococcal protein antigens many of which have demonstrated protection in murine models of infection. The use of protein antigens to induce mucosal immunity against pneumococcal carriage steps around the problems of the serotype 3 capsule being poorly immunogenic, shed from the bacterial surface, and relatively resistant to opsonophagocytosis. We expect PBV to have a greater effect in reducing SPN3 carriage than currently available vaccines. This proposal is to manufacture GMP grade PBV using the same production path as the published Phase 1 study, packaged ready for DBRCT testing, and then to test the vaccine for prevention of carriage in a DBRCT design using a SPN3 experimental human pneumococcal carriage model. We will compare both PBV and PCV against placebo to determine reduction in SPN3 experimental carriage incidence and density. Reduction in incidence and density of carriage are associated with decreased transmission of pneumococci. We will then plan a phase 3 study of prevention of natural SPN3 carriage and transmission in Malawi, using a similar design to the current carriage and transmission vaccine study of PCV13. Co-incidently we will develop a regulatory and commercialisation plan for the optimal route to market for PBV. We expect that PBV will be effective against SPN3 carriage, and therefore be an important additional strategy to anti-capsular immunoglobulin based disease preventing vaccines in Africa and Asia.