Investigation of the humoral immune response to pneumococcal polysaccharides and the role of a conjugate pneumococcal vaccine in secondary prevention of invasive pneumococcal disease in HIV-infected Africans. (360G-Wellcome-061230_Z_00_D)

Invasive pneumococcal disease (IPD) is the only important HIV-related problem in sub-Saharan Africa which is potentially vaccine preventable. Conservative estimates suggest 1 million cases of adult IPD occur annually in this region as a consequence of HIV-infection. In our recent efficacy trial in Uganda, the 23-valent pneumococcal polysaccharide vaccine (PPV) increased the risk of IPD/pneumonia. The efficacy and role of the newer conjugate pneumococcal vaccines (CPV) remains unknown. I aim to investigate potential mechanisms of vaccine failure and harm associated with the use of PPV, and assess the response to and efficacy of CPV in a randomised controlled trial. CPV will be used to probe for defects in serological response to polysaccharides in a) previous PPV vaccine recipients b) individuals with past IPD, to describe and categorise the prejudicial effects of exposure to vaccine-purified or natural polysaccharide. A double-blind, randomised placebo controlled trial of CPV as secondary prophylaxis to prevent recurrent IPD will be performed in HIV-infected Malawian adults. Proven efficacy of the vaccine as secondary prophylaxis will be a fair indicator of potential as primary prophylaxis. Initial studies of the B-cell mechanisms that underpin altered or deleterious serological response will commence with validation of appropriate and "field-friendly" methods for the isolation of polysaccharide responsive B-cells, for future molecular-based descriptions of B-cell populations and dynamics.