Population differences in vaccine response (POPVAC)-2: the impact of environmental exposures and selected interventions on waning of vaccine-induced immune responses
Medical Research Council
MRC/UVRI and LSHTM Research Unit Uganda
We propose that parasite infections contribute substantially to population differences in vaccine response; and that their effects are mediate We will test this hypothesis through four linked objectives among Ugandan adolescents. An immunisation programme comprising relevant live and inert vaccines will be given over one school year, with primary endpoints one month postimmunisation. A secondary endpoint at one year will assess response waning. 1. We will compare vaccine response profiles in urban adolescents (low parasite burden) with two rural cohorts, chosen for high schistosomiasis and high malaria prevalence. 2. We will establish whether current parasite infections have causal effects using individually-randomised, placebocontrolled interventions targeting the dominant infection in each rural cohort. Sample sizes will be robust, powered to detect vaccine response differences of 0.14log10 between study arms (modest effects compared to preliminary data). 3. We will assess herpesvirus-specific antibodies (Luminex), viral loads (droplet digital PCR) and cellular responses (ELISpot); and microbial translocation (MT; PCR for bacterial 16s ribosomal DNA, ELISA for lipopolysaccharide and other biomarkers). Markers of viral activation and MT will be related to parasite exposures and vaccine outcomes. 4. We will investigate pre-immunisation immunological characteristics using simple biomarkers and cell phenotyping, and with in-depth studies (including by mass cytometry) in smaller, representative groups; and link findings to both parasite exposures and vaccine outcomes. Our data will be integrated using causal mediation analyses to determine how urban-rural environment, parasites, "transkingdom" effects and immune responses relate to determine vaccine responses partly by "transkingdom" pathways (activation of herpesviruses; intestinal translocation of microbial products), and ultimately by pre-immunisation immune characteristics of the host.
3.4 Vaccines / P&Cs