Population differences in vaccine response (POPVAC)-2: the impact of environmental exposures and selected interventions on waning of vaccine-induced immune responses

"Vaccines are a key weapon against infectious diseases which continue to have major detrimental impacts on health and development in in low-income countries (LICs). However, the effectiveness of some vaccines is reduced in tropical LICs and in rural vs urban settings. For example, the TB vaccine, BCG, provides 80% protection in some temperate countries, but 0% in some tropical settings.
A potential explanation for this phenomena includes exposure to parasites so to further understanding we will compare the vaccine responses for Ugandan adolescents among three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort who have low parasite exposure; (2) island communities where over 80% have schistosomiasis (a parasitic worm infection); (3) rural communities with high malaria exposure, where over 50% of school-children unknowingly have malaria. We will also look at how parasitic infections interact with other viral or bacterial infections (“transkingdom” effects) and how these indirect effects impact the immune system.
Finally, we will use statistical approaches to explore how the urban-rural environment, parasites, ""transkingdom"" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in tropical LIC settings and inform public health policy to improve effectiveness of vaccine programmes."

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.