The role of helminths and malaria in population differences in vaccine responses

Background: Vaccine responses vary across populations, and particularly between urban and rural settings in low- and middle-income countries. Chronic parasitic infections, particularly helminths and malaria, have been suggested to be among mediators of these differences due to their immunomodulatory effects. This thesis aimed to assess urban-rural differences in vaccine responses among Ugandan adolescents and explore the role of parasitic infections as mediators of these differences.

Methods: A systematic review of the literature on the effects of helminths on vaccine responses was conducted to provide context for subsequent analyses. Vaccine-specific responses to BCG, yellow fever, oral typhoid, HPV, and diphtheria/tetanus vaccines were evaluated among Ugandan adolescents from urban, schistosome-endemic rural, and malaria-endemic rural settings. In the schistosome-endemic rural setting, an observational analysis of associations between schistosomiasis, hookworm infections, and vaccine responses was conducted. The settings were compared and the roles of Schistosoma mansoni and malaria in the observed differences in vaccine responses were assessed using causal mediation analysis.

Results: The review synthesised findings from 37 studies and showed, overall, that helminth infections were associated with diminished vaccine responses. However, there was substantial heterogeneity, with effects varying depending on the type of vaccine and helminth species.In the observational analysis, Schistosoma mansoni was inversely associated with responses to oral typhoid and BCG vaccines, while higher infection intensity was linked to weaker vaccine responses overall. Hookworm infection was inversely associated with responses to HPV-16; conversely, it was positively associated with responses to diphtheria vaccine. In the urban-rural comparisons, vaccine responses were generally lower in rural settings, with participants in the schistosome-endemic and malaria-endemic settings showing significantly lower responses to yellow fever, oral typhoid, and tetanus vaccines compared to participants in the urban area. In contrast, peak BCG responses were higher in the malaria-endemic setting than in the urban area.Mediation analysis did not support a significant causal role for current or prior infection with schistosomiasis or malaria in explaining urban-rural differences; however, the confidence intervals were wide. For malaria-endemic versus urban setting, baseline vaccine-specific responses contributed to some but not all differences.

Conclusions: This thesis describes significant geographical variability in vaccine responses, and a complex and heterogeneous influence of parasitic infections on immune responses to vaccines. Schistosomiasis and malaria do not fully explain these differences, suggesting that other environmental factors contribute. Further research should transition from assessing single exposures to a multifactorial approach. This thesis contributes to the discussion on the importance of considering location-specific factors when evaluating vaccine immunogenicity and efficacy. This has implications for vaccine research, policy, and public health strategies in regions with high infection pressures