Schistosome and malaria exposure and urban-rural differences in vaccine responses in Uganda: a causal mediation analysis using data from three linked randomised controlled trials

Abstract

Background: Vaccine immunogenicity and effectiveness vary geographically. Chronic immunomodulating parasitic infections including schistosomes and malaria have been hypothesised to be mediators of geographical variations.

Methods: We compared vaccine-specific immune responses between three Ugandan settings (schistosome-endemic rural, malaria-endemic rural, and urban) and did causal mediation analysis to assess the role of Schistosoma mansoni and malaria exposure in observed differences. We used data from the control groups of three linked randomised trials investigating the effects of intensive parasite treatment among schoolchildren. All participants received the BCG vaccine (week 0); yellow fever (YF-17D), oral typhoid (Ty21a), human papillomavirus (HPV; week 4); and HPV booster and tetanus-diphtheria (week 28). Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, week 52. We estimated the total effect (TE) of setting on vaccine responses and natural indirect effect (NIE) mediated through current or previous infection with S mansoni or malaria, and baseline vaccine-specific responses.

Findings: We included 239 (43%) participants from the schistosomiasis-endemic setting, 171 (30%) from the malaria-endemic setting, and 151 (27%) from the urban setting. At week 8, vaccine responses were lower in rural settings: schistosomiasis-endemic versus urban settings (TE geometric mean ratio for YF-17D plaque reduction neutralisation at 50% (PRNT₅₀) titres 0·58 [95% CI 0·37 to 0·91], for S Typhi O-lipopolysaccharide-specific IgG 0·61 [0·40 to 0·93], and for tetanus-specific IgG 0·33 [0·22 to 0·51]); malaria-endemic versus urban settings (YF-17D 0·70 [0·49 to 0·99], S Typhi O-lipopolysaccharide-specific IgG 0·29 [0·20 to 0·43], and tetanus-specific IgG 0·53 [-0·35 to 0·80]). However, we found higher BCG-specific IFNγ responses in the malaria-endemic versus urban setting (1·54 [1·20 to 1·98]). The estimated NIEs of setting on vaccine responses mediated through previous and current S mansoni and malaria were not statistically significant. For malaria-endemic versus urban settings, baseline vaccine-specific responses contributed to some but not all differences: S Typhi O-lipopolysaccharide-specific IgG at week 8 (57.9% mediated [38·6 to 77·2]) and week 52 (70·0% mediated [49·4 to 90·6]) and BCG at week 52 (46.4% mediated [-4·8 to 97·7]).

Interpretation: We found significant variation in vaccine response between urban and rural settings but could not confirm a causal role for schistosome or malaria exposure. Other exposures require consideration.

Funding: UK Medical Research Council.

Figure 1

Overview of POPVAC studies (A) POPVAC study sites. (B) Schedule of vaccinations and timepoints of vaccine responses measurements. Borders highlighted in grey denote trial groups being compared in the analysis. Samples were collected before vaccinations or anthelminthic treatment at relevant timepoints. HPV=human papillomavirus. *Primary timepoint following BCG, YF-17D, Ty21a, and HPV vaccination. †Secondary timepoint following BCG, YF-17D, Ty21a, and HPV vaccination. Additionally, an HPV dose given to previously unvaccinated girls aged 14 years or older. ‡Intensive group received three doses of praziquantel (40 mg/kg), each dose 2 weeks apart before week 0, followed by praziquantel at week 8 and then quarterly praziquantel until week 52. §Standard group received one dose of praziquantel at week 8. ¶Participants received 3-day courses of either monthly dihydroartemisinin–piperaquine or placebo twice prior to week 0 and monthly during the entire follow-up period. ||Participants were randomly assigned to either receive BCG or no BCG 4 weeks before the first of the other vaccinations. Created with BioRender.com.

Figure 2

Vaccine responses by geographical setting Plots show individual datapoints, with a horizontal line deonotic the geometric mean and whiskers the 95% CI. SFU=ELISpot assay spot forming unit. PBMC=peripheral blood mononuclear cell. PRNT₅₀=plaque reduction neutralisation at 50%. HPV=human papillomavirus.