The effect of intensive praziquantel administration on vaccine-specific responses among schoolchildren in Ugandan schistosomiasis-endemic islands (POPVAC A): an open-label, randomised controlled trial

Abstract

Background: Vaccine responses differ between populations and are often impaired in rural and low-income settings. The reasons for this are not fully understood, but observational data suggest that the immunomodulating effects of parasitic helminths might contribute. We hypothesised that Schistosoma mansoni infection suppresses responses to unrelated vaccines, and that suppression could be reversed-at least in part-by intensive praziquantel administration.

Methods: We conducted an open-label, randomised controlled trial of intensive versus standard intervention against S mansoni among schoolchildren aged 9-17 years from eight primary schools in Koome islands, Uganda. Children were randomly allocated to either an intensive group or a standard group with a computer-generated 1:1 randomisation using permuted blocks sizes 4, 6, 8, and 10. Participants in the intensive group received three praziquantel doses (approximately 40 mg/kg) 2 weeks apart before first vaccination at week 0, and every 3 months thereafter. Participants in the standard group were given one dose of approximately 40 mg/kg praziquantel after the week 8 primary endpoint. Participants in both groups received the BCG vaccine (Serum Institute of India, Pune, India) at week 0; the yellow fever (Sanofi Pasteur, Lyon, France), oral typhoid (PaxVax, London, UK), and first human papillomavirus (HPV) vaccination (Merck, Rahway, NJ, USA) at week 4; and the HPV booster and tetanus-diphtheria vaccine (Serum Institute of India) at week 28. The primary outcome was vaccine response at week 8 (except for tetanus and diphtheria, which was assessed at week 52). The primary analysis population was participants who were infected with S mansoni at baseline, determined retrospectively using either plasma circulating anodic antigen (CAA) or stool PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN60517191) and is complete.

Findings: Between July 9 and Aug 14, 2019, we enrolled 478 participants, with 239 children per group. 276 (58%) participants were male and 202 (42%) participants were female. Among participants who were positive for S mansoni at baseline (171 [72%] in the intensive group and 164 [69%] in the standard group) intensive praziquantel administration significantly reduced pre-vaccination infection intensity (to median 30 CAA pg/mL [IQR 7-223] vs 1317 [243-8562], p<0·001) compared with standard treatment. Intensive praziquantel administration also reduced week 8 HPV-16-specific IgG response (geometric mean ratio 0·71 [95% CI 0·54-0·94], p=0·017), but had no effect on other primary outcomes. Among all participants (regardless of S mansoni status at baseline) intensive praziquantel administration significantly improved week 8 BCG-specific IFNγ ELISpot response (1·20 [1·01-1·43], p=0·038). Recognised adverse effects of praziquantel were reported more frequently in the intensive group. There were no recorded serious adverse events in either group.

Interpretation: We show evidence suggesting that praziquantel administration improves the BCG-specific cellular response, but not humoral responses to other vaccines. Despite observational evidence that helminths impair vaccine response, these results show minimal immediate benefits of reducing helminth burden. The effect of longer-term helminth control should be investigated.

Funding: UK Medical Research Council.

Translation: For the Luganda translation of the abstract see Supplementary Materials section.

Figure 1

Trial schedule YF-17D=yellow fever vaccine. Ty21a=live oral typhoid vaccine. HPV=virus-like particle human papillomavirus vaccine. T–D=tetanus–diphtheria vaccine. Created with BioRender.com. *Primary endpoint following BCG, YF-17D, Ty21a, and HPV vaccination; additionally, an HPV dose was given to previously unvaccinated girls aged 14 years or older. †Secondary endpoint following BCG, YF-17D, Ty21a, and HPV vaccination. ‡A T–D boost was given to comply with the Uganda National Expanded Program on Immunization guidelines.

Figure 2

Trial profile YF-17D=yellow fever vaccine. Ty21a=live oral typhoid vaccine. HPV=virus-like particle human papillomavirus vaccine. PBMCs=peripheral blood mononuclear cells. SFU=spot-forming units. *Some participants had multiple reasons for exclusion †Reasons for not being included in the final analysis included no sample at the primary endpoint, or the sample was available, but the participant did not receive the correctly allocated vaccine. ‡BCG INFγ ELISpot assay—samples that had more than 83·3 SFUs per million PBMCs in the unstimulated well were considered invalid and not included in the final analysis. §In the intensive group, 52 participants did not complete follow-up, and 70 did not complete follow-up in the standard group, totalling 122 participants. The reasons for withdrawal were loss to follow-up (n=104), meeting exclusion criteria during follow-up (n=1) and withdrawal of consent (n=17). ¶Reasons for not being included in the final analysis were no sample at week 52, or the sample was available but participant did not receive a tetanus–diphtheria vaccine at week 28.

Figure 3

PZQ uptake and effect of treatment on S mansoni infection Percentage of patients who received PZQ (A), S mansoni intensity (B) and prevalence (C and D) at each timepoint were compared between trial groups using Wilcoxon rank sum tests and χ² tests, respectively. Furthermore, linear mixed models were fitted to compare S mansoni intensity (B, p=0·03) and prevalence (C, p<0·0001; D, p<0·0001) between trial groups, from week –6 to week 52. CAA=circulating anodic antigen. PZQ=praziquantel. S mansoni=Schistosoma mansoni.