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.

中文翻译：

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吡喹酮强化给药对乌干达血吸虫病流行岛屿学童疫苗特异性反应的影响 （POPVAC A）：一项开放标签、随机对照试验。


背景 疫苗反应因人群而异，在农村和低收入环境中通常会受损。造成这种情况的原因尚不完全清楚，但观察数据表明，寄生蠕虫的免疫调节作用可能有所贡献。我们假设曼氏血吸虫感染抑制了对无关疫苗的反应，并且这种抑制可以被逆转——至少部分是通过强化吡喹酮给药。方法 我们在乌干达库姆群岛 8 所小学的 9-17 岁学童中进行了一项针对曼氏链球菌的开放标签、随机对照试验。儿童被随机分配到强化组或标准组，使用大小为 4、6、8 和 10 的排列块进行计算机生成的 1：1 随机化。强化组的参与者在第 0 周首次接种疫苗前 2 周间隔 2 周接受 3 剂吡喹酮 （约 40 mg/kg），此后每 3 个月一次。标准组的参与者在第 8 周主要终点后给予一剂约 40 mg/kg 吡喹酮。两组参与者在第 0 周都接种了 BCG 疫苗（印度血清研究所，印度浦那）;第 4 周进行黄热病（赛诺菲巴斯德，法国里昂）、口腔伤寒（PaxVax，英国伦敦）和首次人瘤病毒 （HPV） 疫苗接种（默克，美国新泽西州罗威）;以及第 28 周的 HPV 加强剂和破伤风-白喉疫苗（印度血清研究所）。主要结局是第 8 周的疫苗反应（破伤风和白喉除外，它们在第 52 周进行评估）。 主要分析人群是在基线时感染曼氏链球菌的参与者，使用血浆循环阳极抗原 （CAA） 或粪便 PCR 回顾性测定。安全人群包括所有随机分配的参与者。该试验已在 ISRCTN 注册处 （ISRCTN60517191） 注册并已完成。结果 在 2019 年 7 月 9 日至 8 月 14 日期间，我们招募了 478 名参与者，每组 239 名儿童。276 名 （58%） 参与者为男性，202 名 （42%） 参与者为女性。在基线时曼氏血吸虫阳性的参与者中（强化组为 171 [72%]，标准组为 164 [69%]）强化吡喹酮给药显著降低了疫苗接种前感染强度（中位数为 30 CAA pg/mL [IQR 7-223] vs 1317 [243-8562]，p<0·001）与标准治疗相比。吡喹酮强化给药也降低了第 8 周 HPV-16 特异性 IgG 反应 （几何平均比 0·71 [95% CI 0·54-0·94]，p=0·017），但对其他主要结局没有影响。在所有参与者中 （无论基线时的曼氏血吸虫状态如何），吡喹酮强化给药显著改善了第 8 周 BCG 特异性 IFNγ 酶联免疫斑点反应 （1·20 [1·01-1·43]，p=0·038）。吡喹酮的已知不良反应在强化组中报告得更频繁。两组均未记录严重不良事件。解释 我们展示的证据表明，吡喹酮给药可改善 BCG 特异性细胞反应，但不能改善对其他疫苗的体液反应。尽管观察证据表明蠕虫会损害疫苗反应，但这些结果表明减少蠕虫负担的直接益处微乎其微。应调查长期蠕虫控制的效果。 资助英国医学研究委员会。翻译 关于摘要的卢干达语翻译，见补充材料部分。