BACKGROUND Several important vaccines differ in immunogenicity and efficacy between populations. We hypothesised that malaria suppresses responses to unrelated vaccines and that this effect can be reversed-at least partially-by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings. METHODS We conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine on vaccine responses among schoolchildren aged 9-17 years in Jinja district, Uganda. Participants were recruited from two schools and did not have exposure to vaccines of interest after the age of 5 years, with the exception of human papillomavirus (HPV). Computer-generated 1:1 randomisation was implemented in REDCap. 3-day courses of dihydroartemisinin-piperaquine (dosage by weight) or placebo were administered monthly, including twice before the first vaccination. Trial participants were vaccinated with the live parenteral BCG vaccine (Serum Institute of India, Pune, India) at week 0; yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France); live oral typhoid vaccine (Ty21a; PaxVax, London, UK), and quadrivalent virus-like particle HPV vaccine (Merck, Rahway, NJ, USA) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated, and a tetanus-diphtheria booster was given after completion of the trial at week 52. Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, at week 52, and analysis was done in the intention-to-treat population. Malaria parasite prevalence at enrolment and during follow-up was determined retrospectively by PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN62041885) and is complete. FINDINGS Between May 25 and July 14, 2021, we assessed 388 potential participants for eligibility. We enrolled and randomly allocated 341 participants to the two groups (170 [50%] to dihydroartemisinin-piperaquine and 171 [50%] to placebo); 192 (56%) were female and 149 (44%) participants were male. 145 (85%) participants in the dihydroartemisinin-piperaquine group and 140 participants (82%) in the placebo group were followed up until the week 52 endpoint. At enrolment, 109 (64%) of all participants in the dihydroartemisinin-piperaquine group and 99 (58%) of 170 participants in the placebo group had malaria; this reduced to 6% or lower at all follow-up visits in the dihydroartemisinin-piperaquine group. There was no effect of dihydroartemisinin-piperaquine versus placebo on primary outcomes: BCG-specific IFNγ ELISpot response had a geometric mean ratio (GMR) of 1·09 (95% CI 0·93-1·29), p=0·28; yellow fever neutralising antibody was 1·19 (0·91-1·54), p=0·20 for plaque reduction neutralising reference tests (PRNT50) titres (the reciprocal of the last plasma dilution that reduced by 50%) and 1·24 (0·97-1·58), p=0·09 for PRNT90 titres (reciprocal of the last plasma dilution that reduced by 90%); and IgG to Salmonella enterica serovar Typhi O-lipopolysaccharide was 1·09 (0·81-1·46), p=0·58, HPV-16 was 0·72 (0·44-1·77), p=0·19, HPV-18 was 0·71 (0·47-1·09), p=0·11; tetanus toxoid was 1·22 (0·91-1·62), p=0·18, and diphtheria toxoid was 0·97 (0·83-1·13), p=0·72. There was some evidence that dihydroartemisinin-piperaquine reduced waning of the yellow fever response. INTERPRETATION IPT for malaria with dihydroartemisinin-piperaquine did not improve peak vaccine responses, despite reducing malaria prevalence. Possible longer-term effects on response waning should be further explored. 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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使用双氢青蒿素-哌喹进行间歇性疟疾预防治疗对乌干达农村学童疫苗特异性反应的影响 （POPVAC B）：一项双盲、随机对照试验。


背景 几种重要的疫苗在免疫原性和功效方面因人群而异。我们假设疟疾抑制了对无关疫苗的反应，并且在高传播环境中，这种影响至少可以通过每月一次的疟疾间歇性预防治疗 （IPT） 来部分逆转。方法 我们进行了一项个体随机、双盲、安慰剂对照试验，研究了疟疾 IPT 与双氢青蒿素-哌喹对乌干达金贾区 9-17 岁学童疫苗反应的影响。参与者从两所学校招募，5 岁后没有接触过感兴趣的疫苗，人瘤病毒 （HPV） 除外。在 REDCap 中实现计算机生成的 1：1 随机化。每月服用 3 天疗程的双氢青蒿素-哌喹（按体重计算的剂量）或安慰剂，包括第一次接种疫苗前两次。试验参与者在第 0 周接种了活肠外 BCG 疫苗（印度血清研究所，印度浦那）;黄热病疫苗 （YF-17D;Sanofi Pasteur，法国里昂）;口服伤寒活疫苗 （Ty21a;PaxVax，英国伦敦）和四价病毒样颗粒 HPV 疫苗（默克，美国新泽西州罗威）;和类毒素疫苗（破伤风-白喉;印度血清研究所）和第 28 周时的 HPV 加强剂。在第 8 周为之前未接种过疫苗的 14 岁以上女性参与者提供额外的 HPV 疫苗接种，并在第 52 周完成试验后给予破伤风-白喉加强剂。主要结局是第 8 周的疫苗反应，破伤风-白喉在第 52 周的疫苗反应，并在意向治疗人群中进行了分析。 通过 PCR 回顾性确定入组和随访期间的疟疾寄生虫患病率。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 （ISRCTN62041885） 注册并已完成。结果 在 2021 年 5 月 25 日至 7 月 14 日期间，我们评估了 388 名潜在参与者的资格。我们招募并随机分配了 341 名参与者到两组（170 名 [50%] 接受双氢青蒿素-哌喹治疗，171 名 [50%] 接受安慰剂治疗）;192 名 （56%） 参与者为女性，149 名 （44%） 参与者为男性。双氢青蒿素-哌喹组的 145 名 （85%） 参与者和安慰剂组的 140 名参与者 （82%） 接受了随访，直到第 52 周终点。在入组时，双氢青蒿素-哌喹组的所有参与者中有 109 名 （64%） 和安慰剂组的 170 名参与者中有 99 名 （58%） 患有疟疾;在双氢青蒿素-哌喹组的所有随访中，这一比例降至 6% 或更低。双氢青蒿素-哌喹与安慰剂相比对主要结局没有影响： BCG 特异性 IFNγ 酶联免疫斑点反应的几何平均比值 （GMR） 为 1·09 （95% CI 0·93-1·29），p=0·28;黄热病中和抗体为 1·19 （0·91-1·54），斑块减少中和试验 （PRNT50） 滴度（最后一次血浆稀释度减少 50% 的倒数）和 1·24 （0·97-1·58），PRNT90 滴度（最后一次血浆稀释度减少 90% 的倒数）p=0·09;伤寒沙门氏菌血清型血清型 IgG 为 1·09 （0·81-1·46），p=0·58，HPV-16 为 0·72 （0·44-1·77），p=0·19，HPV-18 为 0·71 （0·47-1·09），p=0·11;破伤风类毒素为 1·22 （0·91-1·62），p=0·18，白喉类毒素为 0·97 （0·83-1·13），p=0·72。 有一些证据表明，双氢青蒿素-哌喹减少了黄热病反应的减弱。解释 尽管降低了疟疾患病率，但使用双氢青蒿素-哌喹治疗疟疾的 IPT 并没有改善峰值疫苗反应。应进一步探讨对反应减弱可能的长期影响。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。