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.

IF 19.9 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Lancet Global Health Pub Date : 2024-11-01 DOI:10.1016/s2214-109x(24)00340-1
Agnes Natukunda,Gyaviira Nkurunungi,Ludoviko Zirimenya,Jacent Nassuuna,Christopher Zziwa,Caroline Ninsiima,Josephine Tumusiime,Ruth Nyanzi,Milly Namutebi,Fred Kiwudhu,Govert J van Dam,Paul L A M Corstjens,Robert Kizindo,Ronald Nkangi,Joyce Kabagenyi,Beatrice Nassanga,Stephen Cose,Anne Wajja,Pontiano Kaleebu,Alison M Elliott,Emily L Webb,
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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.
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乌干达血吸虫和疟疾暴露与疫苗反应的城乡差异:利用三项关联随机对照试验的数据进行因果中介分析。
背景疫苗的免疫原性和有效性因地域而异。我们比较了乌干达三种环境(血吸虫流行的农村地区、疟疾流行的农村地区和城市地区)的疫苗特异性免疫反应,并进行了因果中介分析,以评估曼氏血吸虫和疟疾暴露在观察到的差异中所起的作用。我们使用了三项关联随机试验的对照组数据,这些试验调查了强化寄生虫治疗对学龄儿童的影响。所有参与者都接种了卡介苗(第 0 周)、黄热病疫苗(YF-17D)、口服伤寒疫苗(Ty21a)、人类乳头瘤病毒疫苗(HPV;第 4 周)、HPV 加强剂和破伤风-白喉疫苗(第 28 周)。主要结果是第 8 周的疫苗反应,以及第 52 周破伤风-白喉的疫苗反应。我们估算了环境对疫苗应答的总效应(TE)、通过当前或既往感染过曼氏痢疾或疟疾以及基线疫苗特异性应答而产生的自然间接效应(NIE)。第 8 周时,农村地区的疫苗应答率较低:血吸虫病流行地区与城市地区相比(YF-17D 斑块减少中和 50%(PRNT50)滴度的 TE 几何平均比值为 0-58 [95% CI 0-37 至 0-91],伤寒杆菌 O 型脂多糖特异性 IgG 为 0-61 [0-40 至 0-93],破伤风特异性 IgG 为 0-33 [0-22 至 0-51]);疟疾流行区与城市环境(YF-17D 0-70 [0-49 to 0-99],伤寒杆菌 O 型脂多糖特异性 IgG 0-29 [0-20 to 0-43],破伤风特异性 IgG 0-53 [-0-35 to 0-80])。然而,我们发现疟疾流行地区的卡介苗特异性 IFNγ 反应高于城市地区(1-54 [1-20 to 1-98])。通过以前和现在的曼森氏杆菌和疟疾介导的环境对疫苗应答的估计NIEs在统计学上并不显著。对于疟疾流行地区与城市地区,疫苗特异性反应基线造成了一些差异,但并非所有差异:第 8 周(57.9%介导[38-6 至 77-2])和第 52 周(70-0%介导[49-4 至 90-6])的伤寒杆菌 O 型脂多糖特异性 IgG 和第 52 周的卡介苗(46.4%介导[-4-8 至 97-7])。需要考虑其他暴露因素。
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来源期刊
Lancet Global Health
Lancet Global Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH-
CiteScore
44.10
自引率
1.20%
发文量
763
审稿时长
10 weeks
期刊介绍: The Lancet Global Health is an online publication that releases monthly open access (subscription-free) issues.Each issue includes original research, commentary, and correspondence.In addition to this, the publication also provides regular blog posts. The main focus of The Lancet Global Health is on disadvantaged populations, which can include both entire economic regions and marginalized groups within prosperous nations.The publication prefers to cover topics related to reproductive, maternal, neonatal, child, and adolescent health; infectious diseases (including neglected tropical diseases); non-communicable diseases; mental health; the global health workforce; health systems; surgery; and health policy.
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