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.
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,
{"title":"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.","authors":"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,","doi":"10.1016/s2214-109x(24)00340-1","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nVaccine immunogenicity and effectiveness vary geographically. Chronic immunomodulating parasitic infections including schistosomes and malaria have been hypothesised to be mediators of geographical variations.\r\n\r\nMETHODS\r\nWe 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.\r\n\r\nFINDINGS\r\nWe 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]).\r\n\r\nINTERPRETATION\r\nWe 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.\r\n\r\nFUNDING\r\nUK Medical Research Council.","PeriodicalId":48783,"journal":{"name":"Lancet Global Health","volume":"23 1","pages":"e1860-e1870"},"PeriodicalIF":19.9000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lancet Global Health","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/s2214-109x(24)00340-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH","Score":null,"Total":0}
引用次数: 0
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.
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.