Abstract

A natural experiment in Kenya reveals durable immunosuppressive effects of early childhood malaria: a longitudinal cohort study

Safari, M. S. Makori, T. O. Gicheru, E. T. Mburu, M. W. Nyawa, O. K. Shee, F. M. Nyagwange, J. Kagucia, E. W. Ndungu, F. M. Kuria, T. C. Tuju, J. O. Sande, C. J.
Elife. 2026; 14

Permanent descriptor

https://doi.org/10.7554/eLife.107820

BACKGROUND: Chronic malaria exposure has been proposed to modulate immune function, but its long-term effects on antibody-mediated responses to unrelated pathogens remain poorly defined. Whether these effects persist beyond periods of active infection and how early-life exposure shapes humoral immunity over time is not well understood. METHODS: We leveraged a natural experiment in coastal Kenya - where two regions (Junju and Ngerenya) diverged sharply in malaria transmission from around 2004 - to evaluate the long-term immunological consequences of malaria exposure in childhood. Using a protein microarray platform, we measured IgG responses to vaccine and pathogen antigens in 123 children sampled longitudinally over a 15-year period. Active weekly malaria surveillance enabled precise reconstruction of individual exposure histories. RESULTS: IgG responses to Plasmodium falciparum apical membrane antigen 1 (AMA1) tracked closely with clinical malaria episodes, confirming the ability of the microarray platform to detect biologically meaningful variation in antigen-specific immunity. Despite comparable vaccination histories, children from the high malaria transmission setting (Junju) exhibited persistently lower measles-specific IgG levels than children from the low-transmission setting (Ngerenya), a pattern validated by ELISA. In longitudinal analyses, children from Junju exhibited lower antibody responses to a range of unrelated antigens, including Bordetella pertussis, CMV, rubella, and measles, with similar differences evident in cross-sectional analyses at 10 years of age. Within the Ngerenya cohort, children with documented early-life malaria had broadly lower IgG responses at age 10 compared to malaria-naive peers, despite identical geography, vaccines, and follow-up duration. CONCLUSIONS: These findings suggest that malaria exposure during early childhood is linked with durable suppression of antibody responses to unrelated pathogens and vaccines. This effect persists long after infection and may partially explain the overall diminished long-term vaccine effectiveness in malaria-endemic settings. FUNDING: This study was supported by fellowship funding to C.J.S. from the Wellcome Trust (WT105882MA). The funder played no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. M.S.S was funded in whole by Science for Africa Foundation to the Developing Excellence in Leadership, Training, and Science in Africa (DELTAS Africa) program [DEL-22-012] with support from Wellcome Trust and the UK Foreign, Commonwealth & Development Office and is part of the EDCPT2 programme supported by the European Union. For purposes of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Malaria alters the immune system during infection, but it remains unclear whether it leaves lasting effects. Previous studies have suggested that children living in malaria-endemic areas sometimes develop weaker responses to vaccines and other infections, indicating that early childhood exposure may influence immune responses many years later. To explore the effect of malaria infection during early childhood, Safari et al. studied 123 children from two neighbouring communities on the Kenyan coast with different malaria histories. Over 15 years, children in both locations were closely followed with weekly visits to identify malaria cases; blood samples were collected annually. Based on these data, Safari et al. reconstructed individual malaria exposure histories over time and measured antibody levels to different infections and vaccines over more than a decade. They analysed more than 1,200 serum samples and measured antibodies against a range of pathogens and vaccine antigens. In one community, infection rates fell to negligible levels in 2004, while the other community experienced consistent malaria cases over the 15 years. Children who grew up in the area with a persistent malaria burden had lower antibody levels against several unrelated pathogens and vaccine antigens than children from the area where malaria had disappeared. These differences persisted throughout childhood. Safari et al. also found that children who experienced malaria early in life in the malaria-low community had lower antibody levels at 10 years of age than children in the same community who had never had malaria. The more malaria episodes a child experienced, the lower their antibody responses tended to be. The findings of Safari et al. suggest that malaria may leave a long-lasting imprint on the immune system. If confirmed in other settings, this could help explain why vaccines are sometimes less effective in malaria-endemic regions and why the benefits of malaria control may extend beyond preventing malaria itself. Understanding how malaria influences long-term immune development could help improve vaccination strategies and child health in areas where malaria remains common. eng