Malaria circumsporozoite protein-specific antibody titres among HIV-infected and non HIV-infected children under 5 years of age, resident in areas of high malaria transmission in Uganda

Abstract

Background: Malaria and HIV co-endemicity presents a major public health burden in sub-Saharan Africa, with young children bearing the greatest morbidity and mortality. The Plasmodium falciparum circumsporozoite protein (CSP) is the antigenic target of leading malaria vaccines such as, RTS,S/AS01, where CSP-specific IgG antibodies are critical mediators of protection. HIV infection may dysregulate humoral immunity through germinal center attrition, impaired isotype switching, and depletion of long-lived plasma cells, potentially diminishing anti-CSP responses and heightening malaria vulnerability. Furthermore, HIV-exposed uninfected (HEU) children—those born to HIV-positive mothers but uninfected themselves—may exhibit altered immune function due to in utero and perinatal exposures. Understanding the landscape of malaria-specific immunity, as measured by CSP-IgG titres, among HIV-infected (HIV+), HEU, and HIV-unexposed uninfected (HUU) children under five years in Uganda’s high-transmission zones is essential yet remains inadequately characterized. This study investigated the impact of HIV status and sero-exposure on CSP-IgG titres to inform targeted prevention and vaccination strategies in co-endemic settings. Methods: We conducted a hospital-based cross-sectional study from February 2025 to June 2025 among 206 children aged less than 5 years residing in five high malaria transmission districts of Eastern Uganda (Sironko, Budaka, Kibuku, Mbale, Pallisa). Participants were stratified into three groups: HIV+ (n=69), HEU (n=69), and HUU (n=68). Standardized questionnaires captured demographic (age, sex, district, setting, household income), clinical (HIV status, ART adherence, cotrimoxazole prophylaxis [CTX] and adherence, malaria history within past year), and environmental factors (insecticide-treated net [ITN] use frequency/condition, indoor residual spraying [IRS] in past year, presence of stagnant water). CSP-specific IgG titres (ng/L) were quantified using standardized enzyme-linked immunosorbent assay (ELISA). Log-transformed titres were analyzed using multivariable linear regression, adjusting for age, malaria episode history, ITN use, household income, setting, and crucially, CTX use. Models accounted for district-level clustering using mixed-effects approaches. Sensitivity analyses assessed robustness to outliers and missing data. Results: HIV+ children (all on CTX prophylaxis) exhibited significantly lower geometric mean CSP-IgG titres (351.7 ng/L; median: 218 ng/L, IQR: 126-714) compared to HEU (412.4 ng/L; median: 330 ng/L, IQR: 196-600) and HUU children (536.9 ng/L; median: 506 ng/L, IQR: 298-968; Kruskal-Wallis p<0.001). Strikingly, among HEU children, those receiving CTX (n=25) had markedly lower CSP IgG titres (mean: 294.2 ng/L; median: 248 ng/L) than HEU children not on CTX (n=44; mean: 622.7 ng/L; median: 580 ng/L; Mann-Whitney U (p<0.001). Adjusted regression confirmed HIV+ status was associated with a 42% reduction in log-transformed titres (β = -0.42, 95% CI: -0.65, -0.19; p<0.001) relative to HUU children. Increasing age (β = 0.02 per month, p<0.01) and number of prior malaria episodes (β = 0.15 per episode, p<0.001) were independently associated with higher titres. Suboptimal vector control was evident since IRS coverage was minimal (4.9%), and ITN use, while widespread, was often inconsistent ("sometimes"). Conclusion: HIV infection is independently associated with substantially impaired acquisition of malaria CSP-specific antibodies in young Ugandan children, potentially increasing their biological susceptibility in high-transmission settings. The profound suppression of titres among both HIV+ and CTX-using HEU children likely reflects the combined effect of HIV-related immune dysregulation and the confounding prophylactic effect of CTX in reducing antigenic exposure. While consistent ART adherence may attenuate HIV-associated immunosuppression, its specific role in immune response to the CSP antigen warrants further study. Critically low IRS coverage and inconsistent ITN use underscore persistent environmental risks. Our findings advocate for integrated HIV-malaria control that includes optimizing ART and CTX adherence, while simultaneously scaling up effective vector interventions (ITN distribution campaigns, expanded IRS) for HIV-affected children. These findings advocate for integrated HIV-malaria care that prioritizes consistent vector control and considers tailored malaria vaccination strategies for HIV-affected children to mitigate their increased biological susceptibility..