Malaria-Driven Susceptibility to Invasive Non-Typhoidal Salmonella : A Co-infection Study with Implications for Elimination
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Background
Invasive non-typhoidal Salmonella (iNTS) disease causes high childhood mortality in sub-Saharan Africa. Malaria infection is postulated to increase iNTS risk through impairment of bactericidal immunity. We quantify malaria’s causal contribution to iNTS and explore burden mitigation via integrated antimalarial and iNTS prevention strategies.
Methods
We analyzed 443 weeks of surveillance data (September 2017–March 2026) from Kisantu health zone, Democratic Republic of Congo. Analyses included interrupted time series of perennial malaria chemoprophylaxis (PMC; November 2023) and R21/Matrix-M vaccine (October 2024) rollouts, causal mediation analysis, calibration of an age-structured co-infection Susceptible-Infected-Recovered-Susceptible (SIRS) model via the neural ordinary differential equation (ODE) adjoint method, and a 15,435-scenario grid search for NTS infection elimination coverage thresholds.
Findings
Malaria burden was 80% lower at PMC full coverage (incidence rate ratio [IRR] 0·197, 95% CI: 0·096–0·401; p<0·001). A declining iNTS trend emerged post-ramp (IRR 0·990/day, 95% CI: 0·981–0·998; p=0·018). The calibrated SIRS model estimated ~12-fold iNTS susceptibility during malaria infection (ψ M→N = 12·0, 95% CI: 3·6–28·3). Combined malaria prevention strategies provided immediate iNTS burden reduction (</= 37%), but full iNTS elimination requires a ≥70% efficacious iNTS vaccine.
Interpretation
Malaria control interventions deliver meaningful iNTS co-benefits. This analysis support their prioritization along with further evaluation of integrated malaria-iNTS prevention strategies in high-burden settings. Our results show that full NTS elimination additionally requires a high-efficacy iNTS-specific vaccine.
Funding
The Gates Foundation (INV-047715, INV-007844, INV-082265, INV-077454), The European and Developing Countries Clinical Trials Partnership (RIA2017S-2027), and the Swedish Styrelsen för internationellt utvecklingssamarbete (17106)
Research in Context
Evidence before this study
Clinical and mechanistic studies have established that malaria facilitates iNTS disease, including through haem-driven immune dysfunction, with malaria co-infection present in 40–60% of hospitalized iNTS cases. However, this evidence comes from individual-level clinical studies and does not quantify the population-level causal impact of malaria infection on iNTS disease at scale. No prior study has formally measured whether reducing malaria burden in a population also reduces iNTS burden, and intervention coverage thresholds for co-benefits have not been modelled.
Added value of this study
This is the first population-level evidence using a quasi-experimental design to examine the effect of malaria control interventions on iNTS incidence in sub-Saharan Africa. Incorporating a 6-month coverage ramp-up and precipitation adjustment, we document an 80% malaria reduction at full PMC coverage (IRR 0·197, 95% CI 0·096–0·401; p<0·001). Seasonal adjustment eliminated the apparent iNTS incidence spike at PMC rollout (fully unadjusted IRR 2·766, 95% CI 1·453–5·267, p=0·002; adjusted IRR 0·972, 95% CI 0·418–2·262, p=0·948), revealing a seasonal confounding artefact, and uncovered a significant declining iNTS trend post-ramp (IRR 0·990/day, 95% CI 0·981–0·998; p=0·018). We calibrate a mechanistic model estimating ~12-fold malaria–iNTS susceptibility enhancement (ψ M→N = 12·0, 95% CI: 3·6–28·3; Mode 1 MAP), subject to identifiability caveats. The elimination boundary analysis shows that a highly efficient iNTS vaccine is necessary for elimination, while combined malaria and iNTS interventions show synergistic effects at sub-elimination coverage.
Implications of all available evidence
Malaria control should proceed immediately for multiple co-benefits including iNTS burden reduction. Our modeling results support that integrated malaria–iNTS control strategies offer greater benefits on disease burden than sequential approaches. Future research should confirm these findings in other African settings and measure iNTS burden reduction as R21/Matrix-M is rolled out at scale.
