Malaria-Driven Susceptibility to Invasive Non-Typhoidal Salmonella: A Co-infection Study with Implications for Elimination

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{middle dot}197, 95% CI: 0{middle dot}096-0{middle dot}401 ; p<0{middle dot}001). A declining iNTS trend emerged post-ramp (IRR 0{middle dot}990/day, 95% CI: 0{middle dot}981-0{middle dot}998 ; p=0{middle dot}018). The calibrated SIRS model estimated ~12-fold iNTS susceptibility during malaria infection ({psi}M[-&gt;]N = 12{middle dot}0, 95% CI: 3{middle dot}6-28{middle dot}3). Combined malaria prevention strategies provided immediate iNTS burden reduction ([&le;] 37%), but full iNTS elimination requires a [&ge;]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 for internationellt utvecklingssamarbete (17106)