Effectiveness of Malaria Vaccines in Reducing the Risk of Invasive Non-typhoidal Salmonella Disease

Official title

Effectiveness of Malaria Vaccines in Reducing the Risk of Invasive Non-Typhoidal Salmonella Disease (VINS)

Overview

The goal of this observational study is to learn about the impact of malaria vaccination on the risk of invasive non-typhoidal Salmonella disease in children below the age of 5. Eligible participants residing in the Kisantu Health Zone (DRC) and presenting fever are enrolled in healthcare facilities and tested for malaria and iNTS. Using a case-control (test-negative) design, the researchers will look at the malaria vaccination status of participants with and without iNTS infection to determine if the malaria vaccine protects against iNTS.

Detailed description

* This study builds on existing febrile illnesses surveillance in the Kisantu Health Zone, which enrolls patients presenting to participating healthcare facilities with fever.(See specific eligibility criteria) * For participants eligible to receive the malaria vaccine (6-24 months) and included in the study at the surveillance sites (presenting with fever), malaria vaccination status is ascertained with the Expanded Program of Immunization (EPI) card, Alternatively, a dedicated vaccination registration database that was set-up in the study catchment area is searched. The study team can also visit participants' house to verify the EPI vaccination card. R21/Matrix-M malaria vaccine was rolled out in the Kisantu Health Zone as part of the Expanded Program on Immunizations (DRC Ministry of Public Health) on 29th of October 2024. * The laboratory diagnosis of iNTS uses automated blood culture method. Malaria diagnosis is confirmed with microscopic examination of blood smears. Malaria Rapid Diagnostic Tests (mRDTs) are also performed for all participants for routine clinical management and rapid treatment guidance at the healthcare facility level. For laboratory-confirmed iNTS cases, malaria parasitemia and species specification is confirmed by Polymerase Chain Reaction (PCR). * All participants with positive blood culture to iNTS and/or a confirmed malaria parasitemia receive antibacterial and/or antimalarial treatment in accordance with national guidelines. Hospitalized cases with confirmed iNTS, with or without malaria co-infection, are followed until hospital discharge or death. Participants with a positive blood culture for iNTS and discharged after enrollment are followed every 7 to 9 days until disease resolution (defined as no fever in the past 24 hours), death, or up to 21 days post-enrollment to assess symptom severity, hospitalization, and disease outcome.

Interventions

• Biological R21/Matrix-M malaria vaccine
  R21/Matrix-M malaria vaccination was introduced by DRC Ministry of Public Health in the Expanded Program on Immunizations on 29th of October 2024. Children aged 6 months to 24 months are eligible to receive the vaccine. Vaccination follows a 4 doses schedule: a first dose administered between 6 and 11 months of age, a second dose one month after the first dose, a third dose one month after the second dose and a booster dose seven months after the third dose.

Primary outcome measures

• Blood culture-confirmed iNTS disease (including malaria co-infections) in participants who received complete malaria vaccination vs. unvaccinated participants. [Time frame: At presentation (enrollment)]

Secondary outcome measures (5)

• Blood culture-confirmed iNTS disease (including malaria co-infections) in participants who received any dose of malaria vaccine vs. unvaccinated participants. [Time frame: At presentation (enrollment)]
• Culture-confirmed iNTS disease (including malaria co-infections) in participants with at least one severity feature and who received complete malaria vaccination vs. unvaccinated participants. [Time frame: At presentation (enrollment)]
• Blood culture-confirmed iNTS disease (including malaria co-infections) in participants with at least one severity feature and who received any dose of the malaria vaccine vs. unvaccinated participants. [Time frame: At presentation (enrollment)]
• mRDT, blood smear and/or PCR-confirmed malaria disease, including severe malaria cases, with or without culture-confirmed iNTS disease, in participants who received complete malaria vaccination vs. unvaccinated participants [Time frame: At presentation (enrollment)]
• Impact of vaccination using R21/Matrix-M on the incidence of culture-confirmed iNTS and mRDT, blood smear and/or PCR confirmed malaria co-infection (before/after) [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Patients of all ages currently living in the catchment area of the health center presenting to healthcare facility with objective fever of at least 38.0°C tympanic or 37.5 °C axillary OR
• Patients of all ages currently living in the catchment area of the health center presenting to healthcare facility with reported fever ≥3 consecutive days within 7 days of presentation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Democratic Republic of the Congo · 1 center

• Institut National de Recherche Biomedicale (INRB) — Kinshasa

Publications

• von Kalckreuth V, Konings F, Aaby P, Adu-Sarkodie Y, Ali M, Aseffa A, Baker S, Breiman RF, Bjerregaard-Andersen M, Clemens JD, Crump JA, Cruz Espinoza LM, Deerin JF, Gasmelseed N, Sow AG, Im J, Keddy KH, Cosmas L, May J, Meyer CG, Mintz ED, Montgomery JM, Olack B, Pak GD, Panzner U, Park SE, Rakotozandrindrainy R, Schutt-Gerowitt H, Soura AB, Warren MR, Wierzba TF, Marks F. The Typhoid Fever Surve PMID 26933028
• Liang Y, Driscoll AJ, Patel PD, Datta S, Voysey M, French N, Jamka LP, Henrion MYR, Ndeketa L, Laurens MB, Heyderman RS, Gordon MA, Neuzil KM. Typhoid conjugate vaccine effectiveness in Malawi: evaluation of a test-negative design using randomised, controlled clinical trial data. Lancet Glob Health. 2023 Jan;11(1):e136-e144. doi: 10.1016/S2214-109X(22)00466-1. Epub 2022 Nov 25. PMID 36442498
• Bornstein K, Hungerford L, Hartley D, Sorkin JD, Tapia MD, Sow SO, Onwuchekwa U, Simon R, Tennant SM, Levine MM. Modeling the Potential for Vaccination to Diminish the Burden of Invasive Non-typhoidal Salmonella Disease in Young Children in Mali, West Africa. PLoS Negl Trop Dis. 2017 Feb 9;11(2):e0005283. doi: 10.1371/journal.pntd.0005283. eCollection 2017 Feb. PMID 28182657
• Datoo MS, Dicko A, Tinto H, Ouedraogo JB, Hamaluba M, Olotu A, Beaumont E, Ramos Lopez F, Natama HM, Weston S, Chemba M, Compaore YD, Issiaka D, Salou D, Some AM, Omenda S, Lawrie A, Bejon P, Rao H, Chandramohan D, Roberts R, Bharati S, Stockdale L, Gairola S, Greenwood BM, Ewer KJ, Bradley J, Kulkarni PS, Shaligram U, Hill AVS; R21/Matrix-M Phase 3 Trial Group. Safety and efficacy of malaria vacc PMID 38310910
• Nyirenda TS, Mandala WL, Gordon MA, Mastroeni P. Immunological bases of increased susceptibility to invasive nontyphoidal Salmonella infection in children with malaria and anaemia. Microbes Infect. 2018 Oct-Nov;20(9-10):589-598. doi: 10.1016/j.micinf.2017.11.014. Epub 2017 Dec 15. PMID 29248635
• van Santen S, de Mast Q, Swinkels DW, van der Ven AJ. The iron link between malaria and invasive non-typhoid Salmonella infections. Trends Parasitol. 2013 May;29(5):220-7. doi: 10.1016/j.pt.2013.03.006. Epub 2013 Apr 16. PMID 23601932
• Church J, Maitland K. Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review. BMC Med. 2014 Feb 19;12:31. doi: 10.1186/1741-7015-12-31. PMID 24548672
• Crump JA, Sjolund-Karlsson M, Gordon MA, Parry CM. Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections. Clin Microbiol Rev. 2015 Oct;28(4):901-37. doi: 10.1128/CMR.00002-15. PMID 26180063

Identifiers

NCT: NCT07416461 · 2025-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗