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Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

Background: Non-typhoidal Salmonella (NTS) are a major cause of bloodstream infections amongst children in sub-Saharan Africa. A clear understanding of the seroepidemiology and correlates of protection for invasive NTS (iNTS) in relation to key risk factors (malaria, anaemia, malnutrition) in children in Africa is needed to inform strategies for disease control including vaccine implementation., Methodology: The SAiNTS study is a prospective community cohort study with paired serology samples from 2500 Malawian children 0-5 years at baseline and three months to measure age-stratified acquisition of lipopolysaccharide (LPS) O-antigen antibody (IgG) and serum bactericidal activity to the main serovars causing iNTS ( Salmonella Typhimurium and S . Enteritidis). Children are selected from mapped and censused randomly selected households in Chikwawa, Malawi; an area with substantial malaria burden. The sampling framework is set within a malaria vaccination (RTS,S/ AS01) phase 4 cluster randomized trial, known as the Epidemiology Study of Malaria Transmission Intensity (EPI-MAL), allowing exploration of the impact of malaria vaccination on acquisition of immunity to NTS. Risk factor data for invasive disease will be collected using rapid diagnostic tests for malaria and anaemia, anthropometry for malnutrition, and a validated questionnaire for indicators of socioeconomic status, water and sanitation. All data will be recorded through electronic case report forms using the REDCap and the Open Data Kit (ODK) platforms. Stool sample analysis includes NTS culture and pan-Salmonella polymerase chain reaction to assess enteric exposure and biomarkers of environmental enteric dysfunction. Cases with iNTS disease will be followed up for comparison with community controls., Conclusions: The final cohort of 2500 children will allow investigation into the impact of risk factors for iNTS on the acquisition of immunity in children 0-5 years in an endemic setting, including comparisons to partner seroepidemiology studies in three other sub-Saharan African sites (1000 children per site). The data generated will be key to informing iNTS disease control measures including targeted risk factor interventions and vaccine implementation through investigation of correlates of protection and identifying windows of immune susceptibility in at-risk populations., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Dale H et al.)

Background: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group., Methods: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426., Findings: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years., Interpretation: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests YL, SD, LPJ, MBL, and KMN receive funding from the TyVAC grant (grant number OPP1151153). KMN is a voting member of the WHO Strategic Advisory Group of Experts on Immunization (SAGE). RSH is a UK National Institute for Health and Care Research Senior Investigator. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Typhoid fever is a substantial public health problem in Africa, yet there are few clinical trials of typhoid conjugate vaccine (TCV). We assessed immunogenicity and safety of Typbar TCV in Malawi., Methods: This substudy was nested within a phase 3, double-blind, parallel design, randomised controlled trial of TCV in children from Ndirande Health Centre in Ndirande township, Blantyre, Malawi. To be eligible, participants had to be aged between 9 months and 12 years with no known immunosuppression or chronic health conditions, including HIV or severe malnutrition; eligible participants were enrolled into three strata of approximately 200 children (9-11 months, 1-5 years, and 6-12 years), randomly assigned (1:1) to receive TCV or control (meningococcal serogroup A conjugate vaccine [MCV-A]) intramuscularly. Serum was collected before vaccination and at 28 days and 730-1035 days after vaccination to measure anti-Vi antibodies by ELISA. Because of COVID-19, day 730 visits were extended up to 1035 days. This nested substudy evaluated reactogenicity, safety, and immunogenicity by age stratum. Safety outcomes, analysed in the intention-to-treat population, included solicited adverse events within 7 days of vaccination (assessed on 3 separate days) and unsolicited adverse events within 28 days of vaccination. This trial is registered with ClinicalTrials.gov, NCT03299426., Findings: Between Feb 22 and Sept 6, 2018, 664 participants were screened, and 631 participants were enrolled and randomly assigned (320 to the TCV group and 311 to the MCV-A group). 305 participants in the TCV group and 297 participants in the MCV-A group were vaccinated. Among TCV recipients, anti-Vi IgG geometric mean titres increased more than 500 times from 4·2 ELISA units (EU)/mL (95% CI 4·0-4·4) at baseline to 2383·7 EU/mL (2087·2-2722·3) at day 28, then decreased to 48·0 EU/mL (39·9-57·8) at day 730-1035, remaining more than 11 times higher than baseline. Among MCV-A recipients, anti-Vi IgG titres remained unchanged: 4·3 EU/mL (4·0-4·5) at baseline, 4·4 EU/mL (4·0-4·7) on day 28, and 4·6 EU/mL (4·2-5·0) on day 730-1035. TCV and MCV-A recipients had similar solicited local (eight [3%] of 304, 95% CI 1·3-5·1 and three [1%] of 293, 0·4-3·0) and systemic (27 [9%] of 304, 6·2-12·6 and 27 [9%] of 293, 6·4-13·1) reactogenicity. Related unsolicited adverse events occurred similarly in TCV and MCV-A recipients in eight (3%) of 304 (1·3-5·1) and eight (3%) of 293 (1·4-5·3)., Interpretation: This study provides evidence of TCV safety, tolerability, and immunogenicity up to 730-1035 days in Malawian children aged 9 months to 12 years., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa., Methods: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up., Results: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination., Conclusions: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Typhoid fever is an acute infection characterized by prolonged fever following the ingestion and subsequent invasion of Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen. The incidence of typhoid fever has been most reported in children 5-15 years of age, but is increasingly recognized in children younger than 5 years old. There has been a recent expansion of multidrug-resistant typhoid fever globally. Prior typhoid vaccines were not suitable for use in the youngest children in countries with a high burden of disease. This study aims to determine the efficacy of a typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization, by testing it in children 9 months through 12 years of age in Blantyre, Malawi., Methods: In this Phase III, individually randomized, controlled, double-blind trial of the clinical efficacy of TCV, 28 000 children 9 months through 12 years of age will be enrolled and randomized in a 1:1 ratio to receive either Vi-TCV or a meningococcal serogroup A conjugate vaccine. A subset of 600 of these children will be further enrolled in an immunogenicity and reactogenicity sub-study to evaluate the safety profile and immune response elicited by Vi-TCV. Recruiting began in February 2018., Results: All children will be under passive surveillance for at least 2 years to determine the primary outcome, which is blood culture-confirmed S. Typhi illness. Children enrolled in the immunogenicity and reactogenicity sub-study will have blood drawn before vaccination and at 2 timepoints after vaccination to measure their immune response to vaccination. They will also be followed actively for adverse events and serious adverse events., Conclusions: The introduction of a single-dose, efficacious typhoid vaccine into countries with high burden of disease or significant antimicrobial resistance could have a dramatic impact, protecting children from infection and reducing antimicrobial usage and associated health inequity in the world's poorest places. This trial, the first of a TCV in Africa, seeks to demonstrate the impact and programmatic use of TCVs within an endemic setting., Clinical Trials Registration: NCT03299426., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: To determine the efficacy of a new typhoid conjugate vaccine in an endemic setting in sub-Saharan Africa, the Typhoid Vaccine Acceleration Consortium is conducting a phase-3 randomized controlled trial in Blantyre, Malawi. This article describes community and stakeholder engagement activities before and during the trial, challenges, and lessons learned., Methods: In October 2017, Malawi-Liverpool Wellcome Trust (MLW) organized a wide range of community engagement activities, including meetings with Ministry of Health and Education officials at the district and facility level, local community leadership, and parent teacher association groups. We engaged media outlets to include local and international television, radio, and print media. Community members were informed directly through a study jingle played via loudspeaker from a van and by community-based activities.To review engagement activity effectiveness: The MLW team met to discuss progress and challenges; and a focus group discussion (FGD), consisting of trial staff, sought feedback from the community on each engagement modality., Results: The school-based vaccine campaign increased community participation exceeding recruitment targets to date (on average, >200 children/day)., Conclusions: The FGD concluded that the van and local activities improved awareness and turnout for the trial, but prior engagement with local government and community leadership is an essential mechanism to provide details of the study, answer questions, communicate the value of the study, and address safety concerns. Effective community engagement is essential in a large intervention trial. Multiple channels of communication are required to reach the community and deliver information needed for participation and provide opportunity for dialogue with the trial team., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)