Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

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.

Stepwise evolution of Salmonella Typhimurium ST313 causing bloodstream infection in Africa.

Bloodstream infections caused by nontyphoidal Salmonella are a major public health concern in Africa, causing ~49,600 deaths every year. The most common Salmonella enterica pathovariant associated with invasive nontyphoidal Salmonella disease is Salmonella Typhimurium sequence type (ST)313. It has been proposed that antimicrobial resistance and genome degradation has contributed to the success of ST313 lineages in Africa, but the evolutionary trajectory of such changes was unclear. Here, to define the evolutionary dynamics of ST313, we sub-sampled from two comprehensive collections of Salmonella isolates from African patients with bloodstream infections, spanning 1966 to 2018. The resulting 680 genome sequences led to the discovery of a pan-susceptible ST313 lineage (ST313 L3), which emerged in Malawi in 2016 and is closely related to ST313 variants that cause gastrointestinal disease in the United Kingdom and Brazil. Genomic analysis revealed degradation events in important virulence genes in ST313 L3, which had not occurred in other ST313 lineages. Despite arising only recently in the clinic, ST313 L3 is a phylogenetic intermediate between ST313 L1 and L2, with a characteristic accessory genome. Our in-depth genotypic and phenotypic characterization identifies the crucial loss-of-function genetic events that occurred during the stepwise evolution of invasive S. Typhimurium across Africa.

The epidemiology of glycopeptide-resistant enterococci on a haematology unit--analysis by pulsed-field gel electrophoresis.

As part of an interventional study to determine glycopeptide-resistant enterococci (GRE) acquisition on a three-ward haematology unit, rectal swabs were taken weekly from 293 patients recruited to the study between June 1995 and December 1996. The GRE isolates obtained from the first positive rectal swab from 120 colonized patients, the isolates from 7 patients with clinical infection and 43 isolates obtained from the ward environment were compared by pulsed-field gel electrophoresis (PFGE). Sixty-three of 120 patients were colonized by one of strains A-H, while 49 were colonized by unique strains. The first 18 weeks were associated with the highest prevalence of GRE by rectal swab, with a single strain A responsible for 52% of acquisitions on ward 2, 22% on ward 3 and 36% on ward 4. Other smaller ward associated clusters were evident. Environmental sampling of ward 2 during this time showed that all but 2 of 30 isolates were indistinguishable from strain A. As the GRE prevalence fell, rectal swab and environmental isolates became more heterogeneous, and strain A disappeared after week 55. GRE prevalence rose again in the final 15 weeks of the study, and a new predominant strain B emerged on ward 2 responsible for 50% of new acquisitions. In the seven patients with clinical infection with GRE, the clinical isolates were compared with the contemporaneous rectal swab isolate, and were found to be the same in only two cases. An analysis of five long-term carriers colonized for a median of 19 weeks (range 11-34) showed colonization with at least two and in one case six distinct strains, raising the question of how many strains may be colonizing a patient at any one time, and suggesting that multiple colonies should be analysed. These data suggest that cross-infection was an important factor in the spread of GRE when the colonization rate was high.