Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal.

BACKGROUND: Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS: In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS: A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P<0.001). A total of 132 serious adverse events (61 in the TCV group and 71 in the MenA vaccine group) occurred in the first 6 months, and 1 event (pyrexia) was identified as being vaccine-related; the participant remained unaware of the trial-group assignment. Similar rates of adverse events were noted in the two trial groups; fever developed in 5.0% of participants in the TCV group and 5.4% in the MenA vaccine group in the first week after vaccination. In the immunogenicity subgroup, seroconversion (a Vi IgG level that at least quadrupled 28 days after vaccination) was 99% in the TCV group (677 of 683 participants) and 2% in the MenA vaccine group (8 of 380 participants). CONCLUSIONS: A single dose of TCV was immunogenic and effective in reducing S. Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161.).

Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial.

BACKGROUND: Typhoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up. METHODS: We did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing. FINDINGS: From Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9-88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38-123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262-438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously. INTERPRETATION: The final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever. FUNDING: Bill & Melinda Gates Foundation.

Comparison of midwifery-led and consultant-led maternity care for low risk deliveries in Nepal.

OBJECTIVE: To evaluate Nepal's first independent midwifery unit, the Patan Hospital Birthing Centre (BC), as a model for training and service provision for low risk deliveries. Specifically, to compare its efficacy with that of an adjacent Consultant-led Maternity Unit (CMU). METHODS: Unpaired comparison of delivery procedures and outcomes at the Patan Hospital, Lalitpur. The sample was 988 women (550 at BC, 438 at CMU). Women judged to be at low risk of complications were enrolled at delivery at each facility. Information was collected by standardized interviews and record review. Main outcome measures were incidence of complications of labour, technical procedures and access to postnatal care and family planning services. RESULTS: Artificial rupture of membranes was more likely to be performed at the BC (RR 1.26, 95% CI 1.10-1.44). Augmentation of labour with oxytocin was less likely to be performed (RR 0.26, 95% CI 0.20-0.33), as was episiotomy (RR 0.64, 95% CI 0.57-0.72). The incidence of oxytocic augmentation was high at the CMU (205/438: 46.9%). The incidence of moderately or thickly meconium-stained liquor was lower at the BC than at the CMU (RR 0.62, 95% CI 0.43-0.91), a finding that was associated with oxytocic augmentation of labour. No significant differences were found for duration or complications of labour, mode of delivery, birth weight, neonatal Apgar score or admission to the special care baby unit. Women delivering at the BC were more likely to attend both postnatal (RR 1.33, 95% CI 1.18-1.51) and family planning clinics (RR 1.85, 95% CI 1.44-2.38). CONCLUSIONS: After appropriate screening, intrapartum care for low risk deliveries is effectively provided by midwives. The Birthing Centre model should be considered throughout the developing world, particularly as a site for training of skilled attendants.