Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial

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.