Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, W, Y, and X when co-administered with routine childhood vaccines at ages 9 months and 15 months in Mali: a single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial.

Background: Invasive meningococcal disease is a devastating public health problem for the African meningitis belt. We assessed the safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, Y, W, and X (NmCV-5) relative to a licensed, quadrivalent meningococcal conjugate vaccine (MenACWY-TT) when co-administered with routine childhood vaccines at ages 9 months and 15 months.

Methods: In this single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial, children aged 9-11 months who had completed their local infant Expanded Program on Immunization (EPI) vaccines were recruited at the Centre pour le Développement des Vaccins in Bamako, Mali. Participants were randomly assigned (1:1·2) at their 9-month EPI visits to receive a meningococcal vaccine at either their 9-month or 15-month EPI vaccination visits. At each participant's designated EPI visit, they were randomly assigned a second time (2:1) to receive either NmCV-5 or MenACWY-TT. Study vaccines and designated EPI vaccines were prepared and administered by assigned unmasked study personnel. Parents or guardians, investigators, and all other trial staff were masked to meningococcal vaccine assignments. The meningococcal vaccines were co-administered with a measles and rubella vaccine (first dose) and a yellow fever vaccine at age 9 months or with a measles and rubella vaccine (second dose) at age 15 months. The primary endpoint, seroprotective response, was defined as a rabbit complement serum bactericidal antibody titre of 8 or higher, with the estimand, given as the difference in the proportions of participants for each of the five meningococcal serogroups who showed this response 28 days after vaccination, assessed in the per-protocol population. The prespecified non-inferiority margin was -10% for all five serogroups in both age groups. The non-inferiority of the NmCV-5 seroprotective response to serogroup X was evaluated in comparison with the lowest seroprotective response for MenACWY-TT among serogroups A, C, W, or Y. Safety was a secondary endpoint, assessed over 6 months in a modified intention-to-treat population that included all participants who received a randomly assigned meningococcal vaccine. This trial is registered with ClinicalTrials.gov, NCT05093829.

Findings: Between March 24 and Aug 15, 2022, 1325 participants were enrolled and randomly assigned to receive a meningococcal vaccine at either age 9 months (n=602) or age 15 months (n=723). Meningococcal vaccines were administered to 600 of the 602 participants assigned to the 9-month vaccination group during that same period. Between Sept 27, 2022, and Feb 6, 2023, 600 participants received meningococcal vaccines at their 15-month visits. In both groups, 400 participants received NmCV-5 and 200 participants received MenACWY-TT. The per-protocol population assessed in the non-inferiority analysis included 564 participants vaccinated at age 9 months (373 who received NmCV-5 and 191 who received MenACWY-TT) and 549 participants vaccinated at age 15 months (367 who received NmCV-5 and 182 who received MenACWY-TT). Among the participants in the per-protocol population who received NmCV-5 at age 9 months, the difference in seroprotection prevalence for NmCV-5 relative to MenACWY-TT was 0·0% (95% CI -1·0 to 2·0) for serogroup A, -0·5% (-2·3 to 1·9) for serogroup C, -3·0% (-6·3 to 0·8) for serogroup W, and -3·0% (-5·4 to -0·4) for serogroup Y. For serogroup X, non-inferiority was assessed relative to seroprotection for serogroup W in participants who received MenACWY-TT, with a difference of 2·3% (95% CI 0·3 to 4·7). The difference in the prevalence of seroprotection among the participants who received NmCV-5 at age 15 months relative to participants who received MenACWY-TT at age 15 months was 0·8% (95% CI -0·6 to 3·7) for serogroup A, -0·8% (-3·3 to 2·5) for serogroup C, 0·3% (-1·8 to 3·5) for serogroup W, and 1·4% (-0·6 to 4·8) for serogroup Y. For serogroup X, non-inferiority was assessed in relation to seroprotection for serogroup Y in participants who received MenACWY-TT, with a difference of 1·9% (95% CI 0·0 to 4·4). NmCV-5 responses in both age groups were non-inferior to MenACWY-TT responses for all five serogroups. Six serious adverse events were recorded but none were deemed related to vaccination.

Interpretation: When compared with a licensed, quadrivalent meningococcal conjugate vaccine, and given alongside other routine vaccines, a single dose of NmCV-5 was safe and elicited a non-inferior immune response in infants aged 9 months and young children aged 15 months.

Funding: US National Institutes of Health, UK Foreign, Commonwealth & Development Office, and Serum Institute of India.