Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine versus a quadrivalent meningococcal conjugate vaccine in adults in India: an observer-blind, randomised, active-controlled, phase 2/3 study

Abstract

Background: Meningococcal disease remains an important public health problem globally. We assessed the non-inferiority and the lot-to-lot consistency of a pentavalent meningococcal ACYWX conjugate vaccine (NmCV-5; Serum Institute of India, Pune, India) versus a quadrivalent meningococcal ACWY conjugate vaccine (MenACWY-D) in healthy adults.

Methods: In this observer-blind, randomised, active-controlled, phase 2/3 study, healthy adults aged 18-85 years were recruited from nine hospitals across seven cities in India. Participants were grouped by age (age 18-29, 30-60, and 61-85 years), and within each age group they were randomly assigned (3:1) to receive either NmCV-5 or MenACWY-D (Sanofi Pasteur). In the age 18-29 years group, participants were additionally randomly assigned (1:1:1:1) to either lot A, lot B, or lot C of NmCV-5 or MenACWY-D. Block randomisation was used (block sizes of 4, 8, and 12). Study participants and study personnel were masked to treatment assignment. Participants received either a 0·5 mL dose of NmCV-5, containing 5 μg each of conjugated A, C, W, Y, and X polysaccharides, or 0·5 mL MenACWY-D, containing 4 μg of each of conjugated A, C, W, and Y polysaccharides. Vaccinations were administered intramuscularly in the deltoid muscle. The primary outcomes were seroresponse (non-inferiority margin of -10%) and geometric mean titres (GMTs; non-inferiority margin of 0·5) in all participants, and lot-to-lot consistency of NmCV-5 (in participants aged 18-29 years; consistency was shown if the geometric mean ratio [GMR] 95% CIs were within the limit interval of 0·5 to 2). For non-inferiority, serogroup X immune response in the NmCV-5 group was compared with the lowest immune response among serogroups A, C, W, and Y in the MenACWY-D group. Immunogenicity was assessed with a serum bactericidal activity assay that used baby rabbit serum as the complement (rSBA) on days 1 and 29 in the modified per-protocol population (including all participants who were randomly assigned, received vaccine, had a post-vaccination rSBA measurement up to 121 days after vaccination, and no major protocol violations). Solicited events were collected for 7 days and serious adverse events were collected for 180 days, and assessed in the safety population (all participants who received vaccination). This study is registered with ClinicalTrials.gov, NCT04358731, and CTRI, CTRI/2019/12/022436, and is now complete.

Findings: Between Dec 27, 2019, and Sept 19, 2020, 1712 individuals were screened, of whom 1640 were randomly assigned and received NmCV-5 (n=1233) or MenACWY-D (n=407; mean age 26·4 years [SD 12·2], 551 [33·6%] of 1640 were female, and 1089 [66·4%] were male). 1441 participants were aged 18-29 years (362 received lot A, 360 received lot B, and 361 received lot C of NmCV-5 and 357 received MenACWY-D, with one participant mis-randomised by age group and excluded from lot-to-lot consistency analysis). Non-inferiority of NmCV-5 against MenACWY-D was met in terms of seroresponse rates and GMT ratios for all five serogroups. The seroresponse rates were 84·3% (97·5% CI 81·7 to 86·7; serogroup A) or higher in the NmCV-5 group and 54·5% (48·5 to 60·3; serogroup A) or higher in the MenACWY-D group, with the difference in the seroresponse rate between vaccine groups ranging from 0·2 (97·5% CI -2·2 to 2·6) for serogroup W to 29·8 (24·4 to 35·2) for serogroup A. GMTs on day 29 were 7016·9 (97·5% CI 6475·7 to 7603·4; serogroup Y) or higher in the NmCV-5 group and 3646·8 (3188·2 to 4171·5; serogroup Y) or higher in the MenACWY-D group, with GMT ratios between vaccine groups for serogroups A, C, Y, and W ranging from 1·9 (97·5% CI 1·5-2·3) for serogroup W to 2·5 (2·2-2·8) for serogroup A. NmCV-5 induced robust immune responses against serogroup X. Lot-to-lot consistency of NmCV-5 was found for all five serogroups, with 95% CIs for the GMT ratio for each pair of lots being between 0·5 and 2: the lowest lower bound and the highest upper bound of the 95% CI for the GMR between NmCV-5 lot A and lot B were 0·6 and 1·4, between lot A and lot C were 0·7 and 1·6, and between lot B and lot C were 0·8 and 1·6, respectively, for any of the five serogroups. At least one solicited adverse event was reported by 527 (42·7%) of 1233 participants in the NmCV-5 group and 142 (34·9%) of 407 in the MenACWY-D group. No serious adverse events occurred that were determined to be causally related to vaccination.

Interpretation: NmCV-5 was non-inferior to MenACWY-D in terms of seroresponse and GMTs, was safe, and demonstrated lot-to-lot consistency. NmCV-5 is prequalified by WHO and was rolled out in the African meningitis belt in April, 2024.

Funding: Serum Institute of India.