Comparison of the immunogenicity and safety of Euvichol-Plus with Shanchol in healthy Indian adults and children: an open-label, randomised, multicentre, non-inferiority, parallel-group, phase 3 trial

Background Considering the cholera menace in India and to seek licensure of the oral cholera vaccine (OCV), Euvichol-Plus, we conducted a clinical trial to compare the immunogenicity and safety of Euvichol-Plus with Shanchol in healthy Indian adults and children.Methods This phase 3, open-label, multicentre, randomised, non-inferiority, parallel-group, comparative study was conducted at seven sites across India involving 416 healthy adults (aged >= 18-60 years) and children (aged >= 1 to <18 years). Healthy individuals who agreed to participate through a voluntary written informed consent form along with oral or written assent (for children aged 7-18 years) were included. No assent was required for those <7 years, as consent was given by the legally acceptable representatives (LAR). Participants were randomised 1:1 to receive two doses of either Euvichol-Plus or Shanchol orally, 14 days apart. The first dose (1.5 ml) was administered on visit 1, and the second dose at 2 weeks after the first dose during visit 2. Participants were followed up telephonically for 3 consecutive days after each visit and returned for final assessment at 2 weeks after the second dose (visit 3). Blood samples were collected for immunogenicity assessment, and safety analyses were done during all the visits. The primary immunogenicity endpoint was the percentage of participants with >= 4-fold increase in anti-Vibrio cholerae (V. cholerae) O1 Ogawa and O1 Inaba (vibriocidal) antibody titres at 2 weeks after the second dose as compared to baseline titres prior to dosing. The secondary immunogenicity endpoints included the percentage of participants with >= 4-fold increase in anti-V. cholerae O139 antibody titres at 2 weeks after the second dose as compared to baseline titres, and geometric mean titres (GMT) and geometric mean ratios (GMR) as measured by anti-V. cholerae O1 Ogawa, O1 Inaba, and O139 antibody titres at 2 weeks after the second dose as compared to baseline titres. The safety endpoints included assessment of solicited, unsolicited adverse events (AEs), and serious adverse events (SAEs). The clinical trial was registered with the Clinical Trials Registry of India (CTRI/2021/08/035344).Findings The study was performed in two age cohorts: cohort 1 (aged >= 18-60 years, 208 participants [104 in Euvichol-Plus group and 104 in Shanchol group]), and cohort 2 (aged >= 1 to <18 years, 208 participants [104 in Euvichol-Plus group and 104 in Shanchol group]). A total of 414 participants (Euvichol-Plus: 206 and Shanchol: 208) who completed the study (intention-to-treat and per-protocol set) were analysed to compare the vibriocidal titre as an index for immunogenicity. At 2 weeks after the second dose, the percentage of participants in the Euvichol-Plus group who reported a >= 4-fold increase in anti-V. cholerae antibody titres were 68.93% (O1 Ogawa) [95% CI 62.13%-75.18%], 66.02% (O1 Inaba) [95% CI 59.11%-72.46%], and 59.71% (O139) [95% CI 52.67%-66.47%] as compared to 63.94% (O1 Ogawa) [95% CI 57.01%-70.47%], 65.87% (O1 Inaba) [95% CI 58.99%-72.28%], and 56.25% (O139) [95% CI 49.22%-63.10%] in the Shanchol group. The lower limit of 95% CI for treatment difference for all the antibody titres was >= 10% (non-inferiority margin), demonstrating that Euvichol-Plus was non-inferior to Shanchol. The post-vaccination GMT (Day 14 and 28) were more than the pre-vaccination GMT for all three serotypes in both groups. The GMR obtained for Euvichol-Plus over Shanchol for O1 Ogawa, O1 Inaba, and O139 serotypes was >1, indicating non-inferiority of Euvichol-Plus to Shanchol. The safety cohort included 416 participants. Headache was the most common solicited AE, whereas cold and cough were the most common unsolicited AEs in both groups.Interpretation Euvichol-Plus appears to be non-inferior to Shanchol in terms of immunogenicity and safety in healthy Indian adults and children.