This page provides an accessible overview of the published research. Readers should consult the original peer-reviewed article for the complete protocol, statistical analyses, tables, figures, supplementary material and author declarations.
Publication Overview
Title: A double-blind, randomised phase III clinical trial to evaluate safety, immunogenicity, non-inferiority & lot to lot consistency of single component oral cholera vaccine BBV131 (Hillchol®) in comparison to Shanchol™
Journal: Vaccine
Volume and article number: Volume 55 (2025), Article 126998
Available online: 1 April 2025
DOI: 10.1016/j.vaccine.2025.126998
Trial registration: CTRI/2022/01/039734 and NCT05507229
Study type: Phase III, randomised, modified double-blind, multicentre, active-controlled non-inferiority trial
Setting: Ten tertiary-care clinical trial sites across India
Main trial population: 1,800 healthy participants aged one year and above
Investigational vaccine: BBV131 (Hillchol®), a single-component, formalin-inactivated oral cholera vaccine based on a stable Vibrio cholerae O1 Hikojima strain
Comparator: Shanchol™, a WHO-prequalified oral cholera vaccine
King George Hospital role: King George Hospital, Visakhapatnam was one of the participating clinical trial sites. B. S. Chakravarthy is listed as a co-author; the CRediT contribution statement identifies his contribution as data curation.
Why This Vaccine Matters
Cholera is an acute, potentially life-threatening diarrhoeal illness caused by toxigenic Vibrio cholerae. The disease remains closely linked to unsafe water, inadequate sanitation and humanitarian emergencies. Oral cholera vaccines are an important complement to water, sanitation, hygiene and outbreak-control measures.
The publication was undertaken against a background of increasing cholera outbreaks and global constraints in oral cholera vaccine supply. Existing killed whole-cell oral cholera vaccines contain multiple bacterial components, which can complicate manufacturing. A simplified vaccine based on a single stable strain could potentially increase manufacturing efficiency and vaccine availability.
What Is BBV131 (Hillchol®)?
BBV131 is a single-component, formaldehyde-inactivated whole-cell oral cholera vaccine. It uses a recombinant V. cholerae O1 El Tor Hikojima strain designed to express approximately equal amounts of the Ogawa and Inaba O1 antigens.
The vaccine was supplied as a 1.5 mL oral dose in a small plastic respule. The simplified single-strain formulation was developed to support scalable production, affordability and easier presentation while retaining immune responses against both major O1 serotypes.
What is the Hikojima concept? Ogawa and Inaba are the two major serotypes of V. cholerae O1. The engineered stable Hikojima strain used for BBV131 co-expresses antigens associated with both, allowing a single bacterial component to target immune responses to both serotypes.
Study Design
The investigators conducted a phase III, randomised, modified double-blind, multicentre trial to compare the immunogenicity and safety of BBV131 with Shanchol™ and to evaluate consistency across three manufacturing lots of BBV131.
| Design Element | Detail |
|---|---|
| Study period | 19 May 2022 to 2 February 2023 |
| Clinical sites | Ten tertiary-care centres across India |
| Main trial size | 1,800 participants; 1,794 included in the per-protocol analysis |
| Age strata | Adults ≥18 years; children ≥5 to <18 years; young children ≥1 to <5 years |
| Allocation | 3:1 to BBV131 or Shanchol™ within each age group |
| Dosing | Two oral doses on Day 0 and Day 14 |
| Masking | Participants, investigators and personnel involved in assessments, sample collection and testing were blinded; an unblinded pharmacist administered the products because the presentations differed |
| Primary endpoint | At least four-fold rise in vibriocidal antibody titres against Ogawa and Inaba 14 days after the second dose |
| Non-inferiority margin | Lower bound of the two-sided 95% confidence interval for the seroconversion-rate difference ≥ −10 percentage points |
| Lot consistency | Comparison of immune responses across three BBV131 manufacturing lots |
| Additional safety cohort | A separate 1,800-participant, single-arm BBV131 safety study was added |
Participants and Procedures
The main comparative trial enrolled 600 participants in each of three age groups, giving a total of 1,800 participants. Within each age stratum, 450 participants were assigned to BBV131 and 150 to Shanchol™.
Participants received two 1.5 mL oral doses on Days 0 and 14. Blood was collected at baseline and during follow-up on Days 14, 28, 56, 90 and 180. Immune responses were assessed using serum vibriocidal antibody assays against the Ogawa and Inaba serotypes.
Safety monitoring included immediate reactions, solicited adverse events for seven days after vaccination, unsolicited events throughout the study and serious adverse events. An independent data and safety monitoring board reviewed interim safety information during sequential enrolment of the age groups.
Immunogenicity Findings
The primary immunogenicity analysis included 1,794 participants. Fourteen days after the second dose, BBV131 met the predefined non-inferiority criterion compared with Shanchol™ for both Ogawa and Inaba.
| Serotype | BBV131 Seroconversion | Shanchol™ Seroconversion | Difference (95% CI) |
|---|---|---|---|
| Ogawa | 918/1,345 — 68.25% | 305/449 — 67.93% | +0.32 percentage points (−4.6 to 5.4) |
| Inaba | 935/1,345 — 69.52% | 303/449 — 67.48% | +2.03 percentage points (−2.8 to 7.1) |
Because the lower confidence-limit for each comparison remained above the prespecified −10 percentage-point margin, BBV131 was considered immunologically non-inferior to Shanchol™ for both serotypes. Non-inferiority was also met within all three age groups.
Vibriocidal antibody titres rose after vaccination and declined over subsequent months. At Day 180, titres remained above baseline, but the publication emphasises that serum vibriocidal titres are not a complete or established long-term correlate of protection.
Lot-to-Lot Consistency
The study compared immune responses across three commercial-scale manufacturing lots of BBV131. The predefined lot-consistency assessment used geometric mean titre ratios between pairs of lots.
At the key post-vaccination assessment, the pairwise geometric mean titre ratios and their confidence intervals were within the predefined equivalence range for both Ogawa and Inaba. This supported consistent immunogenicity across the three lots and provided evidence of reproducible manufacturing performance.
Safety Findings
In the 1,800-participant comparative trial, 257 adverse events were reported among 236 participants (13.1%). The incidence was similar between BBV131 and Shanchol™ and across the three age groups.
| Safety Measure | BBV131 | Shanchol™ |
|---|---|---|
| Participants with any adverse event | 180/1,350 — 13.3% | 56/450 — 12.4% |
| Participants with solicited adverse events | 151/1,350 — 11.2% | 45/450 — 10.0% |
| Participants with unsolicited adverse events | 35/1,350 — 2.6% | 11/450 — 2.4% |
Common vaccine-related events included oropharyngeal pain, dry mouth, nausea, headache, vomiting and cough, each occurring in fewer than 2% of participants overall. All reported adverse events resolved by the end of the study.
No serious adverse events, adverse events of special interest, medically attended adverse events, vaccine-related discontinuations or deaths were reported in the comparative trial.
The additional 1,800-participant BBV131 safety cohort showed a similar overall safety profile. No serious adverse events, adverse events of special interest, discontinuations due to adverse events or deaths were reported in that cohort.
Clinical and Public Health Significance
Evidence-supported interpretation: In this Indian phase III trial, BBV131 produced non-inferior vibriocidal antibody responses to Shanchol™ against both Ogawa and Inaba and demonstrated a comparable safety profile. The three manufacturing lots produced consistent immune responses.
The single-component formulation and respule presentation may simplify production and handling compared with multicomponent vaccines. The authors argue that these features could help expand oral cholera vaccine supply during a period of substantial global demand.
The trial evaluated immunogenicity and safety rather than direct protection against clinical cholera. Therefore, the findings should not be interpreted as a direct vaccine-efficacy estimate. The publication also notes the importance of future real-world effectiveness and broader immunological studies.
Role of Andhra Medical College and King George Hospital
King George Hospital, Visakhapatnam, was one of the participating centres in this multicentre Indian trial. B. S. Chakravarthy is listed among the publication's authors with the King George Hospital affiliation.
Authorship contribution: The published CRediT authorship statement records B. S. Chakravarthy's contribution as data curation. This page therefore describes him as a co-author and site investigator and does not attribute study leadership, overall trial design or sponsorship to him.
Key Takeaways
- BBV131 (Hillchol®) is a single-component, inactivated oral cholera vaccine based on a stable O1 Hikojima strain expressing Ogawa and Inaba antigens.
- The phase III comparative trial enrolled 1,800 participants aged one year and above at ten Indian centres.
- Participants received two oral doses on Days 0 and 14.
- BBV131 was immunologically non-inferior to Shanchol™ for both Ogawa and Inaba serotypes.
- Non-inferiority was met across adults, older children and children aged one to under five years.
- Three BBV131 manufacturing lots demonstrated consistent immunogenicity at the key assessment.
- Adverse-event rates were comparable between the two vaccine groups, and no serious safety signal was identified.
- The study assessed immune responses and safety; it was not a direct clinical efficacy trial against cholera disease.
- King George Hospital was a participating site, and Dr. B. S. Chakravarthy was a co-author whose stated contribution was data curation.
Original Publication
This webpage is an educational summary. The complete methods, statistical analyses, tables, figures, supplementary data and limitations should be read in the original open-access article.
Funding and disclosures: The article acknowledges support from Bharat Biotech International Limited and contributions from MSD Wellcome Trust Hilleman Laboratories. The published declaration states that the authors had no known competing financial interests or personal relationships that could have appeared to influence the work. Readers should consult the original publication for the complete acknowledgements and author contribution statement.
Dr. B. S. Chakravarthy
Professor & Head, Department of Pediatrics
Andhra Medical College & King George Hospital, Visakhapatnam
Co-author and Site Investigator — Vaccine (2025)