Immunogenicity and safety of Institut Pasteur du Cambodge (IPC) and updated Thai Red Cross (UTRC) intradermal rabies vaccine regimens among healthy adults in India: A phase 4, open label, equivalence randomised controlled trial

BACKGROUND: Shorter rabies post-exposure prophylaxis (PEP) regimens could improve compliance and access by reducing the number of clinic visits and vaccine requirement per patient. We compared the immunogenicity and safety of a 1-week intradermal Institut Pasteur du Cambodge (IPC) regimen with a 1-month intradermal Updated Thai Red Cross regimen (UTRC) using two rabies vaccines widely used in India: Purified Chick Embryo Cell vaccine (PCECV) and the Purified Vero Cell Rabies vaccine (PVRV). METHODS AND FINDINGS: We conducted a phase 4, single-centre, open-label randomised controlled equivalence trial among adult healthy volunteers. Participants were block randomised (1:1:1:1) to receive either the IPC (Days 0, 3, 7) or UTRC (Days 0, 3, 7, 28) intradermal regimen with either PCECV or the PVRV. Rabies virus neutralizing antibody (RVNA) titres were measured up to 1 year. The primary objective of the trial was to determine the immunogenicity of the Intradermal abridged Cambodia regimen with updated intradermal Thai red cross regimen using two different vaccine types among healthy volunteers in India. The primary outcome was geometric mean concentration ratios (GMR) of RVNA on day 42, assessed separately for each vaccine type. Equivalence for each vaccine was predefined as the entire 95% confidence interval for GMR lying between 0.72 and 1.04. The secondary outcomes included proportion of participants with RVNA titres >= 0.5 IU/mL on Days 14, 28, 42, 90, 180, and 365 and vaccine safety. Between October 10, 2023, and December 23, 2023, 400 participants were randomly assigned (100 per group) to PCECV-IPC, PCECV-UTRC, PVRV-IPC, and PVRV-UTRC. 362 (90.5%) completed PEP regimen and blood draw on day 42. In the prespecified modified intention-to-treat analysis, the Day 42 GMR (IPC vs UTRC) was 0.59 (95% CI: 0.47-0.75) for PCECV and 0.76 (95% CI: 0.61-0.95) for PVRV, which did not meet the prespecified equivalence criterion. All participants, irrespective of baseline serostatus, in four groups had RVNA titres ≥0.5 IU/ml at every assessment from day 14-1 year. Adverse events were similar between regimens and mostly mild. There are important limitations in this study. Nearly one-quarter of participants had baseline RVNA titres ≥0.5 IU/mL despite exclusion of participants with a reported history of rabies vaccination or dog bite, suggesting unrecognised prior immunological priming that may have influenced GMC estimates. As the trial was conducted among healthy volunteers rather than people receiving PEP after animal bites, the findings may not fully reflect vaccine performance in routine post-exposure settings. CONCLUSION: The IPC regimen did not meet the prespecified equivalence criterion compared to UTRC. All participants achieved RVNA titres ≥0.5 IU/ml indicative of seroprotection from day 14 till 1 year. Policy decisions regarding replacement of UTRC should consider these immunogenicity findings together with compliance, cost, and vaccine availability. TRIAL REGISTRATION: The trial was registered with the Clinical Trial Registry - India (CTRI/2023/10/058418). URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=OTAxMDA=&Enc=&userName=).