One-Week Intradermal Rabies Regimen Fails Equivalence Test Against Standard Schedule in Indian Trial

A phase 4, open-label, randomised controlled equivalence trial in India has found that a shortened one-week intradermal rabies post-exposure prophylaxis regimen did not meet the prespecified immunogenicity benchmark compared with the standard one-month Updated Thai Red Cross (UTRC) regimen. The study, conducted among healthy adult volunteers and published in PLOS Medicine, compared the abridged Institut Pasteur du Cambodge (IPC) regimen, given on days 0, 3 and 7, against the UTRC schedule, which adds a fourth dose on day 28, using two widely deployed vaccines: Purified Chick Embryo Cell vaccine (PCECV) and Purified Vero Cell Rabies vaccine (PVRV).

Shorter regimens are attractive because they could improve compliance and access by reducing the number of clinic visits and the vaccine volume required per patient. The trial, run at a single centre, block-randomised 400 participants equally between October 10 and December 23, 2023, into four groups of 100: PCECV-IPC, PCECV-UTRC, PVRV-IPC and PVRV-UTRC. Of these, 362 participants, or 90.5 percent, completed the post-exposure prophylaxis regimen and the day-42 blood draw.

The primary outcome was the geometric mean concentration ratio (GMR) of rabies virus neutralizing antibody (RVNA) titres on day 42, assessed separately for each vaccine type. Equivalence was predefined as the entire 95 percent confidence interval for the GMR lying between 0.72 and 1.04. In the prespecified modified intention-to-treat analysis, the day-42 GMR for IPC versus UTRC was 0.59 (95 percent CI 0.47 to 0.75) for PCECV and 0.76 (95 percent CI 0.61 to 0.95) for PVRV. Neither result satisfied the equivalence criterion, meaning the shorter regimen produced measurably lower antibody concentrations at that time point for both vaccines.

Despite this, the trial reported a reassuring secondary finding. All participants, irrespective of baseline serostatus, achieved RVNA titres of at least 0.5 IU/mL, a level indicative of seroprotection, at every assessment from day 14 through one year. Secondary outcomes also included safety, and adverse events were similar between the two regimens and mostly mild.

The investigators highlighted important limitations. Nearly one-quarter of participants had baseline RVNA titres of 0.5 IU/mL or higher, even though people reporting a prior history of rabies vaccination or dog bite were excluded. This suggests unrecognised prior immunological priming in the study population, which may have influenced the geometric mean concentration estimates. In addition, because the trial enrolled healthy volunteers rather than people receiving prophylaxis after actual animal bites, the findings may not fully reflect vaccine performance in routine post-exposure settings.

The authors concluded that the IPC regimen did not meet the prespecified equivalence criterion compared with UTRC, while noting that all participants achieved seroprotective titres from day 14 until one year. They cautioned that policy decisions about replacing the UTRC regimen should weigh these immunogenicity findings together with compliance, cost and vaccine availability, rather than relying on antibody concentrations alone.

This trial was registered with the Clinical Trial Registry of India (CTRI/2023/10/058418), and RVNA titres were measured up to one year after vaccination.

For now, the results indicate that the one-week IPC schedule, while producing seroprotective titres in every participant, generated lower day-42 antibody concentrations than the four-visit UTRC regimen for both PCECV and PVRV. Whether the operational advantages of a shorter schedule could offset this immunogenicity gap remains a question for policymakers, and the authors emphasise that such decisions require consideration of compliance, cost and vaccine supply alongside the equivalence data reported here.

Subject of Research: Immunogenicity and safety comparison of shortened versus standard intradermal rabies post-exposure prophylaxis regimens in healthy Indian adults

Article Title: 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

Article References: Thangaraj, J. W. V., Ullas, P. T., More, B. D., Shanmugam, L., Velusamy, S., Gopal, D., Ramamoorthy, S., Kaliaperumal, K., N. M, M., Arunachalam, S., Ramachandran, R., Ramakrishnan, G., Arunachalam, S., J. M, V. V., Anthuvan Valli, G., Pugalendhi, S., Ramasamy, S., T, K., Hanifah, M., … the Rabies Vaccine Immunogenicity Trial (RVIT) study group (2026). 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. PLOS Medicine, 23(10), e1005079. https://doi.org/10.1371/journal.pmed.1005079

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005079

Keywords: rabies, vaccination, intradermal regimen, post-exposure prophylaxis, equivalence trial, immunogenicity, PCECV, PVRV, India, seroprotection, phase 4 trial, vaccine safety