BACKGROUND: Rabies is almost invariably fatal. A rabies monoclonal antibody (RmAb) was approved in India in 2016 for passive prophylaxis. This post-marketing study aimed to evaluate the long-term safety, immunogenicity, and efficacy of a post-exposure prophylaxis (PEP) regimen containing RmAb.
METHODS: This phase 4, open-label, randomised, active-controlled study was conducted at 15 tertiary care hospitals in India. Patients aged 2 years or older with WHO category 3 rabies exposure by a suspected rabid animal were eligible if the exposure occurred less than 72 h before enrolment, or less than 24 h before enrolment for exposures to the face, neck, hand, or fingers. Participants were randomly assigned (3:1) to receive either RmAb (Rabishield; Serum Institute of India, Pune, India) plus a purified Vero cell rabies vaccine (PVRV; Rabivax-S) or equine rabies immunoglobulin (ERIG; Equirab) plus PVRV as PEP. In each treatment group, patients were further randomly assigned (1:1) to receive PVRV either intradermally or intramuscularly. Study group allocation was done using a permuted block design with random block sizes of eight. A central randomisation list was generated before the study start and randomisation was performed with an interactive web response system. Participants and site personnel were not masked to group assignment. RmAb (3·33 IU/kg) and ERIG (40 IU/kg) were infiltrated into and around the wounds only on day 0 as per WHO 2018 recommendations. PVRV was administered 1·0 mL intramuscularly (days 0, 3, 7, 14, and 28) or 0·1 mL plus 0·1 mL intradermally (days 0, 3, 7, and 28). The primary outcome was treatment-related serious adverse events up to 365 days after immunisation, analysed in the safety analysis set (all participants who received at least one dose of vaccine with treatment). Geometric mean concentrations of rabies virus neutralising antibody were measured in a subset of patients. This study is registered with Clinical Trial Registry-India (CTRI/2019/06/019622) and is completed.
FINDINGS: 4059 participants were enrolled between Aug 21, 2019, and March 31, 2022, and randomly assigned. A total of 3994 participants (3001 male, 993 female) were treated (2996 RmAb plus PVRV, 998 ERIG plus PVRV), of which 3622 (90·7%) participants completed the 1-year follow-up. 11 adverse events were considered causally related to RmAb plus PVRV and 17 were considered causally related to the ERIG plus PVRV regimen. Most adverse events were mild and transient. Seven serious adverse events occurred in the RmAb group and all were causally unrelated. One causally related serious adverse event was reported in the ERIG group. On day 14, the geometric mean concentrations increased to 16·05 IU/mL (95% CI 13·25-19·44) in the RmAb group and 13·48 IU/mL (9·51-19·11) in the ERIG group (point estimate 1·19 [95% CI 0·82-1·72]). No patient developed rabies during the 1-year follow-up period.
INTERPRETATION: RmAb was safe and well tolerated and showed protective efficacy against rabies. A PEP regimen containing RmAb plus PVRV was immunogenic with long-term persistence of immune response.
FUNDING: Serum Institute of India.
| Discipline Area | Score |
|---|---|
| Infectious Disease |  |
| Pediatric Emergency Medicine | |
| Public Health | |
| Emergency Medicine |  |
This phase 4 study looked at rabies monoclonal antibody vs equine based antibody for rabies PEP. In this study, the monoclonal antibody performed as well as the equine immunoglobulin without any cases of rabies with similar adverse events. This is helpful especially in low-income countries where human-derived immunoglobulin is not easily accessible. It would be interesting to see whether this holds up compared with HRIG from a safety standpoint, especially if it is a cheaper alternative.
Although selecting a rabies vaccine is outside the scope of practice or sphere of influence of practicing emergency physicians, awareness of this new monoclonal antibody's efficacy and safety is worthwhile.
This study compared equine rabies immune globulin versus rabies monoclonal antibody in postexposure prophylaxis. Of interest was that they used only infiltration around the wound of the antibody without IM administration of immune globulin. No patient in the study developed rabies. This provides some evidence that we may not need the IM dose of RIG.
Provides an alternative approach to rabies post-exposure prophylaxis. Based on sample size, unable to detect adverse events more rare than 1 in 1000. Additionally, status of source animals (exposure category of rabid or not) was unknown. Further post-marketing surveillance is important to assess real-world vaccine effectiveness and safety.