The impact of COVID-19 pandemic on rabies post-exposure prophylaxis services in Asia.

Human rabies is a preventable disease through post-exposure prophylaxis (PEP) in rabies endemic countries where enzootic cycle of dog rabies occurs. The COVID­19 pandemic has induced an unprecedented challenge for under-funded and already stretched health­care systems particularly in low- and middle-income countries, which are unfortunately bearing a huge burden of human rabies. An analysis of hospital-based PEP data in India, Nepal, Sri Lanka, and Thailand, focus group discussion and key informant interview have been carried out to better understand the impact of Covid-19 pandemic in human rabies prophylaxis. It is necessary to better prepare for human rabies prophylaxis in future pandemics based on lesson learnt from current pandemic. The PEP should be categorized as an emergency medical service, and it should be part of the hospital medical emergency. Mass dog vaccination against rabies should be accelerated to reduce the risk of potential bite of roaming dogs and pet dogs in communities. It is a wise decision to invest in cost-effective preparedness, i.e., mass dog vaccination rather than costly response, i.e., human rabies prophylaxis.

Introduction of intradermal rabies vaccination - A paradigm shift in improving post-exposure prophylaxis in Asia.

The cost of cell culture vaccines for intramuscular administration limits their widespread use in many areas where rabies is present. The innovation of cost-effective multi-site intradermal (ID) vaccination technique was an impetus for high burden countries to phase out production and use of rabies vaccine of nerve tissue origin in public hospitals in subsequent years. The WHO Expert Committee in 1991 recommended intradermal application of modern rabies vaccines for post-exposure prophylaxis. There are many challenges in promotion of ID schedule. Poor patient compliance due to the need for several clinic visits is one of the drawbacks of the presently recommended ID rabies vaccination regimens. A series of clinical trial and field observations in past 3 decade have generated enough evidence-based information to recommend one week ID schedule. Off label use of commercially available human rabies vaccine for ID administration is an issue. The national authority should consider revision of ID vaccination schedule in line with new WHO guidelines.

Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study.

This phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule.

A Japanese Encephalitis Vaccine From India Induces Durable and Cross-protective Immunity Against Temporally and Spatially Wide-ranging Global Field Strains.

BACKGROUND: Japanese encephalitis (JE) is a vaccine-preventable acute disease. We report the results of a phase 2/3 trial of JENVAC, a Vero cell-derived vaccine developed using an Indian strain of JE virus (JEV). METHODS: JENVAC was administered in 2 doses 28 days apart, and immunogenicity was compared to that from a single dose of SA-14-14-2, the only approved JE vaccine and regimen at the time in India. RESULTS: After both the doses, seroconversion and seroprotection were >90% for JENVAC. For SA-14-14-2, seroconversion and seroprotection were 57.69% and 77.56%, respectively, on day 28 and 39.74% and 60.26%, respectively, on day 56. The geometric mean titers at day 28 and day 56 were 145.04 and 460.53, respectively, for JENVAC and 38.56 and 25.29, respectively, for SA-14-14-2. With a single dose of JENVAC, seroprotection titers lasted at least 12 months in >80% of the subjects. Following receipt of 2 doses, 61.17% of subjects retained seroprotection titers at 24 months, and immunogenicity criteria were higher than that for SA-14-14-2 at 12, 18, and 24 months each. Sera from JENVAC subjects neutralized JEV genotypes I, II, III, and IV equally well. Adverse events were not significantly different between the 2 vaccines. CONCLUSIONS: JENVAC elicits long-lasting, broadly protective immunity. CLINICAL TRIALS REGISTRATION: CTRI/2011/07/001855.

Safety and immunogenicity study of a new purified chick embryo cell rabies vaccine Vaxirab-N (Pitman-Moore strain) manufactured in India.

Zydus Cadila Health care, India developed a new purified chick embryo cell rabies vaccine (PCECV, Vaxirab-N; 1 mL) by adapting Pitman-Moore strain of virus on to the chick embryo fibroblast cell line in 2006. During 2007-10, a series of safety and immunogenicity studies were conducted as per ICH-GCP guidelines after obtaining permission from Drug Controller General of India. In the first study, Vaxirab-N was administered to 35 healthy adult volunteers by intramuscular (IM) route using pre exposure regimen. The geometric mean concentration (GMC) of rabies virus neutralizing antibody (RvnAb) of 7.5 IU/mL on day 35. In the second study, Vaxirab-N was administered to 35 healthy adult volunteers using simulated post- exposure prophylaxis regimen by IM route. A GMC of 6.3 IU/mL on day 14, 13.2 IU/mL on day 28 and 8.6 IU/mL on day 90 was obtained. In the third study, Vaxirab-N administered by intradermal (ID) route using Updated Thai Red Cross (TRC) regimen in 36 healthy adult volunteers showed GMC of 7.8 IU/mL on day 14, 11.5 IU/mL on day 28 and 6.0 IU/mL on day 90. The 4th study was multi centric and Vaxirab-N was administered to 129 animal bite cases by IM route using post-exposure Essen regimen. The GMC following this schedule was 8.2 IU/mL on day 14, 13.01 IU/mL on day 28, 7.92 IU/mL on day 90 and 3.72 IU/mL on day 180. Mild to moderate adverse events were reported to Vaxirab-N but no serious adverse events were reported in any of these studies. In conclusion, Vaxirab-N developed by Zydus Cadila was found to be safe and immunogenic by both intramuscular and intradermal route and is recommended for rabies prophylaxis (CTRI No. 2010/091/000055 and 2010/091/000509).

Immunogenicity, safety and tolerance of a purified duck embryo vaccine (PDEV, VAXIRAB) for rabies post-exposure prophylaxis: Results of a multicentric study in India.

Rabies continues to be a major public health problem in India. Nearly 17 million people are getting exposed to this disease every year. Therefore the need for effective post-exposure prophylaxis with safe and potent modern rabies vaccines continues to exist. Purified Duck Embryo Vaccine (PDEV) was introduced in this country to meet the ever increasing need for modern rabies vaccines. In this study we have assessed the safety, imunogenicity and tolerance of an indigenously manufactured PDEV in people exposed to dog and other animal bites. One hundred and fifty people (5-59 years) who were having WHO category II or III animal bites were vaccinated with PDEV using the Essen Intramuscular regimen and rabies immunoglobluin (RIG) was administered to category III exposures. Their blood samples were analyzed for rabies virus neutralizing antibody response (RVNA) by Rapid Fluorescent Focus Inhibition Test (RFFIT) on day 0, 14, 30, 90, 180 and 365. Adverse effects to vaccines were monitored during the course of vaccination. There was 100% sero-conversion from day 14 onwards with adequate RVNA titers (>=0.5 IU/mL) up to day 365. The incidence of side effects was minimal and self limiting. Hence it can be concluded that indigenously manufactured PDEV (Vaxirab) is a safe and immunogenic vaccine and can safely be used for post-exposure prophylaxis.

Immunogenicity and safety study of Indirab: a Vero cell based chromatographically purified human rabies vaccine.

A chromatographically purified Vero cell rabies vaccine, Indirab manufactured by Bharat Biotech International Limited, Hyderabad, India was subjected to safety and immunogenicity studies by both intramuscular and intradermal routes of administration in parallel with a reference vaccine, Verorab. A Pre-exposure study was undertaken in 239 subjects by intramuscular (IM) route (Study I), Post-exposure study in 188 patients by intramuscular route (Study II) and Simulated post-exposure study in 134 subjects by intradermal (ID) route (Study III). All subjects in these studies were administered with either the test or the reference vaccine as per WHO approved intramuscular and intradermal regimens. The blood samples were collected on days 0, 14 and 35 in case of Study 1, and days 0, 14, 28 and 90 in case of studies II and III. In all studies both vaccine groups had adequate antibody titers (>0.5 IU/mL) on all days tested post-vaccination and there was no significant difference in the titers observed (p>0.05). Some side effects like pain, induration, itching and fever were noted in both vaccine groups in all studies. Both vaccines were well tolerated. Hence it can be concluded that Indirab is as safe and immunogenic as Verorab when administered by both intramuscular and intradermal routes.

A comparative study on the safety and immunogenicity of Purified duck embryo vaccine [corrected] (PDEV, Vaxirab) with purified chick embryo cell vaccine (PCEC, Rabipur) and purifed vero cell rabies vaccine (PVRV, Verorab).

Rabies is a fatal but preventable disease. Cell culture vaccines (CCV) and purified duck embryo vaccines (PDEV) are currently recommended by WHO for post-exposure prophylaxis. In India, a PDEV (Vaxirab) is being manufactured and is in use since 2003. In the present study, we have evaluated the safety, immunogenicity and tolerance of this vaccine with two other WHO approved CCVs, viz., purified chick embryo cell vaccine (PCEC, Rabipur) and purified vero cell rabies vaccine (PVRV, Veroroab). This study was an open label, randomized phase IV comparative clinical trial. A total of 152 people bitten by dogs and other animals were recruited from 4 different centres from India. They were randomly assigned to receive one of the vaccines by Essen intramuscular regimen (52 subjects received Vaxirab and 50 each Rabipur and Verorab) and rabies immunoglobulin was also administered in all category III exposures. Their blood samples were collected on day 0 (prior to vaccination), 14, 28, 90 and 180. Side effects if any were monitored. The rabies neutralizing antibody titers in their blood samples were estimated by the rapid fluorescent focus inhibition test (RFFIT). Subjects in all three groups had neutralizing antibody titers by day 14 (>0.5 IU/mL) and geometric mean titers (GMT) observed for different vaccines on all days tested did not vary significantly (p>0.5). Side effects observed were minimal and did not vary significantly among the groups. The results of the present study indicate that PDEV (Vaxirab) is as safe, tolerable and immunogenic as both PCEC (Rabipur) and PVRV (Verorab). Thus this vaccine can be a good alternative to WHO approved CCVs for rabies post-exposure prophylaxis.

Rabies awareness in eight Asian countries.

Rabies is a deadly zoonotic disease most often transmitted to humans through a dog bite. Human mortality from endemic canine rabies is estimated by WHO to be around 55,000 deaths annually, with over 31,000 deaths in Asia alone, mostly children. Most of these deaths could be prevented through post-exposure prophylaxis (PEP), including immediate wound washing, rabies immunoglobulin administration and vaccination. Unfortunately, at-risk populations are not well-informed of the risk of rabies and what to do in the event of an animal bite. In order to identify the main gaps in rabies information and better define the most urgent information actions to be undertaken, the Asian Rabies Expert Bureau (AREB) conducted a multicentre, multi-country survey of patients seeking rabies post-exposure prophylaxis in rabies prevention centres from 1 July 2007 to 31 January 2008, in Bangladesh, China, India, Indonesia, Pakistan, the Philippines, Sri Lanka, and Thailand. Questionnaires were completed for 4377 subjects in the eight countries. Data was collected regarding the patient, former rabies exposures, the present wound, rabies exposure management, and rabies awareness. Two major issues were identified where active information of the population could make a difference: the necessity to apply appropriate wound care and to consult the nearest rabies prevention centre as soon as possible.

A comparative study on the immunogenicity, safety and tolerance of purified duck embryo vaccine (PDEV) manufactured in India (Vaxirab) and Switzerland (Lyssavac-N): a randomized simulated post-exposure study in healthy volunteers.

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.

The real cost of rabies post-exposure treatments.

The total costs to all payers, i.e., a societal perspective, of four rabies post-exposure regimens were evaluated in two dog bite centres and four local health centres in India. Results showed that the Thai Red Cross intra-dermal regimen (TRC-ID), which uses only one-fifth of the IM dose of purified vero cell vaccine (PVRV) was at most 20% more expensive than use of Purified Chick Embryo Cell (PCEC) vaccine at one-tenth of the IM dose: this cost difference needs to be balanced with the small margin of safety of low potency doses. In local health centres where the staffs are not specially trained in rabies vaccination, the Zagreb intra-muscular regimen is an economical option.