Comparison of a Novel Human Rabies Monoclonal Antibody to Human Rabies Immunoglobulin for Postexposure Prophylaxis: A Phase 2/3, Randomized, Single-Blind, Noninferiority, Controlled Study.

Background: Lack of access to rabies immunoglobulin (RIG) contributes to high rabies mortality. A recombinant human monoclonal antibody (SII RMAb) was tested in a postexposure prophylaxis (PEP) regimen in comparison with a human RIG (HRIG)-containing PEP regimen. Methods: This was a phase 2/3, randomized, single-blind, noninferiority study conducted in 200 participants with World Health Organization category III suspected rabies exposures. Participants received either SII RMAb or HRIG (1:1 ratio) in wounds and, if required, intramuscularly on day 0, along with 5 doses of rabies vaccine intramuscualarly on days 0, 3, 7, 14 and 28. The primary endpoint was the ratio of the day 14 geometric mean concentration (GMC) of rabies virus neutralizing activity (RVNA) as measured by rapid fluorescent focus inhibition test for SII RMAb recipients relative to HRIG recipients. Results: One hundred ninety-nine participants received SII RMAb (n = 101) or HRIG (n = 98) and at least 1 dose of vaccine. The day 14 GMC ratio of RVNA for the SII RMAb group relative to the HRIG group was 4.23 (96.9018% confidence interval [CI], 2.59-6.94) with a GMC of of 24.90 IU/mL (95% CI, 18.94-32.74) for SII RMAb recipients and 5.88 IU/mL (95% CI, 4.11-8.41) for HRIG recipients. The majority of local injection site and systemic adverse reactions reported from both groups were mild to moderate in severity. Conclusions: A PEP regimen containing SII RMAb was safe and demonstrated noninferiority to HRIG PEP in RVNA production. The novel monoclonal potentially offers a safe and potent alternative for the passive component of PEP and could significantly improve the management of bites from suspected rabid animals. Clincical Trials Registration: CTRI/2012/05/002709.

A randomized non-inferiority clinical study to assess post-exposure prophylaxis by a new purified vero cell rabies vaccine (Rabivax-S) administered by intramuscular and intradermal routes.

BACKGROUND: Rabies is a 100% fatal disease but preventable with vaccines and immunoglobulins. We have developed a new purified vero cell rabies vaccine (Rabivax-S) and evaluated its safety and immunogenicity in post-exposure prophylaxis by intramuscular (IM) and intradermal (ID) routes. METHODS: This was a randomized active-controlled non-inferiority study in 180 individuals (age 5years and above) with suspected rabies exposure (90 each with WHO Category II and Category III exposures). The participants received either Rabivax-S (1mL IM; five doses), Rabivax-S (0.1mL ID; eight doses) or purified chick embryo cell vaccine (PCEC, Rabipur®) (1mL IM; five doses). The IM doses were given on Day 0, 3, 7, 14 and 28 while the ID doses were given on days 0, 3, 7 and 28. Category III patients also received a human rabies immunoglobulin (HRIG) on Day 0. Adverse events (AEs) were recorded with diary cards till day 42. Rabies neutralizing antibody levels were measured on day 0, 7, 14, 28 and 42. RESULTS: In both the category II and III patients, the geometric mean concentration (GMC) ratios of Rabivax-S IM and Rabivax-S ID groups to PCEC IM were more than 1, thus proving the non-inferiority. GMCs were similar or higher in Rabivax-S groups at all the time points. Seroresponse against rabies (RFFIT titre⩾0.5IU/mL) was achieved in all participants. Mostly mild local and systemic adverse events were reported across the three groups and all resolved without sequelae. CONCLUSIONS: Rabivax-S was well tolerated and showed immunogenicity comparable to a licensed rabies vaccine by both IM and ID routes in post-exposure prophylaxis. Registry No.: CTRI/2012/11/003135.

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen).

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.

An immunogenicity, safety and post-marketing surveillance of a novel adsorbed human diploid cell rabies vaccine (Rabivax) in Indian subjects.

In 1999, Serum Institute of India indigenously developed an adsorbed human diploid cell rabies vaccine (Rabivax). During 2000-04, this new vaccine was subjected to a series of immunogenecity and safety studies. Initially, an experimental batch of Rabivax (adsorbed) was assessed on ten healthy adult volunteers and its response was comparable with that of Merieux inactivated rabies vaccine (MIRV, lyophilized) which was used as a control. Subsequently, Rabivax (adsorbed) was assessed on forty-five suspect rabid dog bite cases with MIRV as control. The vaccine was found to be equally safe and immunogenic as MIRV and showed better rabies virus neutralizing antibody (RVNA) response on day 90 than MIRV. A post-licensing study conducted on 150 cases of suspect rabid animal bites showed it to be safe and immunogenic. To assess its long-term sero-efficacy some of these subjects tested after one year of follow up showed that 84% of them had adequate RVNA titers. In addition, a routine post-marketing surveillance done on 1608 animal bite cases demonstrated that Rabivax (adsorbed) was safe and efficacious. The adverse events to Rabivax (adsorbed) included pain at injection site (3.4%), swelling with induration (2.8%), fever and headache (1.4%). No serious adverse event was reported from the studies. In conclusion, Rabivax (adsorbed) is an immunogenic, safe and efficacious vaccine for rabies prophylaxis in humans.

Assessing the safety of post-exposure rabies immunization in pregnancy.

Fourteen pregnant women who received rabies post-exposure prophylaxis (PEP) at the anti-rabies clinic (ARC) of Kempegowda Institute of Medical Sciences (KIMS) were followed up for assessing the safety of modern rabies vaccines and equine rabies immunoglobulin (ERIG) in pregnancy. The women were in the age range of 18-28 years, mostly from urban area (64%) and exposed to suspect rabid dogs (86%). They had received purified vero cell rabies vaccine (Verorab = 8 and Abhayrab = 4), purified chick embryo cell vaccine (Rabipur = 2) by Essen regimen; and equine rabies immunoglobulin (Equirab = 7 and Pasteur anti-rabies serum = 1). None of the pregnant women reported any adverse events to either vaccine or equine rabies immunoglobulin. All had safe vaginal deliveries and in all cases both the mother and the child were found to be healthy and normal.

Assessing the burden of human rabies in India: results of a national multi-center epidemiological survey.

OBJECTIVE: Human rabies has been endemic in India since time immemorial, and the true incidence of the disease and nationwide epidemiological factors have never been studied. The main objectives of the present study were to estimate the annual incidence of human rabies in India based on a community survey and to describe its salient epidemiological features. METHODS: The Association for Prevention and Control of Rabies in India (APCRI) conducted a national multi-center survey with the help of 21 medical schools during the period February-August 2003. This community-based survey covered a representative population of 10.8 million in mainland India. Hospital-based data were also obtained from the 22 infectious diseases hospitals. A separate survey of the islands of Andaman, Nicobar, and Lakshadweep, reported to be free from rabies, was also undertaken. RESULTS: The annual incidence of human rabies was estimated to be 17,137 (95% CI 14,109-20,165). Based on expert group advice, an additional 20% was added to this to include paralytic/atypical forms of rabies, providing an estimate of 20,565 or about 2 per 100000 population. The majority of the victims were male, adult, from rural areas, and unvaccinated. The main animals responsible for bites were dogs (96.2%), most of which were stray. The most common bite sites were the extremities. The disease incubation period ranged from two weeks to six months. Hydrophobia was the predominant clinical feature. Many of the victims had resorted to indigenous forms of treatment following animal bite, and only about half of them had sought hospital attention. Approximately 10% of these patients had taken a partial course of either Semple or a cell culture vaccine. The islands of Andaman, Nicobar, and Lakshadweep were found to be free of rabies. CONCLUSION: Human rabies continues to be endemic in India except for the islands of Andaman, Nicobar, and Lakshadweep. Dogs continue to be the principal reservoir. The disease is taking its toll on adult men and children, the majority from rural areas, due to lack of awareness about proper post-exposure immunization. The keys to success in the further reduction of rabies in India lies in improved coverage with modern rabies vaccines, canine rabies control, and intensifying public education about the disease.

Evaluation of a new premedication protocol for administration of equine rabies immunoglobulin in patients with hypersensitivity.

OBJECTIVES: The present study was undertaken to standardize skin testing and to develop a safe and effective premedication protocol for administration of ERIG in those with skin test positivity/hypersensitivity. METHODS: A method of grading of skin testing was developed using injection histamine as a positive control. This was evaluated by using it on 517 subjects who had severe (WHO category III) exposure to rabies. A premedication protocol consisting of injections pheniramine, ranitidine, hydrocortisone and adrenaline was evaluated by using it on fifty one subjects who were skin test positive/hypersensitive to ERIG. RESULTS: The premedication protocol was safe and effective as all the S1 subjects could be administered the full dose of ERIG despite being skin test positive/hypersensitive to ERIG. Besides the premedication drugs/protocol did not affect the immune response to vaccine and ERIG therapy.

An assessment of rabies free status of the Island of Andaman, Nicobar and Lakshadweep: results of the WHO sponsored national multicentric rabies survey.

The Islands of Andaman and Nicobar and Lakshadweep have been reported to be rabies free from time immemorial. Recently, a survey of the islands of Andaman and Nicobar & Lakshadweep was done between July and August 2003 to assess their rabies free status. It was revealed that these islands continue to remain rabies free. However, in Andamans the increasing dog population, poor vigil on import of dogs and lack of laboratory surveillance for rabies posed a threat to this status. The Lakshadweep islands, which are free of dogs, however, faced a threat from the lack of vigil on the entry and presence of cats and poor surveillance for rabies in them.

Boosting effect of purified chick embryo cell rabies vaccine using the intradermal route in persons previously immunized by the intramuscular route or vice versa.

BACKGROUND: At present, in the event of re-exposure to rabies, 2 booster doses are recommended for people who have been previously vaccinated with cell culture rabies vaccines by the conventional intramuscular route. As the intradermal route of vaccination is likely to be introduced in the future, we investigated the immune response to a cell culture rabies vaccine after crossing over from the intramuscular to the intradermal route and vice versa. METHODS: Twenty healthy adult volunteers who had received a primary course of rabies vaccination with purified chick embryo cell rabies vaccine by either the intramuscular (n = 10) or intradermal (n = 10) route received booster vaccination with the same vaccine by the alternative route. The regimen used was 0.1 ml of vaccine by the intradermal route at two sites (deltoid area) for the intramuscular group, or 1 ml of vaccine by the intramuscular route (deltoid muscle) to the intradermal group on days 0 and 3. RESULTS: There was a 15-fold rise in the rabies virus neutralizing antibody response both by the intradermal and intramuscular routes of booster vaccination (p < 0.0001). Thus, the change of route of purified chick embryo cell booster vaccination did not alter the anamnestic immune response to the vaccine. No side-effects were observed after vaccination with either of the routes. CONCLUSION: Purified chick embryo cell vaccine was found to be safe and immunologically efficacious following booster vaccination after cross-over from the intradermal to the intramuscular route and vice versa.

An epidemiological study of animal bites in India: results of a WHO sponsored national multi-centric rabies survey.

This was a WHO sponsored national multi-centric rabies survey and one of its objectives was to find out the incidence of animal bites, anti-rabies treatment practices, Pet dog population and their care. Twenty-one medical colleges chosen with geoscatter representation conducted the survey during February-August, 2003. The survey was conducted in 18 states, covering a population of 52,731 chosen randomly from 8500 households. The annual incidence of animal bites was high, 1.7% and it was more in rural areas (1.8%), children (2.6%) and poor/low income group (75%). The main biting animal was dog (91.5%), mostly stray (63%), followed by cat (4.7%). A high proportion of bite victims did not wash their wounds with soap and water (39.5%), preferred Government hospitals (59.9%) and nerve tissue vaccine (46.9%). The use of rabies immunoglobulin was low (2.1%). A single animal bite episode led to a loss of 2.2 man-days and the cost of medicines including anti-rabies vaccine was Rs.252 (US$6). The recourse to indigenous treatment (45.3%) and local application to wound (36.8%/) was quite prevalent. About 17% of households reported having a pet/domesticated dog and the pet dog: man ratio was 1: 36. Pet dog care/management practices were not satisfactory with a low veterinary consultation (35.5%) and vaccination (32.9%). The situation was slightly better in urban areas. The people also reported the presence (83%) and menace (22.8%) of stray dogs. It is recommended to initiate appropriate community awareness and dog vaccination campaigns and effective stray dog control measures.

Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines. Results of a meta-analysis.

A meta-analysis was done to study the relationship between antigenecity and immunogenecity of human rabies vaccines. The data of ten cell culture human rabies vaccine studies conducted at a single centre during 1993-2004 were used in the study. The vaccines studied included Purified Chick Embryo Cell Vaccine (Kaketsuken, Japan and Rabipur, India), Purified Vero cell Rabies Vaccine (Verorab, France), Human Diploid Cell Vaccine (MIRV, France and Rabivax, Adsorbed and Lyophilized, India) and Rhesus Diploid Rabies Vaccine (adsorbed, USA). Interestingly, it was revealed that an higher antigenecity of rabies vaccines viz. potency of > or = 5 IU per single intramuscular dose did not result in significantly higher immunogenecity, as measured by rabies virus neutralizing antibody (RVNA) titers in the vaccinees, both on day 14 (t = 0.42, p > 0.66, GMR = 1.06, 95% CI of GMR = 0.82, 1.37) and day 90 (t = 0.80, p > 0.43, GMR = 1.15, 95% CI of GMR = 0.74, 1.14). However, as there are no reports of meta-analysis of cell culture human rabies vaccine trials, to confirm this observation the authors recommend further studies in this regard.

Evaluation of a new five-injection, two-site,intradermal schedule for purified chick embryo cell rabies vaccine: A randomized, open-label, active-controlled trial in healthy adult volunteers in India.

BACKGROUND: Human rabies is an ongoing significant public health problem inmany developing countries, with India reporting the highest incidence of rabies-related deaths (∼20,000 per year). Many people living in India cannot afford the standard IM postexposure prophylaxis (PEP) with cell-culture vaccines, which are administered using a 5-dose regimen developed in Essen, Germany. A potentially less expensive intradermal (ID) regimen, based on the Essen regimen, has been developed at the Kempegowda Institute of Medical Sciences (KIMS), Bangalore, India. OBJECTIVE: The objective of this study was to compare the immunogenicity and local and systemic tolerability of the KIMS-1D regimen with those of the standard Essen IM regimen in healthy adult volunteers in India. METHODS: This randomized, open-label, active-controlled trial was conductedat the Antirabies Clinic, Medical College, KIMS. Healthy adult volunteers were randomly assigned to receive purified chick embryo cell vaccine (PCECV) using the KIMS-1D regimen (0.1 mL injected ID at 2 body sites on days 0, 3, 7, 14, and 28 ["2-2-2-2-2"]) or the Essen IM regimen (1 mL injected IM at 1 body site on the same days Subjects were followed up for 365 days by the treating physician and encouraged to voluntarily report any adverse events (AEs). Serum rabies virus-neutralizing antibody (RVNA) concentrations were measured before the first injection on day 0 (baseline) and on days 14, 28, 90, 180, and 365, using the rapid fluorescent focus inhibition test. RESULTS: Ninety-one subjects were enrolled and included in the tolerabilityand immunogenicity analyses. The ID group comprised 45 subjects (26 men, 19 women; mean [SD] age, 20.84 [1.48] years); the IM group, 46 subjects (28 men, 18 women; mean [SD] age, 21.02 [1.16] years). The most common local AEs were pain at the injection site (2/225 [0.9%] in the ID group and 10/230 [4.3%] in the IM group; P < 0.006) and itching at the injection site (5/225 [2.2%] in the ID group and none in the IM group; P = 0.026). All of the AEs were transient and resolved without the need for medication. All subjects had serum RVNA concentrations ≥0.5 IU/mL-considered protective by the World Health Organization-at all follow-up visits. However, the mean RVNA concentrations in the IM group were significantly higher compared with those in the ID group from days 14 to 365 (all, P < 0.001). CONCLUSION: In this study in healthy volunteers, PEP with PCECV administered using the KIMS-ID regimen was well tolerated and immunologically efficacious for 365 days. Adequate RVNA levels were maintained with the KIMS-ID regimen from days 14 to 365, although these levels were significantly lower than those achieved in the group receiving the Essen IM regimen (all, P < 0.001).

Simulated post-exposure rabies vaccination with purified chick embryo cell vaccine using a modified Thai Red Cross regimen.

OBJECTIVES: Currently, two intradermal regimens for the administration of cell culture rabies vaccines are approved by the WHO for rabies post-exposure prophylaxis: the two site Thai Red Cross regimen (TRC) and the eight site regimen. For the TRC regimen the volume of vaccine recommended per dose is 0.1 ml of purified Vero cell rabies vaccine (PVRV) and 0.2 ml of purified chick embryo cell vaccine (PCEC). The objective of the present study was to evaluate comparatively the immune response to PCEC and PVRV vaccines administered by the TRC regimen using a uniform dose of 0.1 ml of vaccine. METHODS: Forty-two subjects received TRC regimen (2-2-2-0-1-1) with 0.1 ml of PCEC vaccine and 38 subjects received the same regimen with PVRV. The rabies neutralizing antibody response in these subjects on days 10, 28, 90 and 180 was determined by the standard mouse neutralization test (MNT). RESULTS: There was adequate antibody response with both the vaccines and 100% seroconversion was observed by day 10. Furthermore, the antibody titers obtained with PCEC did not differ significantly from those obtained with PVRV on all days tested (p > 0.05). CONCLUSIONS: It can be concluded from the results that an adequate antibody response can be obtained with PCEC vaccine when administered by the TRC regimen even after reducing the quantity of vaccine from 0.2 ml to 0.1 ml per intradermal dose. The feasibility of using this regimen in true post-exposure cases needs to be further evaluated.

A community survey of dog bites, anti-rabies treatment, rabies and dog population management in Bangalore city.

This survey was conducted by using a 30 cluster random sampling technique to comprehensively study the nature and magnitude of rabies and its related problems in human and dog population. The city has an estimated dog population of 3.25 lakhs of which 2 lakhs (61.5%) are stray dogs and 1.25 lakhs (38.5%) are pet dogs. The dog:man ratio was about 1:12 and the pet:stray dog ratio of 1:2. The awareness about Animal Birth Control (ABC) programme was low (34%) and only 20% had faith in it. The annual incidence of dog bites was 1.9% persons. It was more in males (64%) and mostly from stray dogs (64%). About 86% of them received anti-rabies vaccination and none received life saving Anti-Rabies Serum (ARS). The annual incidence of human rabies was 15 and dog rabies 58 resulting in a ratio of 1:4 approximately as a rabies contagion index. The implementation of ABC programme was weak (10.4% coverage) and is recommended for acceleration and improvement. Similarly modern anti-rabies immunization, including anti-rabic serum, shall replace the outdated sample (sheep brain) vaccine.

Post-exposure prophylaxis with purified vero cell rabies vaccine during pregnancy--safety and immunogenicity.

This study was conducted with the main objective of determining the safety and immunogenicity of purified vero cell rabies vaccine (PVRV) during pregnancy. Twenty nine pregnant women exposed to rabies were vaccinated with PVRV as per the Essen regimen advocated by World Health Organization. None of the women experienced any adverse side effects to the vaccine. The intrauterine growth and development monitored by ultrasound examination was found to be normal and the outcome of pregnancy was satisfactory. There were no congenital anomalies in any of the infants born and they were healthy and had normal growth and development during the one year follow-up period. The rabies neutralizing antibody titers from day 14 to day 365 following vaccination in these women was adequate and well above the minimum protective level of 0.5 iu/ml of serum. Protective levels of antibodies were also present in serum of some of the babies tested, for up to 3 months of age. The mothers and infants followed for one year period were doing well at the end of the study period. Consequently, PVRV was found safe and immunogenically efficacious during pregnancy.

Post exposure rabies prophylaxis with Purified Verocell Rabies Vaccine: a study of immunoresponse in pregnant women and their matched controls.

The present controlled clinical trial evaluates the immunoresponse to Purified Verocell Rabies Vaccnine (PVRV) by Essen schedule of vaccination during Pregnancy. Seventeen Pregnant women with history of animal bites who received PVRV as per Essen regimen were matched for the confounding variables of age, socio-economic status and doses of PVRV received with seventeen "Non-pregnant women". The mean age was about 24 years, majority (70.6%) belonging to middle socio-economic group and received 3 doses of PVRV. Contrary to the expectations the rabies neutralizing antibody titres were slightly higher in pregnant women (except day 180) but the difference was not significant (P > 0.2). Both the groups of women had antibody titres above protective level (0.5 IU/ml) from day 14 till day 365 thus indicating immunogenic efficacy of PVRV by Essen regimen during Pregnancy.