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1.  Evaluation of a one week intradermal regimen for rabies post-exposure prophylaxis: Results of a randomized, open label, active-controlled trial in healthy adult volunteers in India 
Human Vaccines & Immunotherapeutics  2012;8(8):1077-1081.
The currently recommended intradermal regimen for post-exposure prophylaxis spreads over a month period which many times lead to low compliance from the patients. There is a need to introduce and evaluate short course regimens to overcome this problem. This study was conducted to evaluate the immunogenicity and safety of a “new one week intradermal regimen” for rabies post-exposure prophylaxis. A total of 80 healthy adult volunteers were enrolled and allocated randomly either to purified chick embryo cell (PCECV) rabies vaccine or purified verocell rabies vaccine (PVRV), 40 in each group. Each subject received intradermally one of the vaccines, using the one week regimen (4–4-4). Blood samples were collected on Days 0, 7, 14, 28,180 and 365 for estimation of rabies virus neutralizing antibody (RVNA) concentration. The sera samples were analyzed by rapid fluorescent focus inhibition test (RFFIT). All subjects in both the groups had adequate RVNA concentration of ≥ 0.5 IU/mL from day 14 to till day 180 and the difference of geometric mean concentrations between the two groups was not significant (p > 0.606). Further to assess the immunological memory produced by this new regimen, a “single visit four site” intradermal booster vaccination was given to those who did not have adequate RVNA concentration on day 365. This resulted in a quick and enhanced RVNA concentration in these subjects thus denoting a successful anamnestic response. The incidence of adverse events was 8.3% in PCECV group and 1.6% in PVRV group (p = 0.001) and the regimen was well tolerated without any dropouts. In conclusion, the new “one week intradermal regimen” is immunogenic and safe for rabies post-exposure prophylaxis and needs to be further evaluated in persons exposed to rabies.
doi:10.4161/hv.20471
PMCID: PMC3551879  PMID: 22699446
rabies; purified chick embryo cell rabies vaccine; purified vero cell rabies vaccine; randomized controlled trial; intradermal rabies vaccination
2.  Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines when administered by intradermal route 
Human Vaccines  2010;6(7):562-565.
The metadata of 10 published studies and 3 vaccine trial reports comprising of 19 vaccine cohorts from four countries conducted over a period of 23 years (1986–2009) was used for metaanalysis. The vaccines studied were purified chick embryo cell vaccine (Rabipur, India and Germany), purified vero cell rabies vaccine (Verorab, France; Indirab, India) and human diploid cell vaccine (MIRV, France). The potency of these vaccines varied from 0.55 IU to 2.32 IU per intradermal dose of 0.1 ml per site. The vaccines were administered to 1,011 subjects comprising of 19 cohorts and using five different ID regimens. The immunogenicity was measured by assays of rabies virus neutralizing antibody (RVNA) titres using rapid fluorescent focus inhibition test (RFFIT) [15 cohorts] and mouse neutralization test (MNT) [4 cohorts]. The statistical analysis of the data was done by Karl Pearson's correlation coefficient to measure the relationship between antigenicity and immunogenicity. It was revealed that, there was no significant linear relationship between antigenicity and immunogenicity of rabies vaccines when administered by intradermal route (p > 0.230 and p > 0.568).
doi:10.4161/hv.6.7.11934
PMCID: PMC3322518  PMID: 20523131
rabies vaccines; intradermal route; antigenicity; immunogenicity; metaanalysis
3.  Evaluation of a human diploid cell strain rabies vaccine: final report of a three year study of pre-exposure immunization. 
The Journal of Hygiene  1982;89(1):101-110.
The antibody responses of 194 volunteers were studied for up to 3 years after primary immunization with one, two or three doses of human diploid cell rabies vaccine, administered either in 0.1 ml volumes intradermally (i.d.) or as 1.0 ml intramuscularly (i.m.). Sero-conversion occurred in 95% of subjects after the first injection and in 100% after the second. The highest titres and most durable antibody responses were induced by three injections of vaccine. Booster doses were administered either by the subcutaneous (s.c.) or i.d. route, after 6, 12 or 24 months to randomly grouped volunteers; these induced responses greater than or equal to 5.0 i.u. per ml in 95% of subjects. The responses were rapid and were neither influenced by the primary regimen nor by the timing and route of the booster dose. Antibody titres after i.d. immunization were only two-fold lower than those induced by the larger volume of vaccine. The findings suggest that the i.d. route is both effective and economic.
PMCID: PMC2134158  PMID: 7096998
4.  Prophylactic immunization of humans against rabies by intradermal inoculation of human diploid cell culture vaccine. 
The antirabies human diploid cell vaccine produced by 1'Institute Merieux, Lyon, France, was administered intradermally to 35 high-risk volunteers using 0.2-ml amounts and various immunization schedules. Three groups never before vaccinated against rabies developed virus-neutralizing antibodies, the titer of which was dose dependent. A single injection stimulated the formation of antibodies. Four inoculations induced the highest antibody levels and the longest persistence of antibody. The administration of a single intradermal booster inoculation was sufficient, even in the case of low-persisting antibody, to elicit a rapid increase of antibodies to high levels. A primary inoculation course of two injections induced a sufficient antibody level which, in case of exposure, could apparently be rapidly elevated by a 0.2-ml intradermal booster inoculation. Adverse side reactions were observed in 7 of 14 individuals after a 1- or 1.5-year intradermal booster inoculation. We therefore suggest that the intramuscular and subcutaneous routes continue to be used for primary vaccinations and that the highly effective intradermal route be restricted to booster inoculations. This is the first long term study of this vaccine and should be a guideline for the pre-exposure treatment of high-risk personnel.
PMCID: PMC274241  PMID: 1254722
5.  Persistence of rabies antibody 5 years after pre-exposure prophylaxis with human diploid cell antirabies vaccine and antibody response to a single booster dose. 
Epidemiology and Infection  1987;99(1):91-95.
In 1978, 22 staff members of the National Institute of Virology, Pune, India, were given two doses of human diploid cell antirabies vaccine (HDCV) for primary pre-exposure prophylactic immunization; the interval between the two doses being approximately 4 weeks. Eighteen of these 22 vaccinees were given a booster dose 1 year later. All 18 vaccinees developed protective levels of antibody; most of them had antibody levels exceeding 10 IU/ml. In 1984, 5 years after the booster dose, 11 (79.0%) of 14 vaccinees tested still possessed neutralizing antibody levels ranging from 0.5 IU/ml to 10 IU/ml. Fourteen days after the administration of a booster dose, the antibody levels ranged from 10 to greater than or equal to 100 IU/ml for all except one vaccine (5.2 IU/ml). These findings demonstrate that the majority of vaccines retained detectable neutralizing antibody after pre-exposure prophylaxis for as long as 5 years and that a single booster dose thereafter evoked a good antibody response.
PMCID: PMC2249170  PMID: 3609177
6.  Persistence of Rabies Antibody 5 Years after Postexposure Prophylaxis with Vero Cell Antirabies Vaccine and Antibody Response to a Single Booster Dose▿ 
This study was done to investigate the antibody response to a Vero cell antirabies vaccine, the persistence of antibody for 5 years, and the effect of a booster dose after this interval. From August 2005 to February 2011, a total of 195 patients were enrolled into our study due to an animal bite. The Essen intramuscular (i.m.) regimen, which is recommended by the WHO for modern vaccines used in postexposure treatment, was adopted in this study. Blood samples were obtained on day 0, day 7, day 14, day 45, year 1, year 2, year 3, year 4, year 5, and year 5 plus 14 days. Immunogenicity was evaluated by the titration of neutralizing antibodies with a rapid fluorescent focus inhibition test (RFFIT). Seroconversion was expressed as the seroconversion rate (SCR). A secondary quantitative evaluation criterion, other than the seroconversion level, was the geometric mean titer (GMT). Of the 195 enrolled patients, 168 (86.4%) of them completed the whole study. No serious adverse reactions to the vaccine were reported during vaccination, the 5-year follow-up period, or revaccination. On day 14, the rabies antibody GMT value was 8.87 IU/ml in the vaccinees. During the next 5 years, the SCR in the ChengDa vaccine group gradually decreased to 34.0% at year 5, down from 90.5% at year 1. There was a significant booster effect: the GMT was 15.22 IU/ml on year 5 plus 14 days. Our findings demonstrate that the ChengDa rabies vaccine offers an alternative with a high degree of efficacy and yet limited side effects and ensures that the exposed patient will be on the safe side of the risk of rabies by the 14th day. Moreover, when followed by a booster dose 5 years later, it could boost the immunity. A further booster is effective in inducing a good neutralizing antibody response even after an interval of 5 years.
doi:10.1128/CVI.05090-11
PMCID: PMC3165231  PMID: 21752947
7.  A comparison of the tolerability of two dilution volumes (0.5 mL and 1.0 mL) of a purified chick embryo cell rabies vaccine administered intramuscularly to healthy adult volunteers: A randomized, intraindividual, assessor-blind study 
Background: The current recommendation of the manufacturer for administering purified chick embryo cell rabies vaccine (PCECV) is to reconstitute the contents with 1.0 mL of water for injection (WFI). However, it has been debated whether a lower volume of WFI (0.5 mL) is likely to cause less pain.
Objectives: The aims of this study were to compare the tolerability of PCECV administered IM at a volume of 0.5 mL versus 1.0 mL of diluent and to determine the immunogenicity of the vaccine when administered according to the World Health Organization-recommended preexposure prophylaxis regimen for rabies immunization.
Methods: This comparative, intraindividual, assessor-blind study was conducted at the Department of Clinical Pharmacology, Topiwala National Medical College and Bai Yamunabai Laxman Nair Charitable Hospital Mumbai, India). Healthy volunteers aged 18 to 50 years received, by randomized sequence, 3 IM injections of PCECV, diluted in 0.5 mL or 1.0 mL of WFI, on study days 0, 7, and 28. Tolerability was assessed at 30 minutes and 24 hours after injection and included assessments for local and systemic reactions. For immunogenicity assessment, rabies virus-neutralizing antibody 0RVNA) titers were assayed at baseline and on day 49 (ie, 3 weeks after the third injection).
Results: Twenty-six subjects (24 men, 2 women; mean [SD] age, 22.4 [2.4] years; mean [SD] body weight, 59.0 [11.3] kg) entered the study. Twenty-five subjects were included in the tolerability assessment; 24 in the immunogenicity assessment. No statistically significant differences were found between dilutions in the frequency of local and systemic reactions. Most reactions were mild. All subjects developed RVNA titers >0.5 IU/mL (indicative of protection) by day 49.
Conclusions: In this population of healthy volunteers, a full antigenic dose of PCECV in a dilution of 0.5 mL WFI is as well tolerated locally and systemically as in a dilution of 1.0 mL. All subjects developed levels of RVNA far exceeding 0.5 IU/mL, which is indicative of protection against rabies.
doi:10.1016/S0011-393X(04)90004-5
PMCID: PMC4052956  PMID: 24936103
rabies vaccine; purified chick embryo cell rabies vaccine; tolerability; volunteer; immunogenicity
8.  Rabies Antibody Titres in Vaccinated Dogs 
The Canadian Veterinary Journal  1984;25(10):383-385.
In a field study, rabies virus neutralizing antibody titres were determined by the microtest modification of the rapid fluorescent focus inhibition test before and after primary vaccination in 30 puppies, and before and after booster vaccination in 59 previously vaccinated dogs. A commercial modified live virus vaccine was used. Three weeks after primary vaccination the mean antibody titre was 102 ± 90, but only 24 dogs presented for booster vaccination had detectable antibody levels (mean titre 12 ± 16). The antibody responses three weeks after booster vaccination (mean 380 ± 216) were significantly greater than the responses to primary vaccination. It was concluded that previously vaccinated dogs could have an anamnestic response to booster vaccination, even when antibodies were not detected in their sera before revaccination.
PMCID: PMC1790664  PMID: 17422460
Rabies; rabies vaccine; vaccination; dogs
9.  Sickness and recovery of dogs challenged with a street rabies virus after vaccination with a vaccinia virus recombinant expressing rabies virus N protein. 
Journal of Virology  1992;66(5):2601-2604.
Dogs were vaccinated intradermally with vaccinia virus recombinants expressing the rabies virus glycoprotein (G protein) or nucleoprotein (N protein) or a combination of both proteins. The dogs vaccinated with either the G or G plus N proteins developed virus-neutralizing antibody titers, whereas those vaccinated with only the N protein did not. All dogs were then challenged with a lethal dose of a street rabies virus, which killed all control dogs. Dogs vaccinated with the G or G plus N proteins were protected. Five (71%) of seven dogs vaccinated with the N protein sickened, with incubation periods 3 to 7 days shorter than that of the control dogs; however, three (60%) of the five rabid dogs recovered without supportive treatment. Thus, five (71%) of seven vaccinated with the rabies N protein were protected against a street rabies challenge. Our data indicate that rabies virus N protein may be involved in reducing the incubation period in dogs primed with rabies virus N protein and then challenged with a street rabies virus and, of more importance, in subsequent sickness and recovery.
PMCID: PMC241012  PMID: 1560518
10.  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).
doi:10.1016/j.curtheres.2005.08.009
PMCID: PMC3964532  PMID: 24672132
rabies; intradermal rabies vaccination; KIMS-ID regimen; randomizedcontrolled trial
11.  Immunization Against Rabies 
The methods used for both pre-exposure and post-exposure immunization against rabies were studied. In pre-exposure immunization duck embryo vaccine should be used. In post-exposure immunization either duck embryo or Semple-type vaccine appears to be effective in stimulating antibody production. Both vaccines may cause neurological sequelae. A dose of vaccine should be given 20-50 days after completion of the primary course of vaccination. Immune serum should be used in all severe exposures especially of the head and neck, and in individuals in whom the commencement of vaccination has been unduly delayed. In individuals who have been previously vaccinated reinforcing doses have been found to be effective even as long as 20 years after the primary vaccination. A tissue culture vaccine has been developed and is about to undergo field trials.
PMCID: PMC1935942  PMID: 6066820
12.  Immune Response in Primates Vaccinated with Duck Embryo Cell Culture Rabies Vaccine 
Applied Microbiology  1973;25(3):327-331.
Adult rhesus monkeys (Macaca mulata) were vaccinated with four inactivated rabies vaccines, including two cell culture vaccines, one zonal purified cell culture vaccine, and a 10% extracted duck embryo vaccine. The vaccines were potency tested by both National Institutes of Health (NIH) and Habel methods and passed one or both tests. However, a vaccine having acceptable potency by one method frequently failed or was marginal by the other procedure. Groups of three monkeys were inoculated with each vaccine by one of two schedules. The first consisted of four weekly 1-ml doses followed by a 1-ml booster dose at 6 months, and the second consisted of seven daily 1-ml doses of vaccine with no booster. Both zonal purified and extracted duck embryo vaccines induced detectable neutralizing antibody by day 7 with either schedule, and antibody titers elicited by the cell culture vaccine remained high through 210 days. However, antibody titers produced by the 10% duck embryo vaccine dropped sharply after their 28-day peak. Duck embryo cell culture vaccines with low or marginal potency as measured by Habel or NIH tests still produced rapid, high levels of serum-neutralizing antibody in primates. LD50 or NIH and Habel tests as measured in mice were not necessarily good indices of antibody response in the primate host. The need for a cell culture potency test that will yield a more predictable correlation with the definitive host's antibody response is discussed.
PMCID: PMC380805  PMID: 4633422
13.  Pre-clinical toxicity & immunobiological evaluation of DNA rabies vaccine & combination rabies vaccine in rhesus monkeys (Macaca mulatta) 
The Indian Journal of Medical Research  2013;137(6):1072-1088.
Background & objectives:
Pre-clinical toxicology evaluation of biotechnology products is a challenge to the toxicologist. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed recombinant DNA anti-rabies vaccine [DRV (100 μg)] and combination rabies vaccine [CRV (100 μg DRV and 1.25 IU of cell culture-derived inactivated rabies virus vaccine)], which are intended for clinical use by intramuscular route in Rhesus monkeys.
Methods:
As per the regulatory requirements, the study was designed for acute (single dose - 14 days), sub-chronic (repeat dose - 28 days) and chronic (intended clinical dose - 120 days) toxicity tests using three dose levels, viz. therapeutic, average (2x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in monkeys. The selection of the model i.e. monkey was based on affinity and rapid higher antibody response during the efficacy studies. An attempt was made to evaluate all parameters which included physical, physiological, clinical, haematological and histopathological profiles of all target organs, as well as Tiers I, II, III immunotoxicity parameters.
Results:
In acute toxicity there was no mortality in spite of exposing the monkeys to 10XDRV. In sub chronic and chronic toxicity studies there were no abnormalities in physical, physiological, neurological, clinical parameters, after administration of test compound in intended and 10 times of clinical dosage schedule of DRV and CRV under the experimental conditions. Clinical chemistry, haematology, organ weights and histopathology studies were essentially unremarkable except the presence of residual DNA in femtogram level at site of injection in animal which received 10X DRV in chronic toxicity study. No Observational Adverse Effects Level (NOAEL) of DRV is 1000 ug/dose (10 times of therapeutic dose) if administered on 0, 4, 7, 14, 28th day.
Interpretation & conclusions:
The information generated by this study not only draws attention to the need for national and international regulatory agencies in formulating guidelines for pre-clinical safety evaluation of biotech products but also facilitates the development of biopharmaceuticals as safe potential therapeutic agents.
PMCID: PMC3734712  PMID: 23852288
Biotech products; combination rabies vaccine (CRV); DNA rabies vaccine (DRV); pre-clinical toxicology; PVRV; purified vero cell-derived inactivated rabies virus vaccine; safety evaluation; toxicology
14.  Comparison of rabies humoral antibody titers in rabbits and humans by indirect radioimmunoassay, rapid-fluorescent-focus-inhibition technique, and indirect fluorescent-antibody assay. 
Journal of Clinical Microbiology  1977;5(3):320-325.
Rabies humoral antibodies were induced in eight New Zealand rabbits by a single intramuscular injection of inactivated suckling mouse brain rabies vaccine. The primary response to immunization was measured in blood samples taken at selected intervals for 6 months. The anamnestic response was measured in blood samples obtained 2 weeks after the rabbits received a booster immunization. The humoral antibody concentrations were measured by the rapid-fluorescent-focus-inhibition technique (RFFIT), indirect fluorescent-antibody assay (IFA), and indirect radioimmunoassay (RIA). The maximal neutralizing antibody titers as measured by RFFIT were attained by the 4th week and persisted into the 24th week. After booster immunization the antibody response was almost 10-fold higher than the highest level attained in the primary response. The antibody levels as measured by IFA and RIA were similar, but the titers as measured by either procedure were almost 10-fold lower than those determined by RFFIT. After booster immunizations the antibody levels, as measured by IFA and RIA, were three- and sixfold higher, respectively, than the maximal levels attained in the primary response. Twenty-two human serum specimens were tested by the same serological procedures, with disparate results. Both RIA and RFFIT effectively differentiated antirabies-positive sera from antirabies-negative sera.
PMCID: PMC274589  PMID: 323278
15.  Protection of dogs against death from experimental rabies by postexposure administration of rabies vaccine and hyperimmune globulin (human). 
Two experiments on simulated postexposure treatment were carried out in dogs using human rabies immunoglobulin (RIGH) and human diploid cell vaccine for human use. In one experiment, when animals were challenged by injecting street virus into the masseter muscle and treated with a combination of RIGH and vaccine, 50% of the animals were protected from rabies. In the other trial, in which animals were challenged by injecting the virus into the femoral muscle, treatment with RIGH and vaccine protected all the animals against rabies. To our knowledge this is the highest rate of postexposure survival in animals reported to date. In addition, five out of eight (62.5%) dogs that received RIGH alone after the virus challenge were protected, while none of the animals receiving vaccine alone were protected from rabies. These trials suggest that animals can be protected from rabies by postexposure treatment. The route of exposure and timing of the administration of vaccine and hyperimmune serum would seem to be important.
PMCID: PMC1255572  PMID: 2590870
16.  Antibody Production in Milk Serum After Virus Instillation of Goat Mammary Gland VI. “Sham Infection” with Special Reference to Rabies 
The ERA strain of rabies vaccine virus failed to propagate or cause clinical manifestations when instilled into the mammary gland of lactating goats. However, the virus did produce neutralizing antibodies in this gland as a result of repetitive viral stimulation, a “sham infection”. The protective property of the concentrated and partly purified milk serum antibody was assessed in mice. In the first trial, protective activity was observed when a single dose of milk serum antibody was administered at intervals up to three days after exposure to virulent rabies virus. In the second trial, using a more concentrated milk serum antibody, about half of the mice were protected when the milk serum was administered up to ten days after exposure to virulent virus.
PMCID: PMC1319960  PMID: 4272951
17.  Exposure to Rabies — An Occupational Hazard for Veterinarians 
The Canadian Veterinary Journal  1982;23(11):317-322.
Interviews to solicit information about animal bites and rabies vaccinations were completed on 1165 of 1175 non-military veterinarians in Illinois in 1968. Two hundred and sixty-one veterinarians reported 380 exposure incidents that precipitated the administration of rabies vaccine; 72 veterinarians had received two or more series of vaccine. Vaccine was administered after exposure from: examination of a patient (n = 230), bite (n = 79), necropsy (n = 17), other causes (n = 13) and unstated (n = 41). Eighty-six percent of the exposures were to dogs or cattle. In 231 veterinarians receiving postexposure vaccinations, where year of first vaccination and year of graduation from veterinary school were known, 97 (42%) were exposed in the six years spanning one year before graduation and four years after graduation. There were 296 veterinarians, including 12 receiving postexposure vaccination, who had received their first series of vaccine as preexposure prophylaxis. Twenty-one percent of all vaccinees (pre- and postexposure) reported reactions to the rabies vaccine. Seventy-two veterinarians reported they had been treated for an animal bite in the previous year.
PMCID: PMC1790226  PMID: 17422197
18.  Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis. 
Epidemiology and Infection  1987;99(3):755-765.
The standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.
Images
PMCID: PMC2249234  PMID: 3428378
19.  Human rabies postexposure prophylaxis during a raccoon rabies epizootic in New York, 1993 and 1994. 
Emerging Infectious Diseases  1999;5(3):415-423.
We describe the epidemiology of human rabies postexposure prophylaxis (PEP) in four upstate New York counties during the 1st and 2nd year of a raccoon rabies epizootic. We obtained data from records of 1,173 persons whose rabies PEP was reported to local health departments in 1993 and 1994. Mean annual PEP incidence rates were highest in rural counties, in summer, and in patients 10 to 14 and 35 to 44 years of age. PEP given after bites was primarily associated with unvaccinated dogs and cats, but most (70%) was not attributable to bites. Although pet vaccination and stray animal control, which target direct exposure, remain the cornerstones of human rabies prevention, the risk for rabies by the nonbite route (e. g., raccoon saliva on pet dogs' and cats' fur) should also be considered.
PMCID: PMC2640781  PMID: 10341178
20.  Oral vaccination of raccoons (Procyon lotor) with genetically modified rabies virus vaccines 
Vaccine  2007;25(42):7296-7300.
Oral vaccination is an important tool currently in use to control the spread of rabies in wildlife populations in various programs around the world. Oral rabies vaccination (ORV) of raccoons represents the largest targeted program to control wildlife rabies in the United States. Currently, the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG) is the only licensed oral rabies vaccine in the US. In the current study, captive raccoons were used to evaluate two previously described constructs of a rabies virus vaccine developed by reverse genetics (SPBNGAS and SPBNGAS-GAS) for immunogenicity and efficacy compared to the V-RG vaccine. Four of five control animals succumbed to rabies virus after severe challenge, while three of five animals vaccinated orally with SPBNGAS succumbed. No mortality was observed for animals administered SPBNGAS-GAS or the V-RG vaccine. The results of this preliminary study suggest that SPBNGAS-GAS provides comparable efficacy to V-RG. Additional studies will be needed to determine the duration of immunity and optimal dosage of SPBNGAS-GAS and to examine its efficacy in other reservoir species.
doi:10.1016/j.vaccine.2007.08.004
PMCID: PMC2094212  PMID: 17826874
Rabies; Vaccine; Raccoons; Oral
21.  Using Intradermal Rabies Vaccine to Boost Immunity in People with Low Rabies Antibody Levels 
Intradermal rabies vaccine is recommended by the World Health Organisation, but not all countries, including England, follow this recommendation. A group of 12 adults in England previously given pre-exposure intradermal rabies vaccine were considered to be non-immune to rabies because their rabies antibody titres were known to be less than 0.5 IU/mL. A cohort study examined the immunizing effect of increasing the participants' cumulative dose of intradermal rabies to 2.0 IU. All patients subsequently demonstrated rabies antibody levels >0.5 IU·mL supporting evidence of adequate sero-conversion. No adverse effects of intradermal rabies vaccine boosting were noted. Within the limits of a small study the findings support the hypothesis that adequate levels of rabies antibody can be achieved by a schedule of intradermal injections delivered on at least three occasions with a cumulative rabies vaccine dose of 2.0 IU.
doi:10.4061/2011/601789
PMCID: PMC3170739  PMID: 21991440
22.  Evaluation of Rabies Biologics against Irkut Virus Isolated in China 
Journal of Clinical Microbiology  2013;51(11):3499-3504.
An Irkut virus (IRKV) was recently isolated from a bat in China. The protective ability of rabies biologics available in the Chinese market and experimental biologics against the rabies virus (RABV) and IRKV were assessed in a hamster model via preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) experiments. The results demonstrated that a single dose of rabies vaccine did not induce adequate protection against IRKV infection. However, routine PrEP with three doses of vaccine induced complete protection against IRKV infection. Higher doses of RABV immunoglobulins and alpha interferon were required during PEP to protect hamsters against IRKV versus RABV infection. Experimental recombinant vaccines containing IRKV glycoproteins induced more-reliable protection against IRKV than against RABV infection. Those findings may be explained by limited cross-neutralization of these viruses (confirmed via in vitro tests) in conjunction with antigenic distances between RABV and IRKV. These results indicate that the development and evaluation of new biologics for PrEP and PEP are required to ensure sufficient protection against IRKV infection in China and other territories where this virus is present.
doi:10.1128/JCM.01565-13
PMCID: PMC3889725  PMID: 23946522
23.  Using Serology to Assist with Complicated Post-Exposure Prophylaxis for Rabies and Australian Bat Lyssavirus 
Background
Australia uses a protocol combining human rabies immunoglobulin (HRIG) and rabies vaccine for post-exposure prophylaxis (PEP) of rabies and Australian bat lyssavirus (ABLV), with the aim of achieving an antibody titre of ≥0.5 IU/ml, as per World Health Organization (WHO) guidelines, as soon as possible.
Methodology/Principal Findings
We present the course of PEP administration and serological testing for four men with complex requirements. Following dog bites in Thailand, two men (62 years old, 25 years old) received no HRIG and had delayed vaccine courses: 23 days between dose two and three, and 18 days between dose one and two, respectively. Both seroconverted following dose four. Another 62-year-old male, who was HIV-positive (normal CD4 count), also suffered a dog bite and had delayed care receiving IM rabies vaccine on days six and nine in Thailand. Back in Australia, he received three single and one double dose IM vaccines followed by another double dose of vaccine, delivered intradermally and subcutaneously, before seroconverting. A 23-year-old male with a history of allergies received simultaneous HRIG and vaccine following potential ABLV exposure, and developed rash, facial oedema and throat tingling, which was treated with a parenteral antihistamine and tapering dose of steroids. Serology showed he seroconverted following dose four.
Conclusions/Significance
These cases show that PEP can be complicated by exposures in tourist settings where reliable prophylaxis may not be available, where treatment is delayed or deviates from World Health Organization recommendations. Due to the potentially short incubation time of rabies/ABLV, timely prophylaxis after a potential exposure is needed to ensure a prompt and adequate immune response, particularly in patients who are immune-suppressed or who have not received HRIG. Serology should be used to confirm an adequate response to PEP when treatment is delayed or where a concurrent immunosuppressing medical condition or therapy exists.
Author Summary
In Australia, the administration of rabies post-exposure prophylaxis (PEP) occurs for potentially exposed returned travellers from endemic regions or for potential local exposure to Australian Bat Lyssavirus. For Australian tourists, delays in commencing PEP or not receiving HRIG or all recommended doses of vaccine are common. We report a case series where serology provided information in four patients with delayed, incomplete, or complicated PEP treatment. Three of these patients reported a dog bite in Thailand and the fourth was scratched by a bat and had bat urine enter his eye in Australia. Management was complicated by lack of HRIG administration, delays in the recommended timeframe for receipt of vaccine doses, and immunosuppression caused by co-administration of steroids and by HIV infection with a normal CD4 count. All patients seroconverted but this was delayed in some cases, and in the HIV-positive subject required a double dose of vaccine delivered intradermally and subcutaneously. In complex or non-standard PEP delivery, including delayed treatment and immunosuppression due to steroid treatment, HIV or another immunosuppressing medical condition, serology can be used to guide further treatment and should be used to confirm seroconversion.
doi:10.1371/journal.pntd.0002066
PMCID: PMC3584984  PMID: 23469301
24.  Evaluating the cost-effectiveness of rabies post-exposure prophylaxis: A case study in Tanzania 
Vaccine  2009;27(51):7167-7172.
Although fatal if untreated, human rabies can be prevented through post-exposure prophylaxis (PEP), which involves a course of vaccination and immunoglobulin administered immediately after exposure. However, high costs and frequent lack of rabies vaccine and immunoglobulin lead to about 55,000 deaths per year worldwide. Using data from a detailed study of rabies in Tanzania, we calculate a cost-effectiveness ratio for PEP when the WHO-recommended Essen regimen, a 5-dose intramuscular vaccination schedule, is adopted. Our analyses indicate a cost-effectiveness ratio for PEP of $27/quality-adjusted life year (QALY) from a health care perspective and $32/QALY from a societal perspective in Tanzania. From both perspectives, it is “very cost-effective” to administer PEP to patients bitten by an animal suspected to be rabid. Moreover, PEP remains “very cost-effective” provided that at least 1% of doses are administered to people who were actually exposed to rabies.
doi:10.1016/j.vaccine.2009.09.027
PMCID: PMC3272373  PMID: 19925948
Cost-effectiveness; Rabies; Post-exposure prophylaxis
25.  Potential cost savings with terrestrial rabies control 
BMC Public Health  2007;7:47.
Background
The cost-benefit of raccoon rabies control strategies such as oral rabies vaccination (ORV) are under evaluation. As an initial quantification of the potential cost savings for a control program, the collection of selected rabies cost data was pilot tested for five counties in New York State (NYS) in a three-year period.
Methods
Rabies costs reported to NYS from the study counties were computerized and linked to a human rabies exposure database. Consolidated costs by county and year were averaged and compared.
Results
Reported rabies-associated costs for all rabies variants totalled $2.1 million, for human rabies postexposure prophylaxes (PEP) (90.9%), animal specimen preparation/shipment to laboratory (4.7%), and pet vaccination clinics (4.4%). The proportion that may be attributed to raccoon rabies control was 37% ($784,529). Average costs associated with the raccoon variant varied across counties from $440 to $1,885 per PEP, $14 to $44 per specimen, and $0.33 to $15 per pet vaccinated.
Conclusion
Rabies costs vary widely by county in New York State, and were associated with human population size and methods used by counties to estimate costs. Rabies cost variability must be considered in developing estimates of possible ORV-related cost savings. Costs of PEPs and specimen preparation/shipments, as well as the costs of pet vaccination provided by this study may be valuable for development of more realistic scenarios in economic modelling of ORV costs versus benefits.
doi:10.1186/1471-2458-7-47
PMCID: PMC1852308  PMID: 17407559

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