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From 1 July 1987 to 31 December 1988, 30% of 247 rabid dogs in Hermosillo, Mexico had a positive history of rabies vaccination. Serosurveys suggested that inactivated suckling mouse brain vaccine (INACT-SMBV) and inactivated tissue culture vaccine (INACT-TC) used before and during the epizootic were poor immunogens. Prospective studies showed that only about one-third of dogs vaccinated with INACT-SMBV were seropositive 5 weeks after vaccination. Lack of vaccine potency was the most likely cause of poor immunogenicity. Rabies vaccines should be evaluated periodically by measuring antibody responses in animals. In some circumstances, minimum seroconversion rates and antibody titres in vaccinated animals may be better measures of immunogenicity than relative potency.

To determine the incidence of and risk factors for adverse reactions following the boosters, we conducted a nationwide prospective study of persons receiving pre-exposure booster vaccination with human diploid cell rabies vaccine (HDCV). Persons who had previously received three pre-exposure doses of HDCV and whose rabies neutralizing antibody titres were < or = 1:5 were enrolled in the study if they stated that they intended to receive a booster. Of the 98 persons enrolled in the study, 40 (41%) were in risk groups for whom boosters are not recommended. Three (3%) of 98 developed generalized urticaria or wheezing within 1 day of receiving boosters and three others (3%) developed urticaria 6 to 14 days after the booster. No differences were found between individuals with reactions (either type) and those with no adverse reaction according to age, gender, occupation, history of previous allergies, or time since or route of primary vaccination. Reactions were somewhat more common among persons who received primary vaccinations by the intramuscular route (i.m.) and booster vaccinations by the intradermal route (i.d.) (3/15, 20%) or primary vaccinations i.d. and booster vaccinations i.m. (2/10, 20%), and somewhat less common among persons who received both these vaccinations i.d. (1/52, 2%) or i.m. (0/7). The number of persons who develop allergic reactions may be minimized by administering vaccinations only when vaccination is strictly indicated. The influence of the route of primary and booster vaccinations on the development of reactions deserves further study.

In November 1989, the epizootic of rabies affecting raccoons in the mid-Atlantic states reached New Jersey. An economic evaluation was conducted in 2 counties first affected by the epizootic to estimate the costs of the epizootic and to assess the costs and benefits of orally administering a newly developed recombinant rabies vaccine to prevent further spread of the disease. Data on expenditures associated with prevention of rabies in human beings and domestic animals and laboratory testing of suspect animals were collected and analyzed for 1988 (before the epizootic) and 1990 (first full year of the epizootic). Benefit-cost ratios were calculated and used to evaluate the economic advisability of the vaccine at various vaccination program alternatives. Two indices of capital investment analysis, payback period and net present value, were used to evaluate the economic benefits of the rabies vaccine. Expenditures were estimated to be $1,952,014 in 1990 (primarily for pet animal vaccinations), compared with $768,488 in 1988. Benefit-cost ratios ranged from 2.21 for the most expensive vaccination program alternative to 6.80 for the least expensive alternative. The payback period varied from 0.69 to 2.11 years, and the net present value ranged from $2,105,453 to $4,877,452. The high costs of this epizootic necessitated the reallocation of scarce public health resources to various rabies prevention activities, particularly the vaccination of dogs. This study also demonstrated the usefulness of benefit-cost analysis in developing public health strategies. Although the mass application of this recombinant vaccine was found to be economically beneficial, other qualitative considerations must be used to supplement these findings.

We compared three vaccination strategies in three rural communities in Mexico to determine the factors associated with the success of vaccination programs in areas where canine rabies is poorly controlled. In town A, intensive publicity and community participation were used; owners were instructed to bring their dogs to temporary centralized clinics for vaccination. In town B, only brief precampaign publicity was used, followed by vaccination at a centralized site. Minimal publicity was also used in town C, but the vaccination campaign was conducted house to house. A total of 5,426 residents and 1,597 dogs were counted in the three towns (mean human:dog ratio 3.4:1). In Town A, 70.1% (472 of 673) of the dogs were vaccinated; the campaign required 40 person-minutes per dog. Significantly greater proportions were vaccinated in town B (262 of 318 [82.4%]; P less than 0.001) and town C (483 of 561 [86.1%]; P less than 0.00001); each of these latter campaigns required 10 person-minutes per dog. The following factors were positively associated (by multivariate analyses) with vaccination of individual dogs: non-intensive publicity, house-to-house vaccination, dogs owned by a single member of the household, and dogs acquired greater than 15 days after birth. Intensive publicity did not increase the overall success of the vaccination program; the efficiency of centralized versus and house-to-house vaccination was comparable.

We evaluated four baits for the delivery of oral rabies vaccines to dogs. In a controlled study in a town in rural Mexico, 177 randomly selected dogs were assigned to receive one of four experimental baits (two of which were developed by the Denver Wildlife Research Center [DWRC]): one of two cylindrical polyurethane sponges with a corn meal coating (one fried in corn oil [DWRC-corn], the other in fish oil [DWRC-fish]), a fish-flavored polymer bait, or a wax bait. Each dog was also offered a commercial dog biscuit. We recorded whether or not the bait was completely consumed, and used the following measures to estimate the amount of oropharyngeal contact with each bait: total chewing time, presence of pieces of bait on the ground following administration, the total area of ground surrounding the location of ingestion that was covered with green dye contained in each bait, and condition of ampules that contained the dye. The dog biscuits were completely consumed significantly more often than the baits (155 of 176 [88%] for the biscuits versus 89 of 176 [50.5%] for the four baits; P less than 10(-6)), but were chewed for a significantly shorter time than the baits (mean time 34 sec for the biscuit versus 60-82 sec for the four baits: P less than 0.001). The ideal bait would probably combine the attractiveness of the commercial biscuit and the ability of the sponge baits to promote contact with the mucous membranes.

Pre-exposure rabies prophylaxis is recommended by the Immunization Practices Advisory Committee of the US Public Health Services (PHS) as a safe and effective method for reducing the risk of rabies in international travellers. The United States Peace Corps provides pre-exposure prophylaxis with human diploid cell rabies vaccine (HDCV) to over 2000 new volunteers each year going to rabies-endemic countries. During the year November 1987 through October 1988, 175 rabies exposures (and no deaths) were documented in Peace Corps Volunteers serving in 31 rabies-endemic countries, for an overall postexposure treatment rate of 43.6/1000 volunteers per year. Although PHS treatment protocols were strictly followed, the postexposure prophylaxis rate for these Peace Corps Volunteers was 550 times higher than that for the US general population, and 55 times higher than the average rate for 30 developing countries. The use of pre-exposure prophylaxis in travellers was not cost-effective and will not become so until the price of a dose of vaccine declines substantially to $7.00 for the Peace Corps, and even lower for groups with less rabies exposure. However, despite the high vaccine cost, pre-exposure prophylaxis continues to be recommended in the Peace Corps for important non-economic reasons which may also be applicable to other groups of travellers.

The 2-1-1 rabies postexposure treatment schedule is an abbreviated regimen in which a tissue culture rabies vaccine is administered intramuscularly at two sites on day 0, and at one site on days 7 and 21. Compared to the standard five-dose intramuscular regimen, the 2-1-1 schedule reduces the number of clinic visits from five to three and the amount of vaccine used by 20%. One hundred Thai patients, who were severely exposed to rabies, were treated with rabies immune globulin and the 2-1-1 regimen using purified Vero cell rabies vaccine. They were followed for 1 year. Rabies antibody titres were measured in 10% of this group. All patients survived and adverse reactions were mild. A satisfactory antibody response (a titre greater than 0.5 IU ml-1) occurred in all ten patients studied at day 14, but persisted for 90 days in 80% and for 360 days in only 50%. The authors therefore do not recommend use of the 2-1-1 schedule in severely exposed patients who also need to receive rabies immune globulin.

Despite the availability of rabies vaccination through private veterinarians and government-sponsored rabies control programs, rabies was reported in an average of 338 cats and dogs per year from 1980 through 1987 in the United States. Information was collected on 90% of the 183 cats and 97% of the 119 dogs that were reported to have rabies in the continental United States in 1988. The median age of rabid cats and dogs was 1 year, and 81% were from rural areas. Compared with rabid cats, rabid dogs were more likely to have been male (66 vs 42%, odds ratio = 2.6), to have been kept as pets (84 vs 43%, odds ratio = 6.8), and to have had reported contact with wildlife before onset of illness (38 vs 14%, odds ratio = 3.8). Rabid cats accounted for a greater proportion of human rabies postexposure prophylaxis, bites to people, and exposures to other animals than did rabid dogs. Although the clinical signs of rabies varied, rabid cats were more likely than dogs to have had aggressive behavior (55 vs 31%, odds ratio = 2.8). In contrast, rabid dogs were more likely than cats to have had an illness consistent with a paralytic process. The median period between onset of illness and death was 3 days (range, less than 1 to 10) in rabid cats and dogs that were allowed to die of rabies. Vaccine failures were documented in 3 (1%) rabid animals (2 cats and 1 dog). All animals had received only a single dose of vaccine in their lifetime and were vaccinated when they were between 3 and 6 months old.

The Thai Red Cross intradermal postexposure rabies treatment schedule was prospectively assessed in 100 Thai patients severely bitten by proven rabid animals. It consists of 0.1 ml of purified Vero cell rabies vaccine containing more than 2.5 IU of rabies antigen per 0.5 ml of reconstituted vaccine given intradermally at two sites on days 0, 3, and 7, followed by one 0.1 ml injection on days 30 and 90. The commercial vaccine used had an antigen content of 3.17 IU per 0.5 ml ampoule. Purified equine or human rabies immuno-globulin was also given on day 0 to patients with severe exposures. As much of the immunoglobulin as possible was infiltrated around the wounds. All patients were followed for 1 year post exposure. There were no deaths; the efficacy of the regimen was 100%. Antibody titre determination in a randomly selected subgroup showed seroconversion in all 10 patients.

The scientific basis of Hawaii's public health rabies prevention program is discussed, as is a proposed minor modification offered to assist Hawaii residents who use guide dogs and who want to travel out of state. Hawaii's current quarantine program has successfully prevented the introduction of the disease. Alternative programs involve risks that are not easily evaluated.

We conducted a randomized controlled trial to evaluate the antibody response of freshman veterinary students to intradermal human diploid-cell rabies vaccine administered concurrently with chloroquine, a drug frequently used for chemoprophylaxis against malaria. Fifty-one students who had not been vaccinated against rabies were enrolled: 26 received 300 mg of chloroquine base per week (the recommended dose for malaria prophylaxis); 25 did not receive chloroquine and served as controls. All subjects received 0.1 ml of rabies vaccine intradermally on days 0, 7, and 28. Chloroquine was administered weekly to the treatment group, beginning nine days before the first dose of vaccine and continuing until day 48. The mean rabies-neutralizing antibody titer for the chloroquine group was significantly lower than that for the control group on each day of testing--i.e., day 28 (P = 0.0094), day 49 (P = 0.0008), and day 105 (P = 0.0002)--although both groups had neutralizing antibody titers on days 49 and 105, according to the criteria of the Centers for Disease Control. The blood concentrations of chloroquine and desethylchloroquine (the major metabolite of chloroquine, which also has antimalarial properties) were negatively associated with log antibody titers. These results indicate that chloroquine taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine.

In November 1982, a U.S. Peace Corps volunteer in Kenya completed pre-exposure rabies prophylaxis with a standard 3 dose intradermal (ID) series of human diploid cell rabies vaccine (HDCV). In May 1983, she was bitten by a dog and died of rabies 3 months later. An initial investigation revealed that the patient, as well as 9 of 11 others immunized at the same time, had no rabies antibody titers (less than 1:5). We therefore instituted investigations into the immunogenicity of pre-exposure HDCV both in the United States and in developing countries. A serosurvey revealed unexpectedly low rabies titers in both Peace Corps volunteers and others immunized in developing countries. Antibody titers measured 2-3 weeks after ID immunization were compared in 9 groups totaling 271 persons in the United States and Kenya. There was no statistically significant difference in antibody titers in the 6 U.S. groups immunized from 1980-1984 (P greater than 0.15); however, groups immunized in the United States had significantly higher titers than a group of Kenyan nationals (P less than or equal to 0.0001), and the Kenyans had significantly higher titers than 2 Peace Corps groups immunized in Kenya (P less than or equal to 0.0001). No single hypothesis proposed (laboratory error, vaccine potency, vaccination technique, or specific immune suppression) accounted for the observed differences. Although we cannot fully explain the poor response to HDCV, it is probably due to multiple factors. We conclude that persons immunized with ID pre-exposure HDCV in developing countries should have rabies antibody titers determined to ensure their seroconversion; for persons immunized in the United States, such titers need not be routinely determined.

Recent studies suggest that human diploid cell rabies vaccine (HDCV) may not always produce acceptable titers after intradermal (id) preexposure prophylaxis. To stimulate accidental deviation from the recommended route of administration and to determine the immunogenicity of smaller-than-recommended doses of HDCV, we injected each of 154 persons either intramuscularly (im) with 100%, 10%, or 3% of the standard im dose of vaccine or id with 10%, 3% or 1% of the standard im dose. Seroconversion (titers of antibody greater than or equal to 1:11) was found in all subjects at 49 and 90 days after vaccination. Titers were higher for subjects receiving 100% of the recommended dose im than for those receiving 10% of this dose id (P less than .01); these titers in turn were higher than those from persons receiving smaller doses (P less than .05). Persons receiving 10% or 3% of the standard im dose had lower titers on day 49 than did those receiving the same dose id (P less than .05).

The human diploid cell rabies vaccine (HDCV) has been shown to be highly immunogenic when used for pre-exposure immunization. However, the high cost of the product and the adverse reactions seen following booster doses of HDCV have limited its use. A purified chick embryo cell (PCEC) rabies vaccine was compared with the HDCV by two routes of administration for reactogenicity, antibody response, duration of antibody, and anamestic response to boosters over a 2 year period. The study showed that the two vaccines were comparable in their immunogenicity and reactogenicity after initial three dose series. No adverse reactions were noted following the 2 year booster with PCEC. The PCEC can be produced at less than one-half the cost of the HDCV.

Systemic allergic reactions following booster immunizations have complicated rabies pre-exposure prophylaxis with the human diploid cell rabies vaccine licensed in the US (conventional HDCV). We conducted two studies comparing an HDCV purified by zonal centrifugation to conventional HDCV. In a study of primary pre-exposure immunization, volunteers received one of four regimens: three 1.0-ml intramuscular (i.m.) or 0.1-ml intradermal (i.d.) doses of conventional or purified HDCV over 28 days. Although volunteers vaccinated i.m. had significantly greater rabies neutralizing antibody titres (VNA) 49 days, 91 days and 26 months after immunization began than volunteers vaccinated i.d. (p less than 0.005-p less than 0.05), there were no significant differences between vaccines. In a study of booster immunizations, 77 volunteers immunized with conventional HDCV 2 years earlier received a 0.1-ml i.d. booster with either conventional or purified HDCV. VNA was significantly greater with the conventional HDCV on days 7 and 28 after booster, but not on day 365. A moderate or severe reaction was reported by 5 (13%) of the 40 persons who received boosters with conventional HDCV, versus none of 37 who received the purified HDCV (p = 0.03). Purified HDCV appears to be preferable to conventional HDCV for booster vaccination.

Persons immunized in developing countries were recently shown to have low titers after pre-exposure immunization with human diploid cell rabies vaccine (HDCV). An investigation into the response to HDCV boosters was conducted to determine if immunologic sensitization had occurred and if there was a response difference in persons immunized in and outside of the United States. Intramuscular (im) booster doses of vaccine were administered to 113 persons previously immunized outside the United States and 47 persons immunized in the United States. The post-exposure booster regimen of a single 1.0-ml im booster, as recommended by the World Health Organization for all but the most severe bites, produced a one-dilution (5-fold) rise in antibody titer in 14 (11%) of 123 persons tested 5 days after booster and in 56 (89%) of 63 persons studied 7 days after booster. Persons immunized in the United States and those immunized outside the United States had similar responses. Persons with low pre-booster titers were more likely to exhibit a 5-fold rise in antibody titer 5 days after booster (P = 0.03) than persons with higher pre-booster titers. The post-exposure booster regimen of 2 1.0-ml im doses (one each on days 0 and 3), recommended in the United States, produced a more rapid response than the single booster regimen in only some persons; a 5-fold response occurred in 6 (50%) of 12 persons 5 days after booster.(ABSTRACT TRUNCATED AT 250 WORDS)