An immunogenicity and efficacy study of purified chick embryo cell culture rabies vaccine manufactured in Japan

Purified chick embryo cell rabies vaccine manufactured by the Chemo-Sero-Therapeutic Institute(Kaketsuken) at Kumamoto, Japan (Kaketsuken) was submitted to an immunogenicity and efficacy study. 52 severely rabies exposed patients were treated with the conventional five doses intramuscular WHO approved ('Essen') postexposure schedule. This included the administration of 40 IU kg-1 of equine rabies immune globulin on Day 0. A control group of equally severely exposed subjects were treated with human diploid cell rabies vaccine manufactured by the Swiss Serum and Vaccine Institute as well as human rabies immune globulin. There were no deaths in either group in the more than 2 years follow-up period. Subjects treated with the chick embryo vaccine showed greater suppression of the neutralizing antibody response by the equine rabies immune globulin than those given the human diploid cell vaccine and human rabies immune globulin. A group of 20 less severely rabies exposed patients who received only the chick embryo vaccine without immune globulin all had antibody titers greater than the WHO minimal acceptable level on Day 14, 30, 90 and 180. Fourteen subjects among the severely exposed vaccine and immune globulin study group were given vaccine boosters on Day 180 because of low antibody titers. It is concluded that chick embryo rabies vaccine manufactured by Kaketsuken is an immunogenic and effective rabies vaccine, but that the potency of future batches must be increased to provide a greater safety margin.     

Persistence of antibodies in children after intradermal or intramuscular administration of preexposure primary and booster immunizations with purified Vero cell rabies vaccine

BACKGROUND: The use of intradermal (i.d.) injections of purified Vero cell rabies vaccine (PVRV) for preexposure prophylaxis has not been well-established. We studied the safety and immunogenicity of i.d. and intramuscular (i.m.) PVRV injections for primary and booster preexposure immunizations. METHODS: One of two rabies preexposure PVRV regimens comprising three doses of either 0.1 ml i.d. or 0.5 ml i.m. administered during 28 days was assigned at random to 190 school children. One booster dose was given 1 year later either i.d. or i.m., according to their initial randomization group. Serologic results were available from 155 (82%) children at 1 year after primary immunization and 118 (62%) children at 2 years after booster. RESULTS: Although children vaccinated i.d. had significantly lower rabies-neutralizing antibody titers after primary immunization as well as after booster than children vaccinated i.m. (P< 0.001 for all time points), there were no significant differences in the percentages of children with adequate titers (> or =0.15 IU/ml) between the i.d. and i.m. groups after both primary and booster immunizations. Mild local reactions were more frequent after i.d. vaccination. Mild or moderate systemic reactions were infrequent and similar after i.d. and i.m. vaccinations. Fever and headache were reported by < or =6%. The reactions after booster were not different from those of post-primary immunization. CONCLUSIONS: Purified Vero cell rabies vaccine appears to be safe and immunogenic for primary and booster preexposure immunizations. An i.d. PVRV preexposure regimen should be useful especially for rabies-endemic countries with low per capita income.     

Evaluation of the safety, immunogenicity, and pharmacokinetic profile of a new, highly purified, heat-treated equine rabies immunoglobulin, administered either alone or in association with a purified, Vero-cell rabies vaccine

A clinical evaluation of a new, purified, heat-treated equine rabies immunoglobulin (PHT-Erig), F(ab')2 preparation, was carried out in Thailand and in the Philippines-two countries where rabies is endemic. An initial prospective, randomised, controlled trial (Study 1), compared the safety and pharmacokinetics (serum concentrations of rabies antibodies) after administration either of PHT-Erig or of a commercially-available, equine rabies immune globulin (Erig PMC). A second trial (Study 2) simulated post-exposure rabies prophylaxis by using a reference cell culture vaccine, the purified Vero-cell rabies vaccine (PVRV), administered in association with either Erig PMC or PHT-Erig. In Study 1, 27 healthy, Thai adults received a 40 IU kg(-1) dose of either Erig PMC (n = 12) or PHT-Erig (n = 15) via the intramuscular (i.m.) route; half of the dose was injected into the deltoid area and the other half into the buttocks. Serum for rabies antibody determination and F(ab')2 concentration was collected at hours (H) 0, 6 and 12, and on day (D) 2, 3, 4, 6, 8, 10, 12 and 15. Both products were safe, with no serious adverse events, and in particular, no anaphylactic reactions or serum sickness was reported. A statistical comparison of the pharmacokinetic parameters did not demonstrate bioequivalence of the two products. Nonetheless, the relative bioavailability of 93% and the similar absorption rates suggest the pharmacokinetic profiles of Erig and PHT-Erig are similar. The antibody level in either group were low throughout the 15-day study period. The geometric mean titer (GMT) values ranged from group 0.027-0.117 IU ml(-1) in the Erig group and from 0.029 to 0.072 IU ml(-1) in the PHT-Erig. There was no significant difference between the evolution of GMT values for the two groups. In Study 2, 71 healthy volunteers received 40 IU kg(-1) via the intramuscular route of either Erig PMC (n = 36) or PHT-Erig (n = 35) on D0, in association with five doses of PVRV on D0, D3, D7, D14 and D28. The safety evaluation was performed during the 28-day follow-up and serum samples for anti-rabies antibody titration were collected on D0 (before injection) D3, D7, D14 and D28. No serious reactions were reported in either group. In particular, no immediate (anaphylactic type) or delayed (serum sickness) allergic reactions were observed. Over the 28-day follow-up period, GMT profiles of the two groups were statistically equivalent. On D14, 100% of the subjects had protective antibody titers (anti-rabies antibodies > or = 0.5 IU ml(-1), which is the WHO-recommended level of seroconversion), and Erig PMC and PHT-Erig were indistinguishable according to the clinical definition chosen. On D28, the GMT values were 33.2 IU ml(-1) (95% CI, 23.8-46.1 IU ml(-1)) in the Erig PMC/PVRV group and 31.4 IU ml(-1) (95% confidence interval, CI, 23.4-42.2 IU ml(-1)) in the PHT-Erig/PVRV group, showing evidence of adequate vaccine-induced antibody responses in both groups. The increased purity, the heat-treatment step introduced in the manufacturing process of PHT-Erig, and the good clinical results substantiate the use of this new generation, purified equine F(ab')2 preparation in the post-exposure prophylaxis of rabies.     

Spiral CT with ionic and nonionic contrast material: evaluation of patient motion and scan quality

STUDY OBJECTIVES: To determine if subcutaneous administration of influenza vaccine is as immunogenic as the intramuscular route, and to evaluate the frequency of local adverse events associated with both routes in elderly anticoagulated men. DESIGN: Single-blind, prospective study of consecutively enrolled subjects. SETTING: Ambulatory clinic at a university-affiliated Veterans Affairs medical center. PATIENTS: Twenty-six men age 60 years or older, receiving therapeutic dosages of warfarin. INTERVENTIONS: Subjects were randomized to receive either intramuscular or subcutaneous injection of a standard trivalent influenza vaccine. MEASUREMENTS AND MAIN RESULTS: Serum antibody titers to the vaccine's components were measured at baseline, and 6 weeks and 4 months after vaccination. Both routes of administration induced comparable serum antibody titers. There were no differences in adverse events at administration sites between routes of administration. CONCLUSIONS: Elderly individuals are able to mount an immune response to influenza vaccine and produce antibody concentrations deemed protective. The routes of administration are similarly effective at inducing an immune response. The intramuscular route in anticoagulated elderly men does not commonly result in local bleeding complications.     

The abbreviated 2-1-1 schedule of purified chick embryo cell rabies vaccination for rabies postexposure treatment

During August 1988 to January 1990, the immunogenicity and safety of purified chick embryo cell rabies vaccine (PCEC) given by the conventional and abbreviated regimens in 82 vaccinees moderately to severely exposed to laboratory proven rabid animals were studied. The 16 vaccinees received PCEC six doses as conventional schedule on days 0, 3, 7, 14, 28 and 90, the 11 vaccinees received six doses of PCEC plus human rabies immune globulin (HRIG) on day 0. The 29 vaccinees received an abbreviated schedule of PCEC as two doses on day 0, one dose each on days 7 and 21 and the 26 cases received PCEC abbreviated schedule plus HRIG on day 0. The kinetics of the neutralizing antibodies on days 0, 7, 14, 28, 56, 180 and 365 were studied for comparative purpose. All vaccinees had high antibody levels from day 14 which last longer than a year and were safe after one year follow up. The adverse reactions of the vaccine were mild and self-limited.     

Comparative study of 2 variants of a modified esophageal transection in the Sugiura-Futagawa operation

From December of 1990 to December of 1997, 119 subjects visited to our hospital to receive post-exposure therapy using purified chick embryo cell rabies vaccine manufactured by the Chem-Sero-Theraptic Institute (Katestuken), because they had been bitten by supposed rabid animals abroad. The forty of the subjects (male: 25, female: 15) wished to have their anti-rabies antibody levels examined. The number of samples taken after 5 or 6 shots rabies vaccine were 30 and 15, respectively. The antibody levels after 6 shots of rabies vaccine varied from 1.0 IU/ml to 10.1 IU/ml. After 5 shots the antibody levels fluctuated from under 0.1 IU/ml to over 8.8 IU/ml, and 3 subjects were found to have antibody titers of under 0.5 IU/ml which is the WHO minimal protective level. Two of these 3 subjects found to have antibodies of 1.0 IU/ml and 3.1 IU/ml. after the 6th injection. However, these 3 subjects had the hazard to have rabies despite post-exposure immunization, because the incubation period of rabies is found to be 1-3 months in about 60% of the cases. The potency of Kaketsuken's rabies vaccine should be increased to provide higher antibody levels.     

Mass human exposure to rabies in New Hampshire: exposures, treatment, and cost

OBJECTIVES: This study assessed the rabies exposure and treatment that at least 665 persons in Concord, NH, received as a result of one proven rabid pet-store kitten in October 1994. METHODS: All treatment recipients were interviewed by person or phone. RESULTS: The median age of the treatment recipients was 14 years; 58% were female. The most common exposures were low risk (e.g., picking up, petting, nuzzling, or being scratched by a potentially rabid kitten). Local reactions to vaccine or immune globulin were reported by 76.5% of recipients, while 48.8% reported at least one systemic reaction. Cost for the biologicals was estimated at more than $1.1 million. CONCLUSIONS: Because of the inadequacy of pet store records, the inconsistent application of treatment guidelines, and other factors, many people received postexposure treatment as a result of contacts that were unlikely to transmit rabies. The rates of local and systemic adverse reactions experienced were consistent with previous reports.     

Protective activity of a murine monoclonal antibody against European bat lyssavirus 1 (EBL1) infection in mice

A mouse model was designed to test in vivo the efficacy of rabies immune globulins and specific neutralizing monoclonal antibodies to prevent European bat lyssavirus 1 infection. Human or equine rabies immune globulins previously found to contain variable amounts of neutralizing bat lyssavirus crossreactive antibodies were passively transferred to mice receiving intramuscularly a lethal dose of bat lyssavirus type 1. Immune globulins did not protect mice well against bat lyssavirus 1 whereas they reduced the mortality caused by rabies virus. In contrast, mice inoculated with bat lyssavirus 1 or rabies virus survived when passively immunized with bat lyssavirus 1 specific monoclonal antibody (mAb 8-2). This monoclonal antibody, an IgG2 alpha, recognized an epitope located in the antigenic site IIa of rabies glycoprotein. A mutation replacing the lysine 198 by glutamate in a rabies variant abrogated sensitivity to this neutralizing antibody. Because of its broad neutralizing spectrum against wild virus isolates, including European bat lyssaviruses, this monoclonal antibody should be a good candidate for rabies immune globulin replacement. It could improve efficacy of rabies vaccination, used either alone or in conjunction with human rabies immune globulins or monoclonal antibody cocktail to supplement their lack of crossreactivity to European bat lyssavirus 1.     

Human contact with bait containing vaccine for control of rabies in wildlife

OBJECTIVE: To document the number of human contacts with bait containing liquid vaccinia-rabies glycoprotein (V-RG) vaccine, to evaluate factors that might affect human contact with bait-vaccine units, and to summarize adverse reactions in people after contact with vaccine. DESIGN: Retrospective 4-year survey of directors of 6 oral rabies vaccination programs. SAMPLE POPULATION: Human residents in areas of vaccination programs. PROCEDURE: Data were collected from report forms and telephone conversations with directors of oral rabies vaccination programs in Florida, Massachusetts, New Jersey, Texas, and New York. Data collected included information regarding human contact with bait and vaccine, sex and age of person involved in contact, human population density, bait density, type of labeling used on bait, and other factors. RESULTS: Human contact with bait was more likely in areas where bait had white labels (vs lettering in black ink) and in areas with high human population densities. Directors of all programs reported that human contact with bait-vaccine units was minimal. Adverse reactions in exposed people were not reported. On the basis of these findings, concerns about V-RG vaccine posing a substantial public health risk remain unfounded. CLINICAL IMPLICATIONS: Directors of oral rabies vaccination programs should systematically collect information about exposures and potential factors affecting exposure of people to bait-vaccine units. People with substantial exposure to V-RG vaccine should be evaluated for immune status and any resulting symptoms should be documented and monitored.     

Prediction of microcirculatory oxygen transport by erythrocyte/hemoglobin solution mixtures

Vaccination with naked DNA may be an alternative to conventional vaccines because it combines the efficacy of attenuated vaccines with the biological safety of inactivated vaccines. We recently showed that the vaccination with naked DNA coding for the immunorelevant glycoprotein D (gD) of pseudorabies virus (PRV) induced both antibody and cell-mediated immunity in pigs and provided protection against challenge infection. To determine whether the efficacy of the naked DNA vaccination against PRV could be improved, we compared three sets of variables. First, the efficacy of the naked DNA vaccine coding only for the immunorelevant gD was compared with a cocktail vaccine containing additional plasmids coding for two other immunorelevant glycoproteins, gB and gC. Second, the intramuscular route of vaccination was compared with the intradermal route. Third, the commonly used needle method of inoculation was compared with the needleless Pigjet injector method. Five groups of five pigs were vaccinated three times at 4-weeks intervals and challenged with the virulent NIA-3 strain of PRV 6 weeks after the last vaccination. Results showed that although the cocktail vaccine induced stronger cell-mediated immune responses than the vaccine containing only gD plasmid, both vaccines protected pigs equally well against challenge infection. Intradermal inoculation with a needle induced significantly stronger antibody and cell-mediated immune responses and better protection against challenge infection than intramuscular inoculation. Our data show that the route of administering DNA vaccines in pigs is important for an optimal induction of protective immunity.     

Glucose-induced oxidative stress in vascular contractile cells: comparison of aortic smooth muscle cells and retinal pericytes

Once onset of clinical rabies develops in an individual, death is inevitable. Thus, it is imperative that, for persons exposed or potentially exposed to rabies virus, prophylaxis must be instituted as soon as possible following the exposure. Local wound management is an essential part of postexposure rabies prophylaxis. Exposed persons should receive a recommended series of a tissue culture or cell culture origin vaccine. The number of doses and route of vaccination differ in various regions of the world and are discussed in the text. The administration of a rabies immune globulin is generally recommended in conjunction with the first dose of the rabies vaccine. Nerve tissue origin vaccines, although used extensively in some parts of the world, are not recommended if cell or tissue culture vaccines are available. Decision trees are presented in the text to aid in determining if rabies vaccine is necessary following a known or presumed exposure to the virus, along with a table outlining the various rabies vaccines available in the World. Rabies pre-exposure immunisation is recommended for those individuals at risk of exposure to the virus. Pre-exposure prophylaxis consists of 3 doses of an approved rabies vaccine administered either intramuscularly or intradermally on days 0, 7, and 21 or 28 with periodic booster doses or titre determination depending on the level of risk of potential exposure to the virus.     

Perceived quality of life before and after implantation of an internal cardioverter defibrillator

One thousand three hundred and seventy-five (1375) persons, who were vaccinated against Rabies with Purified Chick Embryo Cell (PCEC) vaccine from 1984 to 1993, were included in this ten-year longitudinal study, conducted to observe the consistency, immunogenicity, inocuity, safety and efficacy of PCEC vaccine under controlled trial and field conditions. The study period was divided into three phases. Phases I and II covered the premarketing controlled trial and Phase III the post-marketing serosurveillance study of the vaccine. During Phase I, fifteen healthy volunteers were given a pre-exposure regime of vaccine on Day 0, 7 and 21, and the rest 15, simulated post-exposure regime on Day 0, 3, 7, 14, 30 and 90. All the subjects had satisfactory antirabies antibody response with mean titres, of 7.08 and 5.72 I.U./ml respectively, and minimal side reactions. In the Phase II, from 1984-85, 56 persons with proven rabid animal bites were given post-exposure vaccination and all had satisfactory antibody titres with mean titre of 4.45 I.U./ml after 6th dose of vaccine and with minimal side reactions. 19 to 36 months follow up after vaccination revealed no vaccine failures. In the Phase III post-marketing field study conducted from 1985 to 1993, 1289 persons reported to our Centre for consulation and antirabies antibody titre estimation following PCEC vaccination. One thousand two hundred and fifty-two (1252) persons took post-exposure vaccination following bites by rabid animals, contact with an hydrophobia patient and 37 high risk personnel took pre-exposure vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stromal keratitis induced by a unique clinical isolate of herpes simplex virus type 1

The antibody responses of 65 volunteers receiving an i.d. regimen (0.1 ml given at two sites on days 0, 3, 7 and 0.1 ml given at one site on days 30 and 90) were compared with the control group of 35 volunteers receiving the standard i.m. regimen. By day 14, seroconversion was observed in all vaccinees in both groups. Geometric Mean Titers remained higher than 0.5 IU/ml throughout the study period. At the end of the observation period on day 365, antibodies persisted in all subjects. The multisite i.d. PCEC regimen has been proved as immunogenic as the standard i.m. regimen. Both regimens were well tolerated. Thus, it would be the effective and cheapest available rabies post-exposure treatment using tissue culture vaccine.     

Effect of passive immunization or maternally transferred immunity on the antibody response to a genetic vaccine to rabies virus

A plasmid vector, termed pSG5rab.gp, expressing the glycoprotein of rabies virus was tested in young adult or neonatal mice in the presence of maternally transferred immunity or passively administered antibodies to rabies virus for induction of an antibody response. Mice born to rabies virus-immune dams developed an impaired antibody response to genetic immunization at 6 weeks of age, as had been previously observed upon vaccination with an inactivated viral vaccine. Similarly, mice passively immunized with hyperimmune serum showed an inhibited B-cell response upon vaccination with the pSG5rab.gp vector, resulting in both cases in vaccine failures upon challenge with a virulent strain of rabies virus. In contrast, the immune responses of mice vaccinated as neonates in the presence of maternal immunity or upon passive immunization to rabies virus with the pSG5rab.gp construct were only marginally affected.     

Identification and characterization of a major lysosomal membrane glycoprotein, LGP85/LIMP II in mouse liver

To develop a less reactogenic but equally immunogenic vaccine, this study of 91 human volunteers compared the safety and immunogenic potency of a new, cell culture-derived vaccinia virus vaccine administered intradermally and intramuscularly with the licensed vaccinia vaccine administered by scarification. Cutaneous pox lesions developed in a higher proportion of scarification vaccinees. Scarification and intradermal vaccine recipients who developed cutaneous pox lesions had more local reactions but also achieved significantly higher cell-mediated and neutralizing antibody responses than those who did not develop pox lesions. Although less reactogenic, intradermal or intramuscular administration of vaccinia vaccine without the concomitant development of a cutaneous pox lesion induced lower immune responses.     

Field trial of a vaccine against New World cutaneous leishmaniasis in an at-risk child population: safety, immunogenicity, and efficacy during the first 12 months of follow-up

The safety, immunogenicity, and efficacy of a vaccine against cutaneous leishmaniasis in rural Ecuadorian children was assessed in a randomized, controlled, double-blinded study. Vaccine group subjects received 2 intradermal doses of a whole, killed promastigote vaccine cocktail plus bacille Calmette-Guérin (BCG) adjuvant. Control subjects got 2 doses of BCG only. The subjects who received both vaccination doses, 438 in the vaccine group (79.3%) and 406 in the control group (83.4%), were followed for 12 months. No serious adverse side effects were identified in either group. Significantly more vaccine group subjects than controls converted to a positive Montenegro skin test (85.1% vs. 20.1%; chi2 = 279; P < .001). The incidence of cutaneous leishmaniasis was significantly reduced in the vaccine compared with the control group (2.1% vs. 7.6%; chi2 = 8.95; P < .003). The protective efficacy of the vaccine was 72.9% (95% confidence interval = 36.1%-88.5%).     

Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity

OBJECTIVE: To estimate the efficacy and toxicity of typhoid fever vaccines. DESIGN: Meta-analysis of randomised efficacy trials and both randomised and non-randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. SUBJECTS: 1,866,951 subjects in 17 efficacy trials; 11,204 subjects in 20 toxicity studies. MAIN OUTCOME MEASURES: Pooled estimates of three year cumulative efficacy, year specific efficacy, and incidence of adverse events. RESULTS: Three year cumulative efficacy was 73% (95% confidence interval 65% to 80%) for two doses of whole cell vaccines (based on seven trials); 51% (35% to 63%) for three doses of Ty21a vaccine (four trials); and 55% (30% to 71%) for one dose of Vi vaccine (one trial). For whole cell and Ty21a vaccines, regimens of fewer doses were less effective. Efficacy was shown to be significant for five years for whole cell vaccines, four years for Ty21a vaccine, and two years for Vi vaccine. Neither the age of vaccine recipient nor the incidence of typhoid fever in the control group (varying from 6 to 810 cases per 100,000 person years) affected the efficacy of the whole cell or Ty21a vaccines. After vaccination, fever occurred in 15.7% (11.5% to 21.2%) of whole cell vaccine recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine recipients, and 1.1% (0.1% to 12.3%) of Vi vaccine recipients. CONCLUSIONS: Whole cell vaccines are more effective than the Ty21a and Vi vaccines but are more frequently associated with adverse events. Whether the added efficacy of the whole cell vaccines outweighs their toxicity will depend on the setting in which vaccination is used.     

Postexposure treatment of rabies in Pakistan

To evaluate compliance with current World Health Organization (WHO) guidelines for postexposure treatment (PET) of rabies, we interviewed all animal bite victims seeking treatment on the same day of each week from 28 December 1994 through 18 January 1995 at the Civil Hospital of Karachi (Pakistan), a major referral center. Of the 143 patients studied, 109 (76%) sustained bleeding transdermal bites (WHO category III). Overall, wounds were not washed with soap or an antiseptic in 69% of victims. All victims received 5% sheep brain-derived vaccine, and only three of the 109 victims with category III bites received rabies immune globulin. PET of rabies in Karachi was deficient by all WHO standards. Although there is a great urgency to improve PET, it will remain a costly and inefficient method of controlling rabies. Reduction of rabies reservoirs is required to decrease human deaths due to rabies in Pakistan and other developing countries in which canine rabies is endemic.     

Humoral and cellular immune responses of dogs immunized with a nucleic acid vaccine encoding human carcinoembryonic antigen

A nucleic acid vaccine encoding human carcinoembryonic antigen (CEA) was administered to 10 juvenile dogs, 10-15 weeks of age, by four parenteral routes. The routes tested were intramuscular injection using a needle and syringe, intramuscular injection using the Biojector needleless injection device, intradermal injection or intravenous injection. All groups received 150 micrograms of plasmid DNA on weeks 0, 4, 7 and 13. All dogs were bled weekly for 17 weeks and tested for antibody against human CEA. Dogs given plasmid intramuscularly either by needle and syringe or Biojector showed significant antibody responses by week 9 which peaked by week 15. Dogs receiving plasmid intravenously showed slight, unsustained increases in antibody titers while dogs receiving plasmid intradermally had significant titers, but at levels approximately one log less than those induced by intramuscular injection. The five dogs immunized by intramuscular delivery of plasmid DNA were examined for cellular immune responses to human CEA by lymphoblast transformation (LBT) assay. All five showed significant CEA-specific lymphoproliferation when compared with unvaccinated dogs. Physical examination, clinical chemistry, hematology and histopathology examinations revealed no abnormalities associated with nucleic acid immunization.     

Evaluation of a multivalent Pasteurella haemolytica vaccine in bighorn sheep: safety and serologic responses

We examined effects of a multivalent Pasteurella haemolytica vaccine (serotypes A1, A2, T10) on humoral immune responses and P. haemolytica isolation rates in bighorn sheep (Ovis canadensis). Thirty captive bighorns, divided into groups of three on the basis of age, sex, and previous history of pneumonic pasteurellosis, received 0, 1, or 2 vaccine doses. Mild, transient lameness in most bighorns 1 day after initial vaccination was the only adverse effect observed. Oropharyngeal (> or = 75%) and nasal (< or = 50%) isolation rates for P. haemolytica did not differ among treatment groups. Ten of 36 distinguishable biogroup variants accounted for about 87% of the 464 P. haemolytica isolates from bighorns, but prevalences of specific biogroups were not affected by vaccination. Bighorns receiving 1 or 2 vaccine doses showed marked elevations in leukotoxin neutralizing antibody titers beginning 1 wk after vaccination. Agglutinating antibody titers to serotype A1 and A2 surface antigens were also elevated in vaccinated bighorns within 2 wk after vaccination; agglutinating antibody titers to serotype T10 surface antigens were relatively high in all three groups but appeared unaffected by vaccination. Vaccination 7 to 14 wk prior to parturition elevated leukotoxin neutralizing antibody titers in colostrum, but neither leukotoxin neutralizing nor serotype A1 surface antigen agglutinating antibody titers differed through 16 wk of age among lambs born to dams from different vaccine dose groups. Our data demonstrate that this multivalent P. haemolytica vaccine is safe and stimulates marked antibody responses in bighorn sheep. Further evaluation of this vaccine as a tool in preventing and managing pasteurellosis in bighorn sheep appears warranted.