Human Exposure to Brucella abortus Strain RB51 -- Kansas, 1997

On May 26-27, 1997, nine persons (a farmer, four veterinary clinicians, and four veterinary students) in Manhattan, Kansas, participated in an attempted vaginal delivery, a cesarean delivery, and a necropsy on a stillborn calf that died because of Brucella abortus infection. The infection was confirmed by isolation of B. abortus from placental and fetal lung tissue cultures. The National Animal Disease Center, U.S. Department of Agriculture (USDA), identified the B. abortus isolate from the calf as the RB51 vaccine strain. RB51 is a live, attenuated strain that was licensed conditionally by the Veterinary Services, Animal and Plant Health Inspection Service, USDA, on February 23, 1996, for vaccination of cattle in the United States. * Before 1996, vaccine was made by using the S19 strain. This report describes occupational exposure to animals infected with the RB51 strain and emphasizes the need for surveillance of unintentional exposure of humans to RB51 to assess outcomes of such exposures.

The vaccine had caused active B. abortus infection because the 14-month-old heifer delivering the calf was not known to be pregnant when she was vaccinated with RB51 at approximately 8 months of age, which was within the specified age range for vaccination. The heifer was administered the RB51 vaccine dosage recommended for calves, which was 10 times the dosage recommended for adult or pregnant cattle.

The heifer was euthanized after surgery because of the poor prognosis following a uterine rupture and the poor general condition of the animal. Necropsy findings included diffuse placentitis in the heifer and fetal pneumonitis. Evidence that intrauterine infection was caused by the RB51 vaccine strain, and not by field strains of B. abortus or by S19, included immunohistochemical staining specific for RB51 (negative for S19), RB51-specific titer of greater than 1:10,000 on experimental dot-blot assay measuring antibody to RB51, and RB51-specific DNA sequences identified by polymerase chain reaction (PCR).

Persons at risk for infection with RB51 were those who contacted the calf, placenta, blood, or amniotic fluid without wearing gloves, masks, or eye protection. Six women and three men (age range: 23-45 years) were at risk for infection. None of the exposed persons reported having previously had brucellosis or being unintentionally inoculated with Brucella vaccine.

Within 1 week after exposure, eight of the nine persons started a prophylactic regimen of doxycycline (100 mg twice daily for 21-24 days). Three of these persons also received rifampin (600 mg once daily for 4-21 days). None of the exposed persons showed signs or symptoms consistent with brucellosis during the 6-month follow-up period.

Since conditional licensure of the RB51 vaccine, 32 instances of unintentional inoculation or conjunctival exposure to the RB51 vaccine have been reported to the vaccine manufacturer or CDC. Three of the 32 persons, all of whom were unintentionally inoculated while vaccinating cattle, reported inflammation at the inoculation site; another person reported intermittent fever, chills, headache, and myalgia and had elevated levels of serum transaminase and lactate dehydrogenase.

Reported by: B Stauffer, Pottawatomie County Health Dept; J Reppert, MD, Lafene Health Center, D Van Metre, DVM, R Fingland, DVM, G Kennedy, DVM, Kansas State Univ, Manhattan; G Hansen, DVM, G Pezzino, MD, State Epidemiologist, Kansas Dept of Health and Environment. S Olsen, DVM, National Animal Disease Center, Agricultural Research Svc; D Ewalt, PhD, Animal and Plant Health Inspection Svc, US Dept of Agriculture. Meningitis and Special Pathogens Br, Div of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Brucellosis, also known as "undulant fever" or "Bangs disease," is a systemic infection caused by Brucella sp., small Gram-negative coccobacilli that can infect cattle (infection with B. abortus), goats and sheep (B. melitensis), pigs (B. suis), and dogs (B. canis). Worldwide, brucellosis usually occurs in geographic areas with large populations of these animal hosts (1,2). Disease manifestations in animals depend on age and gestational status. The primary sign of infection in female animals is abortion, and in male animals, epididymitis.

Brucellosis in humans is a systemic disease that has an acute or insidious onset; signs and symptoms of the disease include continued, intermittent, or irregular fever of variable duration; headache; weakness; profuse sweaty chills; arthralgia; depression; weight loss; and generalized aches (3). The disease can persist for periods ranging from days to years if not treated properly. B. abortus RB51 infection in humans is possible but has not been documented.

Through a cooperative state and federal effort, the United States is now approaching eradication of the field strain of B. abortus in domestic cattle and bison herds. In the United States, the Brucellosis Eradication Program (BEP) was established formally in 1954 to prevent the considerable economic losses caused by abortions that occurred before, or in the absence of, prophylactic vaccination and to reduce transmission of the disease to humans. Vaccination against brucellosis and testing or depopulation of affected herds have reduced the number of infected cattle herds in the United States. From 1952 to January 1998, the number of known brucellosis-affected herds decreased from 124,000 to 15, and annual losses resulting from abortions, decreased milk production, and reduced breeding efficiency decreased from approximately $400 million to approximately $2.5 million (unadjusted for inflation). In 1996, approximately 5.5 million calves were vaccinated against brucellosis, 11.8 million cattle were tested, and 112 affected herds were depopulated at a total cost of approximately $20.3 million (USDA, unpublished data, 1998). Because these efforts have been successful, the BEP has set a goal of eliminating brucellosis in domestic cattle in the United States by the end of 1998. Bison and elk in the northern Rocky Mountain states are still important reservoirs of B. abortus and provide a potential for reintroduction of brucellosis into domestic livestock (4).

One element of the cooperative state and federal brucellosis eradication efforts is the use of approved Brucella vaccines on female cattle and female bison. The RB51 vaccine strain, a genetically stable, rough morphology mutant of B. abortus strain 2308 that lacks the polysaccharide O-side chain on the surface of the bacteria, replaced the S19 vaccine in 1996 (5). The RB51 vaccine is used in 49 states, ** Puerto Rico, and the U.S. Virgin Islands; it was developed by serial passage in selective media, which resulted in a strain that was equally immunogenic, but less virulent, than the S19 vaccine. In mice, sheep, and cattle, RB51 protects against experimental challenge with B. abortus (6) and is less abortifacient than S19 if administered during pregnancy; abortions have been reported rarely among cattle vaccinated during mid-gestation (7).

Vaccination with RB51 does not result in measurable antibody titers to B. abortus using standard diagnostic tests. This is an important feature for use in efforts to eradicate brucellosis in domestic cattle. Strain 19 causes vaccinated animals to produce antibodies that are indistinguishable on standard diagnostic tests from the antibodies produced by animals infected with Brucella. Because the RB51 vaccine does not cause vaccinated cattle to produce interfering antibody titers, replacing the S19 vaccine with the RB51 vaccine will eliminate the costs associated with the retesting and tracebacks of false-positive reactors. The estimated combined field and laboratory gross savings from using RB51 vaccine total almost $7.45 million per year.

Detection of possible human infection with the RB51 vaccine strain and development of recommendations for chemoprophylaxis are complicated by two characteristics of the new vaccine strain. First, immunologic response to the RB51 strain is not detected on routinely available serologic tests for Brucella. Experimental dot-blot assay employed for serologic measurement of RB51 postvaccination titers has been evaluated under experimental and field conditions in cattle, but this assay has not been validated by using human serum (8). This assay and PCR are being developed by CDC's Special Bacteriology Reference Laboratory for detection of human RB51 infection. Second, RB51 was derived by selection in rifampin-enriched media and is resistant to rifampin in vitro. For postexposure prophylaxis against the previously used live Brucella (S19) vaccine, CDC recommended concomitant regimens of doxycycline and rifampin. Recommendations for antibiotic selection and treatment duration for postexposure prophylaxis to RB51 are difficult to make because virulence of the strain in humans is unknown, and the strain is resistant to rifampin in vitro. If the RB51 strain poses a risk for human infection, the chemoprophylaxis recommendations will require modification. A reasonable interim course of postexposure prophylaxis for adults would be doxycycline 100 mg orally twice daily for 21 days, with addition of other suitable antimicrobials if evidence of infection appears.

Veterinarians and other animal health-care personnel should be made aware of the possible risk for infection associated with the veterinary use of RB51. The epidemiologic conditions leading to possible infection in farmers and veterinarians are not unusual. Using the estimated rate of unintentional needlestick injuries among health-care workers in U.S. hospitals (9) as a surrogate for unintentional inoculations with RB51, at least 11,000 needlestick injuries per 5.5 million injections (i.e., the number of Brucella vaccine doses administered in 1996) can be expected during 1 year. Exposure of farm and veterinary personnel to infected calves or placentas is another potential source of human infection, especially on farms where heifers might be vaccinated mistakenly during mid-gestation (i.e., at which time the calf fetus may be at greatest risk for postvaccination brucellosis) (7).

CDC has established a registry of human exposures to the RB51 vaccine strain; after unintentional, conjunctival, or other suspected exposure to RB51, veterinarians, clinicians, or health department personnel should contact CDC's Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, to report the incident and discuss additional recommendations; telephone (404) 639-3158; fax (404) 639-0817.

References

1. Corbel MJ. Brucellosis: an overview. Emerg Infect Dis 1997;3:213-21.

2. Young EJ. Human brucellosis. Rev Infect Dis 1983;5:821-42.

3. Benenson AS. Brucellosis. In: Control of communicable diseases manual: an official report of the American Public Health Association. 16th ed. Washington, DC: American Public Health Association, 1995.

4. Frye GH, Gilsdorf MJ, Taft A. Report on the status of the Cooperative State-Federal Brucellosis Eradication Program. Presented at the meeting of the U.S. Animal Health Association, Little Rock, Arkansas, October 14-18, 1996.

5. Schurig GG, Roop RM II, Bagchi T, Boyle S, Buhrman D, Sriranganathan N. Biological properties of RB51: a stable rough strain of Brucella abortus. Vet Microbiol 1991;28:171-88.

6. Cheville NF, Jensen AE, Halling SM, et al. Bacterial survival, lymph node changes, and immunologic responses of cattle vaccinated with standard and mutant strains of Brucella abortus. Am J Vet Res 1992;53:1881-8.

7. Palmer MV, Cheville NF, Jensen AE. Experimental infection of pregnant cattle with the vaccine candidate Brucella abortus strain RB51: pathologic, bacteriologic, and serologic findings. Vet Pathol 1996;33:682-91.

8. Olsen SC, Stevens MG, Chevile NF, Schurig G. Experimental use of a dot-blot assay to measure serologic responses of cattle vaccinated with Brucella abortus strain RB51. J Vet Diagn Invest 1997;9:363-7.

9. Henderson DK, Fahey BJ, Willy M. Risk for occupational transmission of human immunodeficiency virus type 1 (HIV-1) associated with clinical exposures: a prospective evaluation. Ann Intern Med 1990;113:740-6.

* The vaccine was licensed conditionally to allow accumulation of additional data on field use under controlled conditions. 

** Pending depletion of remaining stores of the previously used standard vaccine.

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