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Epidemiologic Notes and Reports Systemic Allergic Reactions Following Immunization with Human Diploid Cell Rabies Vaccine

Human diploid cell rabies vaccine (HDCV) has been licensed for use since June 9, 1980. Approximately 400,000 doses have been administered to an estimated 100,000 persons in the United States since that time. The majority of these were for postexposure treatments. Information on possible adverse reactions to HDCV has been collected by CDC from individual physicians and from medical personnel in charge of providing rabies preexposure and postexposure prophylaxis to large cohorts of persons, such as veterinary students and animal-control workers. During the past 46 months, 108 clinical reports of systemic allergic reactions ranging from hives to anaphylaxis were reported to CDC (11 per 10,000 vaccinees). Few patients required hospitalization, and no deaths secondary to the reactions were reported.

The reports of systemic allergic reactions included nine cases of presumed Type I immediate hypersensitivity (1/10,000), 87 cases of presumed Type III hypersensitivity reactions (9/10,000), and 12 cases of allergic reactions of indeterminate type (Table 1). These reactions were classified on the basis of clinical observations only. Type I hypersensitivity reactions refer to immunoglobulin E (IgE)-mediated immediate reactions, such as anaphylaxis and atopy, whereas Type III hypersensitivity refers to immunoglobulin G (IgG)- or immunoglobulin M (IgM)-mediated immune complex disease characterized by antigen-antibody complex deposition in tissues, complement activation, and inflammation (1).

Hypersensitivity reactions presumed to be Type III occurred 2-21 days after a dose or doses of HDCV; patients presented with a generalized or pruritic rash or urticaria, sometimes accompanied by arthralgias, angioedema, fever, nausea, vomiting, and malaise. All nine of the presumed immediate hypersensitivity reactions occurred during either primary preexposure immunization (vaccine administered on days 0, 7, and 21 or 28) or postexposure immunization (vaccine on days 0, 3, 7, 14, and 28 and rabies immune globulin on day 0). However, 81 (93%) of 87 of the presumed Type III hypersensitivity reactions were observed following booster immunization. Although the presumed Type III reactions occurred in six persons during primary immunization series, none were observed following the first dose of the primary series.

Routine boosters of HDCV at 2-year intervals have been recommended for persons with continuing risks of exposure. As increasing numbers of persons received their first routine 2-year boosters, reports of presumed Type III hypersensitivity reactions increased in frequency. In approximately half of known cohorts who received booster immunizations between January 1982 and March 1984, some recipients had presumed Type III hypersensitivity reactions. Sixty-seven (7%) of 962 persons in these cohorts fit the above case description for presumed Type III hypersensivity reactions.

Table 2 illustrates the clinical features in three of the cohorts reporting presumed Type III reactions following booster immunization with HDCV. When performed, urinalyses, blood urea nitrogen (BUN), and serum creatinine determinations have been normal. Elevated white blood cell counts ranging from 14,000 to 24,000 (predominantly polymorphonuclear leukocytes) were reported in two cases. Serum complement levels (C-3, C-4, and CH-50) were depressed in two patients when serum was drawn at the time of most active clinical symptoms; one of these also had detectable cryoglobulins. Serum-complement levels were normal in five other patients whose sera were collected at other times. Respiratory distress was infrequently seen. Most patients' symptoms improved within 2-3 days when treated with antihistamines, but a few required systemic corticosteroids and epinephrine.

Preliminary analysis of epidemiologic features of the illness in several cohorts revealed a male/female relative risk of 2.3 (95% confidence limits, 1.2-4.4). No significant associations have been demonstrated between persons who reported presumed Type III hypersensitivity reactions and age, route of primary or booster immunization (intramuscular or intradermal), timing of booster after primary immunization, history of other allergies, or history of previous immunization with rabies vaccines other than HDCV. HDCV produced by both Merieux Institute and Wyeth Laboratories has been associated with reactions. In two groups for which serologic data were available, no difference was shown in pre-booster antibody titers between reactors and nonreactors, but post-booster titers were significantly higher in those who developed reactions. Most presumed Type III reactions were reported to have occurred following booster doses, but six occurred following two or more doses of HDCV given for primary immunization. Reported by P Schnurrenberger, DVM, School of Veterinary Medicine, Auburn University, Auburn, Alabama; D Dreesen, DVM, J Brown, DVM, PhD, School of Veterinary Medicine, University of Georgia, A Deutsch, MD, Athens, Georgia; M Burridge, PhD, College of Veterinary Medicine, University of Florida, Gainesville; D Howard, PhD, School of Veterinary Medicine, Kansas State University, Manhattan; JT Bell, DVM, College of Veterinary Medicine, Mississippi State University, Mississippi State; G Quinnan, MD, Director, Div of Virology, Center for Drug and Biologics, US Food and Drug Administration; Div of Host Factors, Div of Viral Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Primary immunization with HDCV appears to sensitize some recipients to an, as yet, unidentified component of the vaccine. When booster doses of HDCV are then administered, these persons develop a hypersensitivity reaction clinically consistent with Type III immune complex disease. Until this reaction problem can be resolved, it would be prudent to carefully assess each use of rabies vaccine for routine booster immunization. Persons who have experienced Type III hypersensivity reactions should receive no further doses of HDCV unless: (1) they are exposed to rabies* or (2) they are truly likely to be inapparently and/or unavoidably exposed to rabies virus and have unsatisfactory antibody titers. The routine use of booster immunization in persons without histories of hypersensivity reactions is clearly indicated only in those subjected to inapparent and/or unavoidable exposures to rabies virus. All available data suggest an anamnestic antibody response will occur in any person who previously received primary preexposure immunization with HDCV, even when the antibody titer at the time of the booster was low or undetectable.

Individuals with histories of presumed Type III hypersensitivity to HDCV may be at higher risk of subsequent hypersensitivity reactions, and vaccine should be administered under appropriate medical supervision.


  1. Coombs RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, Coombs RRA, Lachmann PJ, eds. Clinical aspects of immunology. 3rd ed. Oxford: Blackwell Scientific Publications, 1975:761-81. *Postexposure prophylaxis in previously immunized persons consists of two 1-ml intramuscular doses of HDCV, one each on days 0 and 3.

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