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ELECTRONIC ARTICLE |
* Epidemiology and Surveillance Division, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia
Division of Epidemiology, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland
Department of Internal Medicine (Allergy Division), Naval Medical Center, San Diego, California
|| Allergic Diseases Research Laboratory
¶ Mayo Vaccine Research Group, Mayo Clinic and Foundation, Rochester, Minnesota
# Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Methods. We conducted a retrospective case-control study. Cases of anaphylaxis that met a predefined case definition were identified from the US Vaccine Adverse Event Reporting System (VAERS). Mayo Clinic patients who received MMR vaccine uneventfully served as controls. The study subjects were interviewed to obtain the history of allergies. Sera from study subjects and their matched controls were tested for IgE antibodies to gelatin, whole egg, and vaccine viral antigens using solid-phase radioimmunoassay. Data from the Biologics Surveillance System on annual numbers of doses of MMR and varicella vaccines distributed in the United States were used to evaluate possible changes in reporting of selected allergic adverse events.
Results. Fifty-seven study subjects were recruited into the study and interviewed. Of these, 22 provided serum samples for IgE testing. Twenty-seven subjects served as a comparison group and provided a sample for IgE testing; 21 of these completed an allergy history questionnaire. Self-reported history of food allergies was present more frequently in the interviewed study subjects than in the controls, whereas the proportions of people with other characteristics were similar in both groups. None of the interviewed people had a history of food allergy to gelatin. The level of anti-gelatin IgE antibodies was significantly higher among study subjects than among controls, whereas the levels of IgE antibodies against egg and all 3 viral antigens did not differ significantly. Of 22 study subjects, 6 (27%) tested positive for anti-gelatin IgE, whereas none of the 27 controls did. The rate of anaphylactic reactions reported to VAERS after measles virus-containing immunization in the United States between 1991 and 1997 is 1.8 per 1 million doses distributed. No substantial increase in the number of reported allergic events after frequently used gelatin containing MMR and varicella vaccines could be observed during the first 4 years (1997–2000) since the introduction of diphtheria-tetanus-acellular pertussis vaccines for use in infancy.
Conclusion. Anaphylactic reactions to MMR in the United States are rare. The reporting rate has the same order of magnitude as estimates from other countries. Almost one fourth of patients with reported anaphylaxis after MMR seem to have hypersensitivity to gelatin in the vaccine. They may be at higher risk of developing anaphylaxis to subsequent doses of other gelatin-containing vaccines. These people should seek an allergy evaluation before such immunization.
Key Words: anaphylaxis • gelatin • measles-mumps-rubella vaccine • VAERS • vaccine adverse reactions
Abbreviations: MMR, measles-mumps-rubella • IgE, immunoglobulin E • DTaP, diphtheria-tetanus-acellular pertussis • CDC, Centers for Disease Control and Prevention • VAERS, Vaccine Adverse Event Reporting System • COSTART, Coding Symbols for Thesaurus of Adverse Reaction Terms • CPM, counts per minute • OPV, oral polio vaccine • HiB, Haemophilus influenzae type B
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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In 1993, Kelso et al6 first documented a case in which an anaphylactic reaction after MMR II was traced to the gelatin component of the vaccine (14.5 mg of gelatin per dose, according to the manufacturer). After this US report, several Japanese researchers found a similar association in an unusually high proportion of patients. Sakaguchi et al7,8 found that 24 of 26 children with systemic immediate reactions to measles vaccination had anti-gelatin IgE antibodies; of these, 7 had allergic signs and symptoms on ingestion of gelatin-containing foods (2 had reactions before vaccination, and 5 had reactions after vaccination). All of the control children without allergic reactions to the vaccines lacked anti-gelatin IgE. Subsequent studies from Japan suggested that immediate and delayed allergic reactions after other gelatin-containing vaccines (against varicella and Japanese encephalitis) may have been associated with prevaccine sensitization to gelatin.9,10 Nakayama et al11 suggested that usage of gelatin-containing diphtheria-tetanus-acellular pertussis (DTaP) vaccines before immunization with live virus vaccines may have served as a possible source of such a sensitization. Only 1 other publication from the United States reported a link between an immediate hypersensitivity reaction (severe urticaria) to a gelatin-containing vaccine (Varivax) and presence of hypersensitivity to gelatin demonstrated by a positive intradermal test with porcine gelatin in the same concentration as in the vaccine.12 Neither of the 2 patients described had food allergy to gelatin before varicella immunization.
Objectives of this study were to examine whether people with anaphylaxis after receipt of measles virus-containing vaccines in the United States have an unusual profile of self-reported allergies and whether they have significantly higher levels of anti-gelatin IgE antibodies compared with healthy controls. We were also interested in reviewing trends in reporting of selected hypersensitivity adverse events reported after MMR and varicella immunization for the periods before and after introduction of gelatin-containing DTaP vaccines in the US vaccination schedule.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We attempted to contact by mail all probable and possible cases of anaphylaxis reported to VAERS between 1991 and 1997. Those who agreed to participate in the study were interviewed by telephone about the vaccine adverse event and history of possible allergies to food, environment, and drugs. Those who mentioned any allergy were asked to specify to what they were allergic and the timing of onset and symptoms. For study subjects younger than 17 years, parents or guardians were interviewed. The interviewer was not blinded to the case-control status of the study participants. People who completed the interview were asked to submit a blood sample through their health care providers.
Two sources of controls were available for this study: 1) people who reported nonallergic adverse events to VAERS after MMR vaccination (eg, local or a systemic reactions occurring 1–30 days after immunization) and 2) people from the Mayo clinic primary care population, as well as Mayo clinic employees, who received MMR in the past without clinically apparent adverse symptoms. Candidate controls from both groups were matched to study subjects on gender, year of vaccination, and age at vaccination (for study subjects who were younger than 6 years, matched controls were born within 6 months of study subjects; for study subjects who were aged 6–11 years, within 1 year; and for study subjects who were aged 12 and older, within 5 years). Several candidate controls per study subject were available from both sources. For controls from VAERS, the 3 best matched controls from VAERS were contacted, interviewed, and asked to provide a blood sample in the same manner as the study subjects. Mayo clinic controls (or, in case of a minor, their parents), randomly selected from a list of available matches, were contacted via letter and asked to participate in the study and fill in an allergy questionnaire. Those who responded with an affirmative answer were contacted again with instructions to obtain a venipuncture at the clinic. Controls who consented but did not fill in the questionnaire could still provide a blood sample for laboratory testing.
The samples were received and stored at -18°C at a CDC laboratory. Sera from each study subject and its matched controls were tested on the same day, in the same assay. IgE antibodies to gelatin, whole egg, and vaccine viral antigens were measured by solid-phase radioimmunoassay in the Allergic Diseases Research Laboratory at the Mayo Clinic. Methods for preparing and performing the IgE antibody immunoassay appear elsewhere.6,17 The laboratory workers were blinded to the case-control status of the samples. The results of IgE testing were expressed as the percentage of the total radioactive counts per minute (CPM) that were bound to the solid-phase allergen. Differences in the proportion of people with reported allergies among study subjects and controls were analyzed using 
2 and Fisher exact tests. The significance of differences in mean CPM values between the study subjects and control groups was determined using paired t tests. To account for differences in matching (there were 1–3 controls per study subjects), as well as for inter- and intra-assay variability (sera were tested in 2 batches), we used a more appropriate regression method—the random effect model.18 To determine the proportion of study subjects with positive IgE test results, we used the following approach. We first calculated the mean CPM value and its standard deviation for the controls. Then the threshold level of the radioimmunoassay test was defined as mean ± 3 standard deviations. Subjects with CPM above this cutoff value were considered to have positive results.
To assess recent trends in reporting of selected hypersensitivity adverse events, we used automated VAERS data. We determined yearly numbers of reports after MMR and varicella vaccines (administered alone or in combination with each other and/or other vaccines) that were submitted between 1991 and 2000 and that had COSTART codes for anaphylaxis, urticaria, and/or wheezing and the onset of symptoms on the day of vaccination. Year-to-year changes in these numbers were compared with trends in annual vaccine distribution based on data from the CDC Biologics Surveillance System (expressed as millions of doses of the corresponding vaccines distributed).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Among 57 study subjects who completed the telephone survey, 34 (60%) reported having a history of sensitivity to food, drug, and/or environmental allergens. Of these, food allergies were reported by 16 (pork, beef, eggs, chicken, turkey, dairy products, fish, soy, lentils, peanuts, and chocolate); 16 people remembered hypersensitivity reaction to drugs (penicillin, vancomycin, cephalosporin, amoxicillin-clavulanate potassium combination, codeine, aspirin, ibuprofen, trimethoprim, and sulfamethoxazole); 1 had latex allergy, 1 had allergy to neomycin; 15 were sensitive to environmental allergens (dust mites, mold spores, pollen, grass, cats, dogs, horses, and weeds), and 11 had a history of asthma.
Twenty VAERS controls were recruited and completed the allergy history questionnaire. None of these people reported having allergies to foods; 4 reported hypersensitivity to drugs (cefaclor, amoxicillin-clavulanate potassium combination, codeine, and penicillin), 1 reported hypersensitivity to latex, 3 reported hypersensitivity to environmental allergens (pollen, cats), and 4 had a history of asthma. Only 1 of these VAERS controls submitted a blood sample for IgE testing, however. Because of the difficulties with obtaining sera from these subjects, we decided to use controls from the Mayo Clinic for the laboratory analysis part of the study. Nevertheless, the information received from the interviewed VAERS controls was used in the analysis of allergy histories.
A total of 27 Mayo Clinic controls were recruited and provided a blood sample for IgE testing. As a result, 1 study subject had 3 matched controls and 3 study subjects had 2 matched controls; the remaining 18 study subjects had 1 matched control each. Of the 27 controls, 21 also completed an allergy history questionnaire. None reported having allergy to food; 4 had drug allergies (amoxicillin-clavulanate potassium combination, sulfa), 1 had allergy to latex, and 3 had a history of asthma.
Table 1 compares the reported history of allergies among all interviewed study subjects and controls. Of 57 study subjects, 16 (28%) reported having allergy to foods, whereas none of the controls had reported food allergy. There were no statistically significant differences between study subjects and controls in proportions of people with hypersensitivity to drugs, including neomycin, environmental allergens, and latex. None of the study subjects or controls interviewed recalled having allergy to gelatin.
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Study subject 2 (positive for anti-gelatin IgE): On August 15, 1995, a 17-year-old healthy girl developed swelling of lips, wheezing, and trouble swallowing (no hives) 2 minutes after MMR vaccination, diagnosed as anaphylactoid reaction. She was treated with epinephrine and steroids and recovered. The patient reported a history of hay fever, wheezing, and lightheadedness every time she eats chicken or turkey meat, but no symptoms after eating eggs.
Study subject 3 (positive for anti-gelatin IgE): A 12-year-old boy, with mild symptoms of streptococcal pharyngitis, received MMR vaccine on January 8, 1996. Ten minutes after the injection, he developed rhinorrhea and sneezing, followed by tachycardia and hives. The patient was treated with epinephrine, diphenhydramine, and steroids. The reaction resolved in 2 hours.
Study subject 10 (positive for anti-measles IgE): On June 4, 1993, a 15-year-old girl with a history of allergies to pork and lamb meat developed rash on the neck and in the abdomen area, edema and redness of face, itchy throat, and coughing 15 minutes after MMR injection. She fully recovered after treatment with diphenhydramine.
Study subject 13 (positive for anti-gelatin IgE): On January 17, 1992, a 15-month-old healthy boy received a dose of HiB vaccine and then, 5 minutes later, an MMR injection. Immediately after that (within 1 minute), he developed generalized flushing progressing to facial edema and facial and upper body urticaria (no other symptoms). He responded well to epinephrine, diphenhydramine, and dexamethasone. On the next day at home, he had more urticaria treated by the mother with epinephrine, prednisone, and cyproheptadine. The mother observed recurring urticaria throughout most of the child’s life, not consistently coinciding with any specific foods. The boy had a history of eating eggs without problems. On an allergy examination, a test for dermographism produced an urticarial reaction. Screening prick tests with common foods were negative. Prick and intradermal tests with MMR vaccine were also negative. The patient was diagnosed with chronic urticaria with dermographism by a consulting allergist.
Study subject 14 (positive for anti-gelatin IgE): A 23-year-old man without a history of allergies received live measles vaccine on March 4, 1994. Approximately 30 minutes after injection, he experienced visual disturbance (pupils dilated to 7 mm), flushing, numbness to the lips, and difficulty swallowing. He recovered after treatment with epinephrine and diphenhydramine.
Study subject 22 (positive for anti-gelatin IgE): A 5-year-old healthy girl, with a history of hypersensitivity to sulfa, monosodium glutamate, and bee stings, received a dose of MMR vaccine, along with DTaP and OPV on August 7, 1995. In 20 minutes, she developed generalized urticaria and edema. She recovered after treatment with epinephrine and diphenhydramine.
On the basis of the total number of probable and possible cases of anaphylaxis manually reviewed in this study (n = 168), as well as the estimated number of doses of MMR, measles, and measles-rubella vaccines distributed in the United States between 1991 and 1997 (approximately 94 000 000), we can calculate a reporting rate of approximately 1.8 cases per 1 000 000 vaccine doses.
Our review of VAERS automated data indicated that there were no substantial increases in the number of selected hypersensitivity reports (coded as anaphylaxis, urticaria or wheezing) during the first 4 years since the introduction of DTaP vaccines for the primary series in the United States in late 1996 to early 1997. Yearly numbers of such reports after MMR (administered alone or in combination with other vaccines, except varicella vaccine) were stable and paralleled MMR vaccine distribution data (Fig 1). A gradual increase in the number of these reports after varicella vaccine (administered alone or simultaneously with other vaccines, including MMR) also parallels a steady varicella vaccine uptake since its licensure in 1995.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Findings similar to ours were recently presented by a group of Finnish investigators.23 In a large, prospective study that examined the reported adverse reactions after the use of almost 3 000 000 doses of MMR II in 1.8 million individuals, they identified 73 presumably allergic reactions, including 30 cases of anaphylaxis. Presence of anti-gelatin IgE antibodies was found in 5 of the 36 individuals (14%), including 2 vaccinees with anaphylaxis when tested in a CAP System radioallergosorbent test. In a more sensitive Immunospot test, 10 (28%) of 36 sera tested had IgE antibodies to gelatin. Significantly more anti-gelatin IgE-positive people (9 of 10) had a history of allergic disorders compared with those who tested negative (9 of 26). In contrast with what has been reported by us and the Finnish investigators, the vast majority of children with immediate-type reaction to measles, mumps, rubella, and varicella single-antigen vaccines in Japan had positive results of IgE tests as measured in the CAP system (86%, 92%, 100%, and 90%, respectively).24 We believe that this difference is most likely explained by the differences in the type of gelatin used as a part of vaccine stabilizer formulation in live virus vaccines in these countries (Table 4). MMR II gelatin of porcine origin is highly hydrolyzed and has very low molecular weight. In contrast, bovine gelatin added to the single-antigen measles, mumps, and rubella vaccines produced in Japan in the mid-1990s was only partially hydrolyzed and contained a small amount of high molecular weight gelatin. According to Nakayama et al,25 modifications in the stabilizer formulation for the measles and mumps monovalent vaccines (ie, the 1998 switch in Japan to more hydrolyzed porcine gelatin) may have contributed to a decrease in the incidence of allergic reactions after these vaccines. However, the authors also note that the major reason for this observed decrease is discontinuation of the use of gelatin-containing DTaP vaccines. In the United States, several vaccines that contain gelatin in various quantities were introduced to the national immunization program in the middle of the 1990s (Table 5). In 1995, varicella vaccine (Varivax) was licensed for use in children 12 months to 12 years of age. Since 1997, 2 DTaP vaccines (Acel-Imune and Tripedia) became widely used in the United States for the prime series administered before MMR and varicella immunization. The amount of gelatin in both of these DTaP vaccines (Table 5) is comparable to the amounts of gelatin in 4 of the 6 DTaP products used in Japan (48–200 µg/mL).11 In light of what was reported from Japan about hypothesized sensitization to gelatin after changes in the Japanese immunization schedule since 1994 and increased reporting of allergic reactions, one would expect to see a similar increase in the United States.11,26 However, our review of reporting trends of anaphylaxis, urticaria, and wheezing after MMR and varicella vaccination in VAERS does not support this hypothesis (Fig 1). Nonetheless, our cases with anti-gelatin IgE required some previous exposure to gelatin to become sensitized, and this may have come through ingestion of gelatin-containing food or injection of gelatin-containing vaccines.
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Overall the reporting rate of probable and possible anaphylaxis in our study (<2 per 1 000 000 doses of the vaccine distributed) was somewhat lower than estimates from other countries. The highest reporting rate of 10 per 1 000 000 doses of MMR distributed was observed in Finland. A rate of 4.1 cases of anaphylactic and anaphylactoid reactions per 1 000 000 doses of MMR II (Merck) distributed, as reported from Australia after the 1998 Australian measles control campaign, has the same magnitude as the minimum estimated incidence of severe anaphylaxis after measles, mumps, rubella, and varicella single-antigen vaccines in Japan from 1995 to 1997 (6.8, 7.3, 4.4, and 10.3 per 1 million doses of the corresponding vaccine).24,28 However, comparing these rates is difficult because of the different sensitivities of national surveillance systems for vaccine adverse events.29
This study had several limitations. VAERS, like all passive surveillance systems, is subject to underreporting. The reporting rates that we found thus should be considered minimum estimates.30 In addition, not all potential study subjects could be evaluated because of incomplete data provided with the VAERS report. Because of that, the possibility of misclassification of cases exists. There was a potential for recall bias during collection of allergy history information (ie, the controls could be less likely to remember past allergic reactions); however, we did not believe that the differences in recall were significant. Because of its retrospective design, the recruitment rate in this study was lower than hoped for (37% of study candidates selected from VAERS were interviewed, of these 39% agreed to be tested). However, we are not aware of reasons that the decision to participate in this study would relate to the levels of anti-gelatin IgE and, as a result, bias our findings.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Reprint requests to (V.P.) Vaccine Safety and Development Activity, National Immunization Program, Centers for Disease Control and Prevention, Mail Stop E-61, 1600 Clifton Rd, Atlanta, GA 30333. E-mail: vpool{at}cdc.gov
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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N. A. Halsey MD The human papillomavirus vaccine and risk of anaphylaxis Can. Med. Assoc. J., September 9, 2008; 179(6): 509 - 510. [Full Text] [PDF]
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