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PEDIATRICS Vol. 113 No. 1 January 2004, pp. 170-171

Gelatin Allergy

Tetsuo Nakayama, MD
Takuji Kumagai, MD
Laboratory of Viral Infection Control Kitasato Institutes for Life Sciences Tokyo 108-8641, Japan
Pediatric Allergy and Infectious Diseases Society of Sapporo Sapporo 004-0013, Japan

To the Editor.—

We feel relieved after reading the paper by Pool et al and the VAERS Team1 on the prevalence of gelatin allergy in the United States. They conducted a retrospective analysis after measles-mumps-rubella (MMR) vaccination. Among 26 cases of anaphylaxis, only 6 (27%) were positive for anti-gelatin IgE antibodies. The rate of anaphylactic reactions reported to the VAERS is 1.8 per 1 million doses, and no substantial increase in number of reported allergic events after MMR was observed since the introduction of gelatin-containing diptheria-tetanus-acellular pertussis vaccine (DTaP) in 1997. We reported that the cases of anaphylaxis or urticaria showed high positive rates of anti-gelatin IgE antibodies, and we speculated the causal relationship of the sensitization by gelatin-containing DTaP.2 Discontinuation of gelatin-containing DTaP reduced the incidence of anaphylaxis after 1999,3 and we have no report of anaphylaxis after vaccination with live virus vaccines containing hydrolyzed porcine gelatin in the last few years. Thus, we were solicitous for the incidence of anaphylaxis in the United States, but they reported that the incidence of gelatin allergy was lower than that observed in Japan.

But we suppose the different prevalence of anti-gelatin IgE depends on sensitivity for the detection of IgE antibodies against gelatin and especially on the nature of antigen for the assay. The same was the reason why the sensitization against gelatin increased in Japan. Some vaccine manufactures used poorly hydrolyzed bovine gelatin in DTaP, and some used hydrolyzed porcine gelatin. A large number of patients with anaphylaxis had a history of having DTaP containing poorly hydrolyzed bovine gelatin. Poorly hydrolyzed bovine gelatin was immunogenic when administered with alum adjuvant. They did not mention the nature of gelatin in DTaP in the United States in their paper, and we suppose that it was probably highly hydrolyzed porcine gelatin (2–3 kDa). Although it is considered as less immunogenic, gelatin-free DTaP is desirable to avoid the possibility of unnecessary sensitization against gelatin.

REFERENCES

  1. Pool V, Braun MM, Kelso JM, et al. Prevalence of anti-gelatin Ig E antibodies in people with anaphylaxis after measles-mumps-rubella vaccine in the United States. Pediatrics.2002; 110(6) . Available at: http://www.pediatrics.org/cgi/content/full/110/6/e71
  2. Nakayama T, Aizawa C, Kuno-Sakai H. A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin-containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids. J Allergy Clin Immunol.1999; 103 :321 –325[CrossRef][ISI][Medline]
  3. Nakayama T, Aizawa C. Change in gelatin content of vaccines associated with reduction in reports of allergic reactions. J Allergy Clin Immunol.2000; 106 :591 –592[CrossRef][ISI][Medline]
 
Vitali Pool, MD*
Gina Mootrey, DO, MPH*
Robert T. Chen, MD, MA*
Paul M. Gargiullo, PhD{ddagger}
M. Miles Braun, MD, MPH
John M. Kelso, MD
John W. Yunginger, MD
Robert M. Jacobson, MD*
* Immunization Safety Branch
{ddagger} Viral Vaccine Preventable Diseases Branch Epidemiology and Surveillance Division National Immunization Program Centers for Disease Control and Prevention Atlanta, GA 30333, USA
Division of Epidemiology Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research Food and Drug Administration Rockville, MD 20852, USA
Allergy Division Naval Medical Center San Diego, CA 92134, USA
* Department of Pediatric and Adolescent Medicine
Mayo Clinic College of Medicine Rochester, MN 55905, USA

In Reply.—

Drs Nakayama and Kumagai note the difference in the prevalence of anti-gelatin IgE antibodies found in sera from patients suffering anaphylactic reactions to measles-mumps-rubella (MMR) vaccines in their study in Japan (93%)1 and our study in the United States (27%).2 They suggest that this difference may be due to differences in the sensitivity and specificity of tests to detect anti-gelatin IgE, which in turn may depend on the nature of gelatin used in the assay. The solid-phase allergen for the radioimmunoassay we used was made from a random lot of flavored sugared commercial gelatin (Jell-O) and thus not exactly the same gelatin that is present in MMR vaccines. It is not clear if the "bovine gelatin" used in their assay was the same as that used in vaccines manufactured in Japan. However, we believe that differences between the gelatin in the immunoassay and the gelatin in the vaccine are unlikely to be the primary explanation for the difference in prevalence of anti-gelatin IgE found in the Japanese and US studies. In the first case report describing gelatin allergy as a cause of anaphylaxis to MMR, inhibition immunoassays were performed.3 The patient’s anti-gelatin IgE antibodies directed against gelatin (the same type of gelatin used in the assay in our present study) were inhibited not only by both bovine and porcine laboratory gelatins but also by the MMR vaccine itself containing pharmaceutical gelatin. This suggests that common IgE-binding gelatin epitopes are present on a wide variety of animal gelatins regardless of source or use. We also note that the prevalence of anti-gelatin IgE we found in US recipients of MMR suffering anaphylaxis (27%) is remarkably similar to that found in a study from Finland (28%) using different immunoassay techniques.4 We believe a possibly more likely explanation for the difference in Japanese and US prevalence has been proposed by Dr Kumagai himself in a report describing a strong association between gelatin allergy and HLA-DR9, which is unique to Asians, in which he concludes that this association would "seem to provide a key answer to the question why there are so many reports of gelatin allergy in Japan compared to other countries."5

Drs Nakayama and Kumagai note that the addition of poorly hydrolyzed gelatin to diphtheria-tetanus-acellular pertussis (DTaP) vaccines in Japan may have contributed to sensitization to gelatin in some children, resulting in increased risk of anaphylaxis on subsequent MMR vaccination.1 Removal of the gelatin from DTaP vaccines in Japan was followed by a decline in reports of anaphylaxis to subsequently administered MMR vaccines.6 However, the nature of the gelatin in the MMR vaccine was also changed to a more thoroughly hydrolyzed material at the same time. Either or both of these changes could have contributed to the decline in reactions.6 We do not believe that gelatin containing DTaP is a likely contributor to reactions to MMR in the United States, however. During a time when DTaP vaccines that contained traces of hydrolyzed gelatin became widely used, we did not observe an increase in allergic reactions to subsequently administered gelatin-containing MMR or varicella vaccines.2

Certainly we share with Drs Nakayama and Kumagai the conclusion that gelatin is responsible for a noticeable proportion of anaphylactic reactions to gelatin-containing vaccines, although the rates may differ in different countries (as discussed above).

Persons with a history of anaphylaxis after MMR or other gelatin-containing vaccine are likely at increased risk of similar reactions to subsequent doses of other gelatin-containing vaccines such as varicella and some brands of influenza. Therefore, for these persons we continue to recommend an allergy evaluation including assessment of anti-gelatin IgE by skin testing or now commercially available in vitro testing prior to such immunization.

REFERENCES

  1. Nakayama T, Aizawa C, Kuno-Sakai H. A clinical analysis of gelatin allergy and determination of its causal relationship to the previous administration of gelatin-containing acellular pertussis vaccine combined with diphtheria and tetanus toxoids. J Allergy Clin Immunol.1999; 103 :321 –325
  2. Pool V, Braun MM, Kelso JM, et al. Prevalence of anti-gelatin IgE antibodies in people with anaphylaxis after measles-mumps-rubella vaccine in the United States. Pediatrics.2002; 110(6) . Available at: http://www.pediatrics.org/cgi/content/full/110/6/e71
  3. Kelso JM, Jones RT, Yunginger JW. Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin. J Allergy Clin Immunol.1993; 91 :867 –872[CrossRef][ISI][Medline]
  4. Patja A, Mäkinen-Kiljunen S, Davidkin I, Paunio M, Peltola H. Allergic reactions to measles-mumps-rubella vaccination. Pediatrics.2001; 107(2) . Available at: http://www.pediatrics.org/cgi/content/full/107/2/e27
  5. Kumagai T, Yamanaka T, Wataya Y, et al. A strong association between HLA-DR9 and gelatin allergy in the Japanese population. Vaccine.2001; 19 :3273 –3276[Medline]
  6. Nakayama T, Aizawa C. Change in gelatin content of vaccines associated with reduction in reports of allergic reactions. J Allergy Clin Immunol.2000; 106 :591 –592
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics




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