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MMR vaccine and allergy
  1. R LAKSHMAN, Clinical Research Fellow
  1. Sheffield Institute for Vaccine Studies
  2. University of Sheffield and Sheffield Children's Hospital
  3. Sheffield S10 2TH, UK
  4. email: R.Lakshman{at}shef.ac.uk
  5. Sheffield Institute for Vaccine Studies
    1. ADAM FINN, Senior Lecturer in Paediatric Immunology and Infectious Diseases
    1. Sheffield Institute for Vaccine Studies
    2. University of Sheffield and Sheffield Children's Hospital
    3. Sheffield S10 2TH, UK
    4. email: R.Lakshman{at}shef.ac.uk
    5. Sheffield Institute for Vaccine Studies

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      Live measles and mumps vaccine viruses are cultured in chick embryo fibroblasts and may contain minute amounts of egg related antigens.1-3 In view of this, there has been a longstanding debate on the safety of these vaccines in children with severe allergic reactions to egg. Initially it was believed that such children could safely receive the vaccine; Kamin et al in 19654 reported the safe administration of measles vaccine to 22 children with egg allergy confirmed by food challenges.

      Key messages

      • Anaphylaxis is an extremely rare but potentially fatal complication after any vaccination

      • It is difficult to predict which children are likely to have a severe allergic reaction

      • Many of the allergic reactions that occur after administration of gelatin containing vaccines in Japan appear to be due to IgE mediated or cell mediated immune responses to gelatin

      • MMR vaccine is not advised in children with known severe systemic allergic reactions to gelatin or neomycin

      • Children allergic to eggs (including those who have had anaphylactic reactions to egg) do not appear to be at greater risk for anaphylaxis to MMR vaccine than other children

      • All vaccination must be carried out in settings with equipment to deal with anaphylaxis and by personnel trained in its recognition and management. Assuming these criteria are met, vaccinations do not have to take place in the presence of a doctor or on medical premises

      The concern was again raised in 1983 by Herman et al when they reported two children with allergy to egg white protein who had generalised urticaria, angio-oedema, and respiratory difficulty following immunisation with measles vaccine.3Serum IgE reactive with ovalbumin related antigens in the vaccine was demonstrated in both children. They also showed the presence of ovalbumin reacting protein in the vaccine.

      They subsequently evaluated 24 children with egg allergy using skin prick testing with ovalbumin and measles vaccine. They found that children with severe reactions to egg were more likely to have a positive skin reaction on testing with the vaccine, and those who had a positive skin test had IgE antibodies reacting to ovalbumin. Non-allergic children had negative skin tests. From this they recommended that patients with severe reactions to egg white should be skin tested with dilute vaccine, first by scratch test and, if this is negative, by intradermal injection. If both were negative, the vaccine could be given as a single dose of 0.5 ml. If either were positive, they recommended that the vaccine be administered in slowly increasing increments of 0.05 ml, every 15 to 20 minutes. The 1991Red Book published by the American Academy of Pediatrics recommended a similar policy for children with severe reactions to egg.

      However further evidence suggesting that children allergic to eggs were at no greater risk continued to accumulate.4A-D By 1995, of 40 reported cases of anaphylaxis to measles/mumps/rubella (MMR) vaccine given as a single dose, only two involved children with egg allergy (the same two reported by Herman).1 3 5-10 A review of 17 studies from 1963 to 1995 showed only (the same) two of 1227 patients who were allergic to eggs and had been given the vaccine had developed any symptoms suggestive of anaphylaxis11; this included many children with convincing history of severe allergic reactions to egg. Children with or without egg allergy could have positive skin tests using the vaccine and still be safely immunised.1 12-15 Aicken et al carried out skin prick testing on 410 children allergic to eggs with the vaccine and subsequently vaccinated them with a standard single dose.12 Five children had a positive skin prick test, none of whom developed a reaction following vaccination. Four children had a minor reaction to the vaccine, all of whom had negative skin tests. On the other hand, Baxter found that a positive skin prick test with the vaccine might increase the chance of a systemic reaction.16 They performed a skin prick test followed by an intradermal test in 150 children allergic to eggs. Of these, 145 had negative skin prick and intradermal tests, and were given the vaccine without any significant immediate reactions. Of the five with positive skin tests, four had negative intradermal tests and were vaccinated safely. The fifth child developed a 15 mm local reaction and a systemic reaction including urticaria, irritability, and hypotension within 10 minutes of the intradermal test. Approximately half the patients who had an anaphylactic reaction to the vaccine (almost all of whom had no history of allergy to egg) when tested subsequently had positive skin tests.1 5 7 10 17 This suggests that while it is not useful to skin prick test children with egg allergy and it would be impractical to skin prick test all children, a positive skin test may to some extent predict allergy to some component of the vaccine and may increase the risk of an allergic reaction.

      Based on such evidence, the 1997 Red Bookdid not recommend skin testing in children allergic to eggs.18 The Department of Health'sGreen Book,19 while being generally reassuring, ends by saying that if there are any concerns, paediatric advice should be sought with a view to providing immunisation under controlled conditions in hospital. The product leaflet for MMR vaccine continues to prohibit vaccination of children who have history of anaphylactic, anaphylactoid or immediate reactions to eating eggs. Children with egg allergy are regularly referred for specialist advice and day case admission into hospital for MMR immunisation in our centre and, we believe, in most others—a significant use of time and resources.

      Kelso et al in 1993 first suggested that some anaphylactic reactions to MMR may be the result of an allergic reaction to gelatin.10 Hydrolysed gelatin, obtained from animal collagen, is used as a stabiliser in various vaccines including MMR, varicella, and diphtheria, tetanus, acellular pertussis (DTaP). Much of the recent work on gelatin allergy has come from Japan where there has been a recent increase in allergic reactions to MMR vaccine.20 From 1994 to 1997 there were 366 reported cases of allergy to MMR vaccine in Japan, and 34 of these were anaphylactic reactions; from 1989 to 1993 there were no reports of anaphylactic reactions to the vaccine. Before 1993, the immunisation schedule in Japan consisted of a trivalent MMR vaccine followed by a series of DTaP vaccines. From 1994 onwards, this was changed to a series of DTaP followed by MMR vaccines given separately (monovalent MMR vaccines). Both monovalent and trivalent MMR preparations contain gelatin; however, not all DTaP contains gelatin. Among the subjects with adverse reactions, almost all (98%) had received the gelatin containing DTaP before the MMR. Nakayama et al used this data to postulate that prior injection with gelatin containing DTaP had sensitised the children to subsequent reactions to MMR vaccine.20

      There is good immunological evidence suggesting that both immediate and delayed-type hypersensitivity reactions to vaccines containing gelatin result from gelatin allergy.21-23 Sakaguchiet al found that 24 of 26 patients with immediate reactions to MMR vaccine had IgE antibody to gelatin.24 In contrast, this antibody was not found in any of 26 age and sex matched controls who had not reacted to the vaccine. Kumagai et al showed that while patients with non-immediate reactions did not show IgE antibody to gelatin, many of them did show a cell mediated immune response to gelatin.25 Administering gelatin to a sensitised individual by injection would pose the greatest risk for anaphylaxis.21 Because gelatin used as a vaccine stabiliser may be of porcine origin whereas gelatin ingested in food may be of bovine origin, the absence of history of allergy to foods containing gelatin does not eliminate the possibility of a gelatin mediated reaction to vaccine.26 Skin testing with the MMR vaccine of people with a history of systemic anaphylactic reactions following gelatin ingestion may be useful to identify those at risk for similar reactions to the vaccine; however, protocols for such testing or desensitisation have not been published.26 27

      The only gelatin containing vaccine in use in UK is the MMR vaccine*. Drug analysis prints (DAPs) produced by the Committee on Safety of Medicines/Medicines Control Agency (CSM/MCA) list all spontaneously reported reactions on the adverse drug reactions online information tracking database (ADROIT). The DAP for MMR vaccine states that eight cases of angio-oedema and 55 cases of anaphylaxis or anaphylactoid reactions have been received by the CSM/MCA in the period July 1963 to July 1999. No fatalities have been reported associated with allergic reactions. While this cannot be used to estimate the incidence of allergic reactions to the vaccine, there is no recent increase in the number of cases reported. Thus, unlike in Japan, allergy to the MMR vaccine does not seem to be an increasing problem in the UK.

      MMR vaccine contains about 25 μg of neomycin sulfate. Contact hypersensitivity and systemic allergic reactions to neomycin are well known.28 Kwittken et al reported the case of a 7 year old boy who developed anaphylactoid reaction after being given a 0.05 ml dose of the vaccine subcutaneously as part of a desensitisation protocol.29 The child had a convincing history of contact hypersensitivity (but not systemic reaction) to neomycin in the past; however, no specific tests for neomycin sensitivity were done. Elliman and Dhanraj suggested that contact sensitivity to neomycin was not a contraindication to MMR vaccine.30 They reported the case of a 3 year old girl who had developed swelling and erythema to ear drops containing neomycin and had subsequently been given the MMR vaccine as a 0.5 ml single intramuscular dose with no adverse effects. However, there is general agreement that children who have had anaphylactic reactions to topical or systemic administration of neomycin should not be vaccinated.26 While prevaccination screening should include a question about allergy to the vaccine, gelatin or neomycin, there will remain a small risk of severe allergic reaction in any child. Children with egg allergy do not appear to be at a greater risk than the general population.

      In conclusion, anaphylaxis is a rare but potentially life threatening allergic complication of vaccination that must be anticipated in any vaccine recipient. All personnel involved in vaccinating children must be fully aware of this possibility and trained in its emergency management. Most severe reactions occur within a few minutes after the injection and it is extremely unlikely that a child who appears completely well 30 minutes after the vaccination will subsequently develop a severe reaction. Ideally children should be observed in a place equipped to deal with an anaphylactic reaction for at least this time period following vaccination. Any reports of reactions must be fully documented. Severe or unusual reactions must be reported to the CSM by the “yellow card system”; and if possible investigated by IgE RAST and/or skin tests to determine which component of the vaccine was responsible for the allergy.

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      View Abstract

      Footnotes

      • * Information published by the Department of Health on 2 December 1999 indicates that diphtheria tetanus acellular pertussis combined vaccines will shortly be introduced into the UK primary schedule. It may prove that some of these vaccines contain gelatin.

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