Jpn. J. Infect. Dis., 53, 189‑195, 2000

Review

Systemic Allergic Reactions to Gelatin Includedin Vaccines as a Stabilizer
Masahiro Sakaguchi* and Sakae lnouyel
Departmenl ofImmunology and]Infectious Disease Surveillance Center National Institute of Infectious Diseases,

Toyama 1‑2311, Shinjuku‑ku, Too,0 162‑8640, Japan(Received September 28, 2000. Accepted November 7, 2000)
CONTENTS:
1. Systemic immediate‑type reactions to gelatin in live‑virus vaccinesl. 1 Introduction

l.2 Systemic immediate‑type reactions to gelatinin live‑virus vaccines
l.3 Estimate of the minimum incidence oran叩hylaxis to gelatin in live‑vims vaccines

l.4 Relationship between ant1‑gelatinIgE production and DTaP vaccination history
2. Systemic nonimmediate‑type reactions to gelatin in live‑virus vaccines

3･ Systemic immediate‑type reactions to gelatin in inactivated vaccines
4･ System.lC Immediate‑type reactions to gelatin‑containing non‑vaccine items
5. Analysts Of gelatin allergenlClty

SUMMARY: Most of the children who showed systemic immediate‑type reactions, including anaphylactic
shock, to measles, mumps,rubella, and varicella vaccines had IgE antibodies to gelatin; thus we suspected thatthe allerglC Symptoms are Caused by gelatin antigen, which is usually included in these live‑vims vaccines as astabilizer. We hypothesized that the anti‑gelatin IgE is elicited by immunizationwith DTaP (diphtheria‑tetanus‑acellular pertussis) vaccines, which contained a small amount of gelatin as a spillover.protein after purification

ofpertussis toxin. To test this hypothesis, we conducted a case‑control study to determine Whether children with
ant1‑gelatin IgE had received gelatin‑containing DTaP vaccines, and it was indeed found that all such children in
the study had immunization histories thatincluded the gelatin‑containing DTaP vaccines. Based on these rlndings,
the vaccine manufacturers had removed gelatin from all the DTaP and live‑virus vaccines produced in Japan by
2000.

to be caused by gelath allergy: Kelso et al. detected anti‑

1. Systemic immediate‑type reactions to gelatingelatin IgE in a child who suffered from anaphylaxis inin live‑virus vaccines

response to gelatin‑containing MMR vaccine (3). We have

l.1 Introduction

also detected anti一gelatin lgE in many children wi仇systemic

Reports of anaphylaxis in response to measles‑mumps‑

immediate‑type reactions to measles, mumps, and mbella

rubella (MMR) vaccines have been extremely r?re (1,2)･
Although more than 70 million doses orMMR vacclneS Werevaccines (6,7)･ Further, Te have detected anti一gelatin lgE inchildren showing systemlC immediate‑type reactions to vari‑cella and Japanese encephalitis yiTs vaccines (14, 15)･ We

used in the United States (US) from 1990‑1995, only 33 casesof anaphylactic reactions were reported (3 ,4). These adverse

suspected that most of the systemlC Immediate‑type reactions

reactions were also thought to be rare in Japan befわre 1993,

occurrlng after vaccination were caused by the gelatin present

when a Japanese case or anaphylaxis in response to measlesin the vaccines as a stabilizer. However, the mechanism of

was first reported (5). Since then, many children have been

sensitization to gelatin has remained uncertain (1 6).

I.2 Systemic immediate‑type reactions to gelatin in live‑

reported as showlng Systemic immediate‑type reactions,

VIrtIS VaCCIneS

including an叩hylactic shock to measles, mumps, mbella, andSystemic immediate‑type reactions generally appear within
1 h of vaccination (17). Systemic immediate‑type reactions

varicella vFccines in Japan (6‑9)･ It has been suggested that

anaphylaxIS tO MMR vaccines that are derived from chickembryo cells is caused by allergy to egg proteins present inare classified into three号roups‥ a) severeチnaphylaxis

the vFccines (1 0)･ Ilowever･ these systemic immediate‑typeconsisting of cutaneous slgnS (e.g., SyStemlC urticaria,

reactlOnS have also been described in children who tolerated

angioedema) plus airway obstruction (with laryngeal edema

eggs (I 1 ‑ 1 3). It has therefore been suggested that anaphylaxis‑

or wheezing) or anaphylactic shock (with hypotension andinducing components other than egg protein may be present

v.ascular collapse); b) mild anaphylaxis coTSisting of cutaneousin these vaccines (2).

slgnS Plus respiratory symptoms (wheezing and/or cough or

The anaphylactic reactions to these vaccines are thought

laryngeal edema) without severe symptoms (e･g･,. aiⅣay

obstruction); and c) systemic cutaneous signs consistlng Only
*Corresponding author: Tel: +8 1 ‑3‑5285‑1 1 1 1 , Fax : +8 1‑3‑5285‑

of systemic urticaria or angioedema.

1 I 56, E‑mail: msakaguc@nih.go.jp

Measles vaccines are produced by four manufacturers in

189

Japan, and all the vaccines previously contained bovine gelatinin amounts ranglng from 1 to 10 mg per dose. Rubella

reactions occurrlng after vaccination are caused by the gelatin

vaccines are produced by five manufacturers, three of which

present in the vaccines as a stabilizer.
In Japan, a varicella vaccine containlng gelatin has been

produced rubella vaccines containlng bovine gelatin inlicensed fわr nomal and highィisk children since 1986 (18).

amounts ranglng from 1 t0 2.5 mg per dose. Mumps vaccines

This vaccine has protected children agalnSt Varicella infec‑

are produced by four manufacturers, two of which producedtion, and its safety has been confirmed in a clinical trial (18).

mumps vaccines containlng bovine gelatin in amounts rang‑

The live varicella vaccine is derived from infected humaning from 1 to 10mgperdose (17).

embryo lung cells and contains both bovine gelatin (I mg/

dose) and hydrolyzed gelatin (12.5 mg/dose) as stabilizers.

1n our summary data (17), We fわund a strong relationshipbetween the immediate‑type reactions after measles, mumps,

In our I 997 shdy (14), we fわund that children.inoculated

and mbella vaccinations and the presence of antトgelatin lgEwith the varicella vaccine exhibited systemic alIerglC reactions

in sera of the children studied. Table 1 shows data from 1 1 1with the synthesis of antl一gelatin lgE. Table 4 shows data

children who had systemic immediate‑type reactions to measles

from 30 childrenwith systemic immediate‑type reactions tovaccines between 1994 and 1996. 0fthe Ill childrell, 24

varicella vaccines. Of the 30 children, 7 showed severe

showed severe an叩hylaxis, 35 had mild an叩hylaxis w仙out

anaphylaxis, 9 mild anaphylaxis, and 14 Only urticaria (19).

ainvay obstmction or shock, and 52 had systemic cutaneous

Ofthese 30, 27 children (90%) had anti‑̲gelatin lgE･ Sincesigns only. Ofthe I ll, 94 children (86%) had anti‑gelatin

this vaccine is derived from human embryo cells, we canruIe

IgE (17). Table 2 shows the data from 50 children who had

out the possibility or an etiologlC relationship between egg

systemic immediate‑type reactions to rubella vaccines. In

proteins and the anaphylactic reactions. These findings
suggest that such reactions are caused by the gelatin contained

1 994, we found no cases of systemic immediate‑type reactions
to this vaccine, probably because few infants received thein the vaccine. The gelatin‑containlng Varicella vaccine must

vaccine befわre 1994. Ofthe 50 children, 1 1 showed severe

therefわre be used with the same caution as the MMR vaccine.

anaphylaxis, I 3 mild anaphylaxis, and 26 Only generalized

In response to these resu)ts, the gelatin in all measles,

urticaria. Ofthe 50, 46 children (92%) had anti‑gelatin IgE.

mumps,rubella, and variceIla vaccines produced in Japan

Table 3 shows data什om 17 children who had systemic

was eliminated or replaced with gelatin of low allergeniclty

immediate‑type reactions to mumps vaccines. Of the 17

between 1 997 and 2000 (personal communication from thechildren, 2 showed severe anaphylaxis, 7mi1d anaphylaxis,

manufacturers).

1.3 Estimate oftheminimum incidence of anaphylaxis

and 8 Only urticaria. All I 7 children had ant1‑gelatin IgE. We
therefore concluded that most of the systemic immediate‑typeto gelatin in live‑virus vaccines

Table 5 shows an estimate of the minimum incidence in the1996 statistical year of severe anaphylaxis to the live‑virus
Table 1. Systemic immediate‑type reactions to measles vaccines

vaccines (17). The 1996 incidences of severe anaphylaxis toin children

each gelatin‑containlng Vaccine were 8.13, 7.80, 8.33, andAnaphylaxis cutaneous

SevereMild

18.8 cases per million doses ormeasles, mbella, mumps, andSlgnS

to MMR vaccines in the US from 1990‑1995 was reported as

1994

5(

5)h

4(

7)

18(15)

1995

10(

9)

14(13)

17(16)

41(38)

0.5 cases per million doses (4), one order ormagn血de less

9( 7)

17(17)

26(17)

52(41)

than that in Japan, suggestlng that Japanese children were35(33)

52(40)

1 1 1(94)sensitized with ant1‑gelatin lgE at a higher rate than US

1996
Tbta1

24(2 1 )3)

9(varicella vaccines, respectively. The incidence of anaphylaxis

a Japanese statistical year; from April to next March.
hNumber in parentheses is the number ofchildren with ant1‑gelatin IgE.

Table 4. Systemic immediate‑type reactions to varicella vaccinesin children

Table 2. Systemic immediate‑type reactions torubella vaccines

Anaphylaxis cutaneousin children

SevereAnaphylaxis cutaneous
SevereMil°

19̲9̲9m949 59 6 tal

1( 1)b

1995

0

1996
Total

0

0

10( 9)

19(18)

10(10)

16(13)

31(28)

13(13)

26(22)

50(46)5( 5)ll(ll)

03( 3)

6( 6)トSlgnS0

O 2 7 0ノ

1(1)

SlgnS
n■u 円̲u ∩̲u

I( 1)
1994

Mild

2( 2)

5( 5)

5( 5)

12( 9)

24(21)

7( 7)

14(1 1)30(27)

2 7 0ノ ‑ ,1 , ‑a.hThe same as in Table 1.

athThe same as in Table I.
Table 5. Estimate orthe minimum incidence of severe anaphylaxis tofour gelatin‑containlng Vaccines

Table 3. Systemic immediate‑typereactions to mumps vaccines
severein children

Vaccineanaphylaxis Measles Rubella Mumps Varicella
Anaphylaxis cutaneous

SevereM

il°t9191 9m949596 tal

SlgnS

′LU 7

4 7 00 ′b 4 7 ｣ 89 7 つJ 40 7 00 4′0 7 7

1994

0

3(

1995

1(

3)b

′LU O 10ノ (XU つJ

5 4 00 0 2 4 00 つJ′‑U つJ つ1｣

7 つJ ′LU

O 4 4 00
E■.miZ! Ei E

2(

2)

1996

1(

1)

1)

2(

2)

Tota1

2(

2)

7(

7)

円ru n ‑ u ntJu

4 4 00aThe number orcases per million doses of each vaccine.
b Before 1994,rubella vaccine was used only for immunization of 15‑year‑

a.bThe same as in Table 1

old girls in Japan.

190

children. Nakayama et al. also reported the incidence ofroutine childhood vaccination at the end of the 1 940S, followed

anaphylaxis to gelatin‑containing Vaccines from the Kitasato
doses fわr the measles vaccine, 6.52 cases/million doses fわrby the introduction of combined whole‑cell DTP (DTwP)
vaccines (21)･ How.ever, the report of two fatal incidents
after DTwP vaccinatlOn in December 1974 and January 1 975

the rubella vaccine, and 18.5 cases/million doses fわr theled to the temporary suspension ofDTwP vaccination. In April

Institute (a vaccine manufacturer, Tokyo): I 1.9 cases/million

1975, these vaccinations were resumed, With a change h the

mumps vaccine (9).

1.4 Relationship between ants‑gelatin IgE production

age of the initial routine immunization from 3 months to 2

and DTaP vaccination history
As described above, We suspected that most cases ofyears of age. In 1 98 1 , acellu)ar pertussis vaccines replaced

anaphylaxis to hve attenuated viralvaccines containing gelatin

whole‑cell vaccines fbr仇e immunization of2‑year‑olds (2 1 ).

sensitization to gelatin remained uncertain. It has been revealed

In December 1988, followlng 7 years of safe and effective
use ofDTaP vaccines in older children, the Ministry of Healthand Welfare recommended the use of DTaP vaccine forthat the diphtheria‑tetanus‑acellular pertussis (DTaP) vaccines

routine vaccination of 3‑month‑old infants (22). Since 1 989,

produced by some manufacturers contained a small amountof gelatin as a spillover protein during the process of purifying

pertussis toxin ( 1 9). This suggested the possibility that anti‑

children 3 to 24 months old have been receivlng DTaP
vaccines. ln 1994, the Preventive Vaccination Law wasrevised and all infants began to receive DTaP vaccines

gelatin lgE may be produced by the gelatin‑Containlng DTaP

before measles vaccinations (23). Thus, the gelatin‑Containing

vaccines prlOr tO immunization with gelatin‑containlng

DTaP vaccination administered at younger ages may havewere caused by the gelatin. However, the mechanism of

measles vaccines (9)･ Recently, Nakayaヮ1a et al･ reported thatsensitized some children to gelatin. We assume that there is ause of the gelatin‑Containlng DTaP vacclne might be causally

relation between the change in the immunization schedule

related to the development ofgelatin allergy (9). To further

histories of two.groups of children: a) children who had

for DTaP vaccines and the emergence ofanaphylaxis to thevaccines since 1993. Based on these findings, gelatin has been
eliminated from all DTaP vaccines produced in Japan since

showed both ant1‑gelatin IgE and immediate‑type reactions

1 998 (personal communication fTrom the manufacturers).

evaluate this possibility, We compared the DTaP vaccination

to measles, mumps, andrubella vac9nes; and b) children who
showed no reactlOnS tO these vacclneS. All lgE‑positive 54

2. Systemic nonimmediate‑type reactions to gelatin(100%) children had received gelatin‑containing DTaPin live‑virus vaccines

vaccines (Table 6)(20). By contrast, of the 101 children used

as a control, 72 (71%) had received DTaP vaccineswithgelatin

We have observed systemic nonimmediate‑type reactions,and 29 (29%) had received DTaP vaccines free of gelatin.

consistIng of systemic cutaneous slgnS, appearing Several

Therefore, a highly significant relationship was found tohours or more after live‑virus v.accination (24)･ Most of theexist between pnor vaccinationwith gelatin‑containlng DTaP

patients demonstrating these nonlmmediate‑type reactions had

vaccine and subsequent anti‑gelatin IgE production (P <no ant1‑gelatin lgE.

Kumagai et al. reported on cellular immune responses in

0.001) (Table 6) (20).

We suspect that the sudden increase in the incidence ofchildrenwithboth immediate‑and nonirrmediate‑type reactions

anaphylaxis in the early 1990s is related to changes in theto vaccines (8). In their study, all six patients with immediate‑

immunization schedule of DTaP vaccines (Fig. 1 ). In Japan,

type reactions had IgE to gelatin, whereas none of the 21

killed whole‑cell pertussis vaccines were introduced f♭rpatients with nonirrmediate‑type reactions had IgE to gelatin.
All six patients with immediate‑type reactions and 1 7 of theTable 6. DTaP vaccination histories ofchildren withant1‑gelatin

responses specific to gelatin. In contrast, the tests were nega‑

2 1 patients with nonimmediate‑type reactions showed T celllgE and systemic immediate‑typeallergic reactions to vaccines

tive in 14 control subjects, who had no adverse reactions to

the vaccines.

AllerglC reactions
Ilistory of DTaP vaccine

Taniguchi et al. reported that 61 of the 76 patients with+

nonimmediate‑type reactions showed T cell responses specificwithgelatinwithout

54

gelatinO

72

to gelatin (25)･ In contrast, none of 14 control subjectswith

29

no adverse reactions to the vaccines had T cell responses

Significant relationship between histories of vaccinationwith

specific to gelatin. Further, they reported that activatedgelatin‑containing DTaP vaccine and ant1‑gelatin lgE production

memory T (CD4'CD25'CD45RO+) cells w.ere induced byco‑culhre with gelatin in patients with nonlmmediate‑type(P< 0.001).

reactions.

Ohsaki et al. further analyzed T cell responses in patients

Measles DTa I

with reactions to gelatin‑containing vaccines (26). In theirstudy, aH eight patients with immediate‑type reactions and†llthe eight patientswith nonimmediate‑type reactions showed

1981‑1988
0

1

T cell responses specific to gelatin. Lymphocytes of patients2with immediate‑type reactions expressed not only IL4 andIL‑13 mRNA but also IFN‑ and IL‑2 mRNA. On the other
hand, lymphocytes of patients with nonimmediate‑type reac‑
DTaP Nea$les

tions expressed these cytokines very weakly or sometimes
not at all.

1 994･

The results or these studies suggest that an immune
0

1

2

years

after

blrth

response to gelatin may also play a role in the pathogenesis

or nonimmediate‑type reactions to gelatin‑containlng live‑

Fig. 1. Childhood immunization schedule in Japan.

191

Further, we examined antトgelatin lgG in sera or children

Specific IgE to gelatin and DTP toxoids in their sera, andfound that none of the children had ant1‑gelatin IgE. Ofthe

VlmS VaCClneS.

who suffered from systemic adverse reactions after measles,

eight children, two had detectable levels or anti‑toxoid lgE.

rubella, and mumps immunization with gelatin‑containlng

Ten children who showed no allerglc reaction to the DTaP

live‑virus yaccines (27)･ Of75 children who had nonimmediate‑vaccines were used as controls. Among them, four had

type reactlOnS With no aサgelatin lgE, 22 (29%) had anti‑

detectable levels of anti‑toxoid lgE. Based on these results,

gelatin lgG. The lgG posltlVity was well comlate4 with thethere was no clear relationship between the specific IgE tolymphocyte proliferation assay positivlty･ In contrast, as a

the vaccine's component proteins and systemic urticaria tonegative control, none of the children with no allerglC reac‑

DTaP vaccines (19).
All DTaP vaccines containthimerosal (a mercury‑containing

tion to live‑ virus vaccines had antトgelatin lgG. Systemic

nonimmediate‑type alleTglC reactions, which mainly consist

Pr芦anic compound), which has been cofTn70nly used as anof systemic cutaneous slgnS, appearlng Several hours or more

lnJeCtable drug preservative. HypersensltlVltyto thimerosal

after exposure, have also been reported alter varicella vaccina‑

has been reported to be copmPn (39)･ Okada et al･ reported thattion. We obtained similar results in our study: some children
with systemic non‑immediate‑type allergic reactions had anti‑

a child with systemic urtlCarla in response to DTaP vaccines
had an immediate‑type positive skin test to thimerosal(34)･

gelatin IgG (28)･ These results also sヮggest the possibility

However, there is cu汀ently no method fわr measurlng anti‑that some nonimmediate‑type react10nS tO the varicellathimerosal lgE･ In the future, such a methodtshould be devel‑

vaccine are caused by immune reactions to gelatin.

oped.

4. Systemic immediate‑type reactions to gelatin‑

3. Systemic immediate‑type reactions to gelatincontaining non‑Vaccine items

in inactivated vaccines

vaccine, including systemic urticaria and/or angioedema, have

Recombinant human erythropoietin (EPO) is widely used
for the safe and effective treatment of anemia in chronic

been reported (29‑32)･ Inactivated JE vaccines also cont?in

dialysis Patients. There has been one report of anaphylaxis

Systemic allergic reactions to the Japanese encephalitis (JE)

associated with EPO, in which the patient had IgE antibody

gelatin as a stabilizer. We reported in 1997 that children had
systemic immediate‑tⅥ)ら reactions to the JE vaccine (1 5). In

to recombinant EPO (40).Asa stabilizer for the injectablea subsequent study (33), we identified two different pattems of

EPO product, human serum albumin (HSA) was replaced withsystemic immediate‑type reactions to仇e JE vaccine contain‑

bovine gelatin between 1995 and 1996 in Japan･

lng gelatin as a stabilizer. One group of affected children had

We previously reported the case of a woman who experi‑

cutaneous and respiratory symptoms (e.g. , systemic urticaria

enced anaphylaxis in response to the gelatin stabilizer in an

and wheezing), and the other showed cardiovascular symp‑

EPO product. She had undergone intravenous EPO therapy

toms (e.g. , hypotension and cyanosis) Without cutaneous andresplratOry Symptoms. The children in仇e fbmer group had

since 1 990 and had demonstrated no allerglC reaction to HSA‑
containing EPO products. In 1995, she received a new EPO

ant1‑gelatin IgE in their sera, whereas those in the latter groupproduct that contained bovine gelatin as a stabilizer. Severe

did not. We believe that the two pattems may have been causedby different mechanisms or different allergens. The immun0‑

began immediately after intravenous lnJeCtlOn Of the product.

anaphylaxis (hypotension and airway obstrTCtionwith cough)She was found to have anti‑bovine gelatin IgE ( 1 3.7 Ua/ml),
but no anti‑EPO IgE (41). These results suggest that anaphy‑

10glCal mechanism of the adverse reactionsinthe latter group
has not yet been determined.

laxis to EPO products is associatedwith hypersensitivityto

Recently, an incidence of systemic urticaria beginning 1 0
min after the administration of DTaP vaccine was reported in

the gelatin included in the products･

a child (34). Children immunized with DTP, DT, or T vaccines

In J叩an,叩prOXimately 1 00,000 dialysIS patients received

have also been reported to have specific lgE to the toxoids (35‑

EPO products containlng gelatin from 1995 to 1996･ Inter‑

37). Accordingly, it has been suggested that there is a relation‑

estlngly,血e above一mentioned case was the only reported caseship between anti‑toxoid IgE and the local side effects to thesein which severe immediate‑type reactions to gelatin‑containing
EPO products occurred. Thus, this would appear to be an

vaccines (38).

extremely rare case of hypersensitivlty tO bovine gelatin in

In a 1998‑study (19), we fわund that eight children had

systemic urticariawithin 30min of the administration ofDTaP
vaccines that contained gelatin. We measured the levels of

the adult Japanese population.

It was reported that a woman who experienced urticaria

Table 7. Children with fわod allergy to gelatin

Food allergy to gelatin
Ch‑1 d N0

Timing2 4 2 5 ′0 1 4

Symp

tom

Post Systemic urticaria, angioedema around eyes, vomltlng
Post Systemic urticaria

11122

Post Systemic urticaria

Post Systemic urticaria, vomltlng, Wheezlng, coughPost Systemic urticaria,airway obstruction with laryngeal edema
Pre Systemic urticaria

Pre Systemic urticaria, lip swelling

Post: Gelatin food allergy occurred after allergic reactions by vaccination; Pre: Gelatin foodallergy occurred before allerglC reactions by vaccination.

192

after chewlng gelatin‑containlng fhlit gums had IgE antibody

(a)

(b)

to gelatin as detected by radioallergosorbent as.say (42)･ Kelso

et al. reported that a patientwith anaphylaxIS tO the MMR

SDS‑PAGE lmmunoblot

vaccine also had allerglC reactions a洗er eating gelatin‑contain‑

ing food (3). TTleSe findings suggest that some children who had
anaphylaxis in response to vaccines may have a fわod allergy

to gelatin.
1

We previously detected the occurrence of fわod allergy to

2

3

1

2

3

gelatin in 7 of 26 children who showed allerglC reactions tolive‑virus vaccines (Table 7)(7). Their clinical histories
showed that all seven had immediate‑type reactions (ら.g.,

systemic urticaria, angioedema, lip swelling, wheezlng andcough,airwチy obstruction, Or vomiting), upon ingestinggelatin‑contalnmg fわods. Five of the seven children showed

α1ー■}一■■■the immediate‑type reactions to fわod gelatin within 1 month

α2‑

after the vaccination. lt therefore appeared that the vaccina‑tion tnggered the subsequent onset of fわod‑allerglC reactions

‑‑

‑‑

α2→‑

■

Fig. 2. Analysis ofSDS‑PAGE (a) and immunoblotting (b). Lane 1,

to gelatin.

denaturedtype I collagen; lane 2, a I chain; lane 3, a2 chain.

5. Analysis of gelatinalIergenicity

cross‑reactivity between the gelatins (Table 8)(50)･ Serup

Gelatin is prepared by the partial hydrolysis of mainly type
I collagen from various animal sources (e.g., bovine andsamples taken from 1 0 children who showed anaphylaxis ln

poやe hide and bones) (43)･ We fわund that 10 children withresponse to vaccines containing bovine gelatinwere tested inthis study. The IgE in most of the children reacted to kangaroo

ant1‑gelatinIgE had specific IgE to type I collagen (44). Typeand mouse gelatins to which the children had little or no

I collagen consists of α 1 and α2 chains (45). IgE antibodies

exposure as either a food or a vaccine stabilizer. The IgE

in their sera reacted with the α2 chain, but not the α 1 chain

binding to kangaroo and mouse gelatins was completely(44). Further,type I collagen preparations showed two bands

inhibited by bovine gelatin, whereas reciprocal inhibition wasof α 1 and α2 chains by SDS‑PAGE (Fig. 2a), and IgE fromnot complete, indicating that antlgenic cross‑reactivity lS

the pooled serum of three patients reacted onlywith the α2present between the marrmaliangelatins. Most of the children

chain upon immunoblotting (Fig. 2b). Further, we reported

who displayed sensitivlty tO bovine gelatin showed IgE

the CDNA co°ing sequence fbr仇e α2 chain of bovine type

I collagen (46). The encoded amino acid sequence shows 93%

reactivity to other mammalian gelatins. This reactlVlty may
be prlmarily due to the antigemic cross‑reactivity between

identity to the α2 chain of human type I collagen (47). It

mammalian gelatins.

was reported that the amino acid sequence orthe α 1 chain

Recently, We found that some patients with fish allergleSof bovine type i collagen shows 98% identity with the α 1suggest that the α2 chain has higher immunogenicity andshowed IgE reactivity to fish gelatin (5 1). There is a cross‑reactivityamong fish gelatins, butthere is little cross‑reactivity
between fish and bovine gelatins. Fist gelatin (type I collagen)allergenicitythan the α 1 chain. In gelatin allergy, denatured

might therefore be a slgnirlCant allergen in fish allergies.

chain ofhumantype I collagen (48,49). nLeSe homology data

bovine type I collagen is a major allergen, and IgE‑bindingsites exist in the a2 chain of type I collagen.

ACKNOWLEDGMENTS

We reported the reactivity of IgE in bovine gelatin‑sensitive

We are grateful to Dr. Michael Kramer, Infectious Diseasechildren to gelatins from various animals and the antlgenic

Table 8. Reactivity ofanti‑gelatin lgE to gelatin from various animals
Children no.
1

BovinePorci ne2a〓H〓士.=±･.

3+I I I I I I i‑ +

+++

十十+

二 二十±･± ･.

4

5

十{ } +} + +‑+ + l一 +6

十 +I I + ±± J ±±十一 ++7

iI,二,･.I.±±±士,

8++I } l l +l± l I F一一 ++9+}±±{± l +±±+ + +

10

+++十

〓州〓f.

Kangaroo
Guinea plg

+

Rat

+

+

Mouse
Chick
Tadpo leCodfish±+ +SalmonS hark+一十

Oc topus
Ascaris±aThe results are expressed as a percentage or the binding or lgE to each animal gelatin compared with that tobovinegelatin: ++++ ≧100%,十十十≧75%, 75%>十十≧50%, 50%> + ≧25%, 25%> ± ≧5%, ‑ >5%

193

15･ Sakaguchi, M., Yoshida, M., Kuroda, W., Harayama, 0.
and lnouye, S. ( 1 997): Systemic immediate‑type reactions

Surveillance Center, National Institute of infectious Diseases,
Tokyo, for critically reading the manuscnpt.

to gelatin including in Japanese encephalitis vaccines.
ⅥlCCine, 15, 12ト122.

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