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1970;46;397-402 PediatricsSkinner, E. Charlton Prather and
Joseph K. David
Robert O. Baratta, Myrna C. Ginter, Morris A. Price, James W.
Walker, Richard G. MEASLES (RUBEOLA) IN PREVIOUSLY IMMUNIZED
CHILDREN
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Online ISSN: 1098-4275. Copyright 1970 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. American
Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007.has been published continuously since
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PEDIATRICS is the official journal of the American Academy of
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( Received December 10, 1969; revision accepted for publication
April 7, 1970.)R.O.B. is Epidemic Intelligence Service Officer,
NCDC, located in the Florida Division of Health.ADDRESS: ( R.O.B. )
Section of Ophthalmology, Department of Surgery, Vanderbilt
University School of
Medicine, Nashville, Tennessee.ADDRESS FOR REPRINTS:
Writer-Editor, Epidemiology Program, National Communicable Disease
Cen
ter, 1600 Clifton Avenue, N.E., Atlanta, Georgia
30333.PErnAnucs, Vol. 46, No. 3, September 1970
397
MEASLES (RUBEOLA) IN PREVIOUSLY IMMUNIZED CHILDRENRobertO.
Baratta, M.D., Myrna C. Ginter, M.D., Morris A. Price, M.D., James
W.
Walker, M.D., Richard G. Skinner, M.D., E. Charlton Prather,
M.D., andJoseph K. David, M.D.
From the Division of Health, FloridAs Department of Health and
Rehabilitative Services, Jacksonville,the Consolidated Health
Department, City of Jacksonville, the Jacksonville Hospitals
Educational
Program, Incorporated, and the National Communicable Disease
Center, Health Services andMental Health Administration, Public
Health Service, U.S. Department of Health,
Education and Welfare, Atlanta, Georgia
ABSTRACT. Within a 3-month countywide epi-demic of measles in
Jacksonville, Florida, 28 casesoccurring among a kindergarten
enrollment of 145were carefully studied since 25 of these
childrenhad been previously immunized with a live, atten-uated
measles virus vaccine and immune globulin.Nineteen children had
been vaccinated prior totheir first birthday. Six children were
vaccinated at13 to 20 months of age. The median measles (ru-beola)
hemagglutination-inhibition (HI) antibodytiter in sera of five
convalescent patients immu-nized before their first birthday was
1:320 and forcomplement fixation it was 1:128. Sera from
nineclassmates who did not contract the diseaseshowed a median HI
antibody of 1:40 and a me-dian complement fixing antibody (CF) of
1:16. Sixhad been vaccinated before their first birthday.
In a control group of five other children, three
had been immunized prior to 12 months of age,one at 13 months,
and one at 18 months. Sera fromthe three earliest contained no
antibody; how-ever, sera from the other two had detectable
anti-body.
The analysis of serologic data supported the con-tention that
the outbreak was causally related todefective protection associated
with the use of vac-cine plus globulin in infants. It also
demonstratedpersistence of CF antibody many years after
fin-munization and suggested the presence of abooster
phenomenon.
A review of the clinical illness of the 25 childrenwho had been
given the vaccine and 22 who hadnot revealed little difference in
the severity of thedisease. Pediatrics, 46:397, 1970, MEAsLES,
RU-BEOLA, MEASLES vAccINE, VACCINE FAILURE, POST-VACCINE MEASLES,
IMMUNIZATION.
BETWEEN December 1, 1968, and Febru-ary 28, 1969, 293 cases of
measles were
reported to the Florida State Division ofHealth from Duval
County (Jacksonville).The attack rate for the population of515,000
was 0.05%. Twenty-eight of thecases occurred among 145 children
enrolledin a private kindergarten (attack rate19.3%). The fact that
private physiciansnoted that many of these children had pre-viously
been given measles vaccineprompted the epidemiologic
investigationreported here.
SUBJECTS AND METHODSThe administrator of the kindergarten
provided information about children with
measles as well as identifying information onall pupils.
Specific immunization history, in-eluding date and type of vaccine
adminis-tered, vaccine lot number, and geographi-cal location when
immunized, was securedfor all patients and for a group of
non-illstudents when the information was avail-able. Date of onset
of illness, height andduration of fever, duration of rash,
andpresence or absence of cough, coryza, con-junctivitis, and
complications were ob-tamed for all ill students from the recordsof
local physicians. Parents of children notseen by a physician were
contacted directlyfor similar information. Specific data re-garding
temperature, i.e., how and whentaken, was not available for these
patients.
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Dec January
ONSET
398 MEASLES IN IMMUNIZED CHILDREN
Fic. 1. Measles cases in a kindergarten by date of onset in
Jacksonville, Florida. December 20, 1968, toJanuary 31, 1969. Date
of onset is unknown in two cases. One through eight (vertically) in
the number of
cases.
Upon request from their private pediatri-cian, seven
kindergarten students submitteda single convalescent blood specimen
forantibody studies. Sera were obtained fromnine non-ill pupils
selected from a group ofkindergarten classmates who matched
thepatients in age and immunization history.An additional group of
five non-ill childrenwith immunization histories similar to
thekindergarten students were identifiedthrough the physicians who
had immunizedthe kindergarten children. The five wereenrolled in
kindergartens or elementaryschools where measles was not present.
Ablood specimen was obtained from each ofthem.
A group of 22 patients reported from thecounty at large among
children who hadnot received measles vaccine were con-tacted so
that the severity of their clinicalillness might be evaluated.
Parental recol-lection was the only source of information.
Serologic evaluation was performed intwo separate laboratories;
each employing adifferent test. Complement fixing (CF) an-tibody
titers were determined by the Flor-
ida State Division of Health laboratoriesutilizing the LBCF
microtechnique1 andcommercial measles CF antigen.
Micro-hemagglutination-inhibition (HI) antibodytiters were measured
by the Viral Immuno-serology Unit, Laboratory Division, Na-tional
Communicable Disease Center.2 ANorrby-type antigen was used for the
microHI determinations.
Epidemiology
RESULTS
Twenty-eight 5-year-old students in akindergarten with an
enrollment of 145contracted measles during December 1968and January
1969. The outbreak began onDecember 20, 1968, when an
unimmunizedchild became ill. Sporadic cases then occur-red until
the week ending January 24, when17 cases were reported (Fig. 1).
The out-break was limited to two of four classrooms.The activity
schedule brings these classestogether for meals and outdoor
recreation.
This kindergarten serves middle and up-per socioeconomic
families. Kindergarten
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ARTICLES 399
records indicated that all but three childrenhad previously
received measles vaccine(overall apparent immunization level,98%).
All three contracted measles duringthe outbreak ( attack rate,
100%) . Of the142 remaining enrollees, 25 developed mea-sles (
attack rate, 17.5%).
Each of the 25 previously immunized pa-tients had received live,
attenuated chickembryo measles virus vaccine with measlesimmune
globulin ( MIG). In no instancewas the amount of MIG recorded. Of
these25 patients, 24 had been immunized byphysicians in the
Jacksonville area and onehad been immunized in Virginia. Dates
ofvaccination ranged from October 1963through September 1965.
Although vaccinelot numbers were not recorded in every in-stance,
it is known that more than one lot ofvaccine was used. All vaccine
was suppliedby the only manufacturer whose productwas available at
that time. At the time ofimmunization, 19 of the 25 children
wereless than 12 months of age. One child wasvaccinated at 6
months, four children werevaccinated at 8 months, six children
werevaccinated at 9 months, six children werevaccinated at 10
months, and two childrenwere vaccinated at 11 months. Six
childrenhad been given the vaccine at 13 to 20months of age.
Reactions at the time of vac-cine administration could not be
recalledby any parent. The rate of true vaccine fail-ures could not
be calculated, though, be-cause of a lack of specific immunization
his-tory among the remaining students.
Serology
CF and HI titers were measured in conva-lescent sera obtained
from seven kindergar-ten patients. Six of the seven patients
hadpreviously been immunized, one at 13months and five at less than
1 year. Theages at the time of vaccine administrationfor this group
ranged from 6 to 9 months.Immunization in this group took place
be-tween November 1963 and May 1965 inthe offices of private
pediatricians. The in-terval between onset of illness and speci-men
collection ranged from 9 to 41 days,
TABLE IM EAMLSN (RUBEOLA) HEMAGGLUTINATION-INHIBITION
AND COMPLEMENT FIXATION ANTIBODY TITERS IN
NoN-Iu CHILDREN. ALL PREVIOUSLY IMMUNIZED
WITH LIVE, ATTENUATED CHICK EMBRYO
MEA.SLIO VIRUS VACCINE AND MEASLmIMMUNE GLOBULIN,
JACKSONVILLE,
FLORIDA-JANUARY 1969
,
urn-
ber
Age at.
Immuni-.
zation (mo)
Date oflmmunzza-
.(ton
MeaslesIII
.
Titer
MeaslesCF
.
Tzlerj
1 8 9-14-63 1:640 1:642 9 2-19-65 1:5
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400 MEASLES IN IMMUNIZED CHILDREN
TABLE II
MAXIMUM TEMPERATURE, DURATION OF FEVER, AND DURATION OF RASH
RECORDED DURING CLINICAL
COURSE OF MEASLES IN IMMuMzsu AND UNIMMUNIZED CHILDREN
Pr eviouly I mmunized (nimmu ni?ed
MaximumTemperature
Recorded
%Cumula-
live
Durationof
fevert
%
Cumula-live
Durrilionof
ra8ht
%Cumula-
live
Maximum %Temperature Cumula-
Recorded live
Durationof
fvert
%Cumula-
live
Durationof
raskt
%Cumula-
live
101 or less102103104105106
100% (22)01% (20)68% (15)45%(I0)
0%(0)0%(0)
1234.5678
100% (23)95% (22)87% (20)61%(14)39%(9)30%(7)30%(7)
0%(0)
34567
S9
1011
100% (24)83% (20)54% (13)33%(8)12%(3)
0%(0)0%(0)0%(0)0%(0)
101 or less 100% (23)102 87% (20)103 74% (17)104 48%(II)105
17.3%(4)106 4.3%(I)
1234.5678
100% (24)96% (23)83% (19)67%(16)42%(10)1Z%(3)
0%(0)0%(0)
34567
89
1011
100% (23)91% (21)74% (17)48%(1O)43%(10)
4.3%(I)4.3%(1)4.3%(1)
0%(0)
Total number of cases indicated in parentheses.
t The fever and rash lasted 1 or more. I or more. etc. days.
Clinical IllnessThe clinical illness of the previously im-
munized children was almost the same asthat of their unimmunized
counterparts.The temperature of 74% of the unimmun-ized children
and 68% of the immunizedchildren rose to 103#{176}For higher. The
dura-lion of fever was also not significantly dif-ferent in the two
groups. Rash was noted in43% of the unimmunized children for 7
ormore days. Only 12% of the immunizedchildren noted this finding
(Table II). Allchildren had at least one of the symptomsof cough,
coryza, or conjunctivitis.
Otitis media developed in two of the fin-munized children and in
four of those notimmunized. There was no history of pneu-monia or
central nervous system complica-tions in any of the children. In no
instancewas the illness in an immunized child moresevere than in
any unimmunized one.
DISCUSSION AND RELEVANCELive, attenuated measles virus
vaccine
was first licensed in the United States in1963, but it has since
been modified. Fur-ther attenuation was desirable because ofthe
relatively high incidence of clinical sidereactions.4 For this
reason the simultaneousadministration of measles immune globulinwas
originally recommended.
Though the recommended dosage ofstandardized MIG was 0.01 cc/lb
of body
weight, many immunization campaignspromulgated the use of 0.3 cc
regardless ofweight.7 Probably other regimens wereused, i.e.,
either of the two dosage sched-ules with gamma globulin which had
notbeen titered specifically for measles neutral-izing
antibody.
In February 1965, the recommended agefor immunization was
changed from 9months5,6 to 12 months89 when it had beenshown that
residual and maternal antibodyinterfered with the immunologic
responseof infants under 12 months of age. This in-terference in
infants under 1 year of agewas more pronounced if measles
immuneglobulin had been used simultaneously withthe vaccine.10
Krugman, Reilly, Alexander,and others have empirically
demonstratedthat a significant number of children immu-nized with
live virus vaccine and MIG priorto 1 year of age are left
susceptible to mea-sles.11#{176}
The group selected from outside the af-fected kindergarten
further corroboratesthis empiric finding. Three children in
thisgroup who received vaccine plus MIG be-fore they were 1 year
old now show no de-tectable antibody even to the more
sensitiveNorrby HI antigen (Table I, I.D. No. 10-12).
Since the majority of the kindergartenpatients had been
immunized with vaccineplus globulin before they were 1 year
old,
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ARTICLES 401
they were susceptible to measles. This, then,is our explanation
for the majority of thecases that were recorded. We are
left,though, with six cases which occurred inchildren who received
vaccine after 12months of age. We assign these to the ex-pected 3
to 5% seroconversion failure rate17or, alternatively, presume that
commercialgamma globulin unstandardized for mea-sles antibody was
administered at the timeof vaccination.
The true extent of the problem of suscep-tibility in previously
immunized children isunknown. Without an external reactionsuch as
that seen with smallpox vaccine, the3% expected failures go
undetected. Sinceseroconversion rates for the group under 1year of
age who received gamma globulinmay be as low as 75%, 25% of all
childrenwho were so immunized may still be sus-ceptible.
Furthermore, this particular groupof children (those who were under
a yearold in 1965) has now reached kindergartenand first grade
school levels. Here, as theycluster, they may play an important
epide-miologic role in future measles experienceby serving as a
hidden reservoir of suscepti-bles.
Any rise in antibody titer after exposureto a wild virus implies
a potent antigenicstimulus, i.e., viral replication or
infection.Also, a reexposure precipitates an antibodyresponse ( HI
) that appears sooner andquantitatively is greater than that
whichfollows the first experience with an antigenor virus. The data
which include CF titersas high as 1 : 128 in the non-ill
kindergartengroup would certainly indicate that theyparallel HI
titers (Table I). These datawould support the supposition that
thereare subclinical cases of measles, i.e., abooster phenomenon in
previously immu-nized children. One can speculate on therole
immunized but exposed children canplay in the spread of measles.
They mightfunction as asymptomatic carriers.
The sera was not fractionated by sucrosegradient nor was it
treated with 2-mercap-toethanol to separate 1gM and IgG anti-body
responses. This procedure has beenshown to be of value in
differentiating a re-
cent (primary) measles infection from asecondary stimulus with
the measles anti-gen.18
A recent British report concluded thatvaccinated children who
contracted mea-sles had on the average milder symptomsthan those in
an unvaccinated group whohad the disease. They also recorded
asmaller number of complications, i.e., otitismedia, pneumonia, and
convulsions, in thissame vaccinated group.19 It was a
strongimpression of one of the authors that the ill-ness in his
postvaccinee kindergarten pa-tients was modified in some way. This
con-elusion could not be reached for the groupas a whole ( Table
II).
SUMMARY
Within a countywide measles epidemic, akindergarten outbreak
occurred in Jack-sonville, Florida. This kindergarten wascarefully
studied since it represented a con-centrated occurrence of clinical
measles inpreviously immunized children. Sera wereobtained from
seven convalescent patients,nine non-ill classmates, and five
non-ill stu-dents enrolled in other kindergartens.These specimens
were evaluated both bycomplement fixation and
hemagglutinationinhibition techniques. The latter employedthe
sensitive Norrby-type antigen.
The antibody levels of the convalescentcases substantiated the
illness as measles( rubeola). The serologic data from a con-trol
group of non-ifi children included amedian HI antibody titer of
1:40 and a me-dian CF titer of 1: 16 within the same kin-dergarten,
and lower antibody levels fromthe children in other
kindergartens.
Nineteen of the 25 immunized patientshad received vaccine plus
immune globulinbefore they were 1 year old. This factor washeld
responsible for the majority of kinder-garten cases. The six other
patients hadbeen immunized after their first birthday.Complete
denominator data (those at riskwith specific vaccine histories)
were notavailable for the kindergarten.
There was evidence of subclinical casesand a booster phenomenon
in immunizedchildren. There was no difference between
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402 MEASLES IN IMMUNIZED CHILDREN
the clinical illness of the immunized and theunimmunized
groups.
REFERENCES1. Standardized diagnostic complement fixation
method and adaptation to micro test. PublicHealth Monograph No.
74. Washington,D.C. : United States Government PrintingOffice,
1965.
2. Cuinee, V., Henderson, D. A., Casey, H. L.,Wingo, S. T.,
Ruthig, D. W., Cockburn,T. A., Vinson, T. 0., Calafiore, D. C.,
Winkle-stein, W., Karzon, D. T., Rathbun, M. L.,Alexander, E. R.,
and Peterson, D. R.:Cooperative measles vaccine field trial.
PartII. serological studies. Pr.nwrmcs, 37:657,1986.
3. Norrby, E. : Hemagglutination by measles vi-nls : 4. A simple
procedure for production ofhigh potency antigen for
hemagglutination-inhibition (HI ) tests. Proc. Soc. Exp. Biol.Med.,
111:814, 1982.
4. Krugman, S., Cues, J. P., Jacobs, A. M., andFriedman, M. S. :
Studies with live attenu-ated measles-virus vaccine.
Comparativeclinical antigenic and prophylactic effects af-ter
inoculation with and without gammaglobulin. Amer. J. Dis. Child.,
103:353,1962.
5. Statement on the status of measles vaccines.Ad Hoc advisory
committee on measles con-trol interim report. U.S. Public Health
Ser-vice, Department of Health, Education, andWelfare. J.A.M.A.,
183: 1112, 1963.
6. Statement on the Status of Measles Vaccines.Committee
Statement: Committee on Con-trol of Infectious Diseases. American
Acad-emy of Pediatrics Newsletter, p. 7, March,1963.
7. Warren, R. J., Nader, P. R., and Levine, B. H.:Measles immune
globulin. Proposed stand-ard dose given with live attenuated
measlesvirus vaccine. J.A.M.A., 203:186, 1968.
8. Measles Vaccines-Status and Recomrnenda-tions For Use.
Recommendations of thePublic Health Service Advisory Committeeon
Immunization Practice. Morbidity Mor-tality Weekly Reports, 14:64,
1965.
9. Current Status of Measles Vaccine and MeaslesVaccine
Schedules. Progress Report andRecommendations. Committee
Statement:Committee on Control of Infectious Dis-eases. American
Academy of PediatricsNewsletter, p. 7, May 1965.
10. Measles Vaccines. Recommendation of the
Public Health Service Advisory Committeeon Immunization
Practices. Morbidity Mor-tality Weekly Reports, 16:269, 1967.
11. Krugman, S., Giles, J. P., Friedman, H., andStone, S.:
Studies on immUnity to measles. J.Pediat., 66:471, 1965.
12. Reilly, C. M., Stokes, J., Buynak, E. B., Gold-ner, H., and
Hilleman, M. R. : Living attenu-ated measles-virus vaccine in early
infancy.New Eng. J. Med., 265:165, 1961.
13. Unpublished data supplied by Medical De-partment, Merck
Sharpe and Dohme Re-search Laboratories, West Point, Pennsylva-ma,
1964 and 1966.
14. Meyer, H.: Response of Volta children to jetinoculation of
combined live measles, small-pox and yellow fever vaccines.
Bull.W.H.O., 30:783, 1964.
15. Alexander, E. R., Bansmer, C. A. M., Harris,E. S., Giles,
B., and Sparks, M. J.: Measlesvaccination in infants. Amer. J. Dis.
Child.,108:470, 1964.
16. Krugman, S.: Unpublished data, 1964 and1966.
17. Katz, S. L., Enders, J. F., and Holloway, A.:Use of
Edmonston attenuated measles strain.A Summary of Three Years
Experience.Amer. J. Dis. Child., 103:170, 1962.
18. Schaffner, W., Schluederberg, A., and Byrne,E. B.: Clinical
epidemiology of sporadicmeasles in a highly immunized
population.New Eng. J. Med., 279:783, 1968.
19. Vaccination against measles: Clinical trial oflive measles
vaccine given alone and livevaccine preceded by killed vaccine.
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AcknowledgmentWe are grateful to and wish to thank Miss
Elsie
E. Buff, Virologist, Bureau of Laboratories, FloridaState
Division of Health, for the careful determina-lions of the
complement-fixing antibodies, and Dr.Helen L. Casey, Chief, Viral
ImmunoserologyUnit, Laboratory Division, National
CommunicableDisease Center, Atlanta, Georgia, for the
exacting,Norrby-type hemagglutination-inhibition
antibodydeterminations. This study could not have beencompleted
without their help. We are also gratefulto the practicing
pediatricians in Jacksonville, Flor-ida, who cooperated in record
reviews, the adznin-istrators of the kindergarten, and, finally,
the par-ents of the involved students who patientlyanswered our
many questions.
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1970;46;397-402 PediatricsSkinner, E. Charlton Prather and
Joseph K. David
Robert O. Baratta, Myrna C. Ginter, Morris A. Price, James W.
Walker, Richard G. MEASLES (RUBEOLA) IN PREVIOUSLY IMMUNIZED
CHILDREN
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