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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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( 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.


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


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


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,


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



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. Secondreport to the Medical Research Council bythe Measles Vaccines Committee. Brit. Med.J., 2:449, 1968.

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.


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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