ARTICLES
Measles
Vaccine
Efficacy
in Children
Previously
Vaccinated
at 12 Months
of Age
James S. Marks, M.D., Thomas J. Halpin, M.D., M.P.H., and Walter A. Orenstein, M.D.
I”rom tIi’ I’i(’lil S(’rI’ic’e.6 I)it’ision, Buri’aii of Epkh’mmiiology. Cemltc’r for I)isea.s’e Control. .‘tl(1nta. (111(1flu’ ()Iiio 1)’jirtmiimi1 ()f .tI(’U!tll, Colflnibf,.s’
ABSTRACT. During a large outbreak of measles in Ohio in
1976 it was possible to measure measles vaccine efficacy by
age at time of vaccination and mII1ber of ‘ears since
vaccination. Using a summed incidence tisethod to control
for the confounding varial)le introduced by mass
imiminiza-tion clinics held during the outbreak, vaccine efficacy ‘as
greater than 95% for children vaccinated at 12, 13, and 14 or
niore months of age. Vaccine efficacy for those vaccinated at 12 iiionths of age was notably l)etter than for those vacci-nated at younger ages but not different froni those vacci-nated at older ages. .‘lthough recently administered vaccine appeared iore efficacious than vaccine administered in the past, this difference was not significant when controlled for age at vaccination. Evaluation of the mass clinics held during the outl)reak demonstrated that 59.6% of the inadeqtiatelv
immunized children attended the clinics, l)ut this was not sul)stantiallv different from the lroportioIl of adequately
illi iiiunized ‘ho attended (52.4%). Reconi Illendatiolls for
Illeasles revaccination need not include children previotlsly vaccinated at 12 nlonths of age or greater. Pediatric-s
62:955-960, 1 978, flle(lSle,S’ L’Q(’(’ifl(’, U(!C(’lll(’ efll(’ac.’y, 1)lC(lSle-S’.
Despite a 90% reduction in reported cases of
neasles since the introduction of live attenuated
measles vaccine in the United States in 1963,
significant questions have reii ained regarding
optimun age at vaccination and duration of
vaccine-induced ill3munity. Vaccine effectiveness
has classically been measured by two methods.
The first is ascertainment of rates of
seroconver-sion after administration of vaccine and the
second is determination of the protective effect of
the vaccine in an outbreak situation. For measles
vaccine these two methods have generally been in close agreement . Duration of vaccine-induced
imiimnity has been studied either by measuring
serial titers in patients known to have
serocon-verted or by analyzing vaccine efficacy during an
outbreak by the number of years since
vaccina-tion.
Initial recommendations for routine measles
immunization suggested that vaccination occur at
9 months of age.’ This was changed to 12 months
of age in 1965 by the American Academy of
Pediatrics (AAP) and the Public Health Service
Advisory Committee on Immunization Practices
(ACIP) when maternal antibody to measles was
found to persist at low levels until the 11th month
of life and potentially interfere with
seroconver-sion after measles vaccination. Serologic and epidemiologic studies oti the protective effect of
the vaccine during outbreaks substantiated this.’ 7
This difference was of sufficient magnitude to
lead to the additional recommendation that all
children previously immunized prior to 1 year of
age be revaccinated.
Recent information by Yeager et al., Krugman,’
and Shasby et al.’ on seroconversion after
measles vaccination has indicated that children
vaccinated at 12 months of age have lower rates
of measurable antibody than children vaccinated
at older ages.
These serologic data led to the recent change in the recommended age for routine measles
vacci-Received January 23: revision accepted for publication Max’
24, 1978.
Dr. Marks is now with the Robert Wood Johnson Clinical Scholar Program, Yale University, New 1-laven, Connecticut, and Dr. Orenstein is now with the Department of Pediatrics, USC School of Medicine, Los Angeles.
Presented in part at the 105th annual meeting of the American Public Health Association, November 2, 1977. ADI)RESS FOR REPRINTS: (T.J.H.) Bureau of Preventive
Medicine, Ohio Department of Health, 246 N. High Street,
90
-80
-70
60
H
so -1
40 J C A S
F:
S
METHODS
r-BACKGROUND
Vaccine Efficacy
3O-Measles cases 1)%’ date of rash onset in Licking County,
Ohio.
nation from 12 months to 15 months
by
both theAAP and ACIP.” However, clinical vaccine
effi-cacy in an outbreak situation has not been well
evaluated for children previously vaccinated at 12
months of age. It is important to examine vaccine
efficacy in this setting to substantiate the need for
changes in recommendations for vaccination and
to evaluate the potential need for revaccination of
these children. From October to December 1976,
Licking County, Ohio experienced an outbreak of
measles. Because this outbreak occurred just at
the time of the change in routine immunization
recommendations, and because these changes
were the source of some confusion in planning
niass vaccination clinics, we decided to look at
the efficacy of vaccine delivered at 12 months of
age.
Licking County, Ohio, is a semi-rural county
located 30 miles east of Columbus. It has a
population of approximately 107,799 of which
40,(XX) live in the principal city of Newark. Prior
to this October 1976 outbreak there had not been
a case of measles reported for more than two
years. The county schools have about 27,000
students. There are two major health departments
in the county, one for the city of Newark and one
for the remainder of the county.
The outbreak began in October 1976 with peak
activity during the week of November 19 to 26
(
Figure). County-wide school-based irn muniza-tion clinics were held during the week of
Decem-her 3 to 10 in which more than 14,000 students
were vaccinated.
When it became obvious that large numbers of
cases were occurring in the county, a
school-based surveillance system was established to
provide more complete information on the
outbreak. In this surveillance system a person in
each school was designated to contact each child
absent three or more consecutive days. This
person asked the parent if the child had a rash
with the current illness and then determined the
day of onset of any such rash.
An intensive epidemiologic investigation was
carried out in three elementary schools with a
total enrollment of 953 students and an attack
rate of 5% or greater for each school. Each
student from these schools with a suspected case
of measles was contacted, and a parent was
interviewed with regard to clinical symptoms and
signs, whether a physician was seen, vaccine
status, vaccine source, date of vaccination, and
whether siblings had become ill. Date of
vaccina-tion was verified by written record in the parent’s
possession or by contacting the source of the
vaccination.
The clinical case definition was as follows:
fever (temperature greater than 38.3#{176}C [101#{176}F],
if measured), rash for four days or longer, and any
one of the following: cough, runny nose,
conjunc-tivitis, or photophobia.
The records of well classmates were reviewed
with regard to vaccination status and date of
vaccination. For children whose school records
failed to indicate vaccination, the family was
contacted to ascertain vaccination and/or illness
status. Exact dates of vaccination were obtained
either from written records in the parent’s
posses-SiOfl or by contacting the provider. Age at
vacci-nation was categorized as less than 1 1 months of
age, 11 I’nonths, 12 months, 13 months, and 14
months or later. The single month intervals began
with the anniversary date of the month and
extended up to the next month’s anniversary date.
As a check on the completeness of the
school-based case reporting in the three schools, a
portion of children not reported as cases were
called to inquire about rash.
The usual method used for computation of
vaccine efficacy is the attack rate in the
unvacci-nated minus the attack rate for the vaccinated
divided by the attack rate in the unvaccinated. In
order to control for those children vaccinated
TABLE I
A(;E DISTRIBUTION AN!) ATTACK RATE OF MEASLES CASES LICKING Coum’, OHIO 1976 TO 1977
od.
Clinic Efficacy
RESULTS
was used. In this method the number of people at
risk of contracting disease is multiplied by the
length of the risk period in weeks.’2 Thus, instead
of a traditional attack rate a summed incidence
rate (cases per 1,000 person-weeks-at-risk) is used
to compute the vaccine efficacy. Children
vacci-nated during the outbreak are considered at risk
uiitil ten days after vaccination. For purposes of defining the period of risk, each school was
considered to be a separate outbreak in which the
first case was an import who theoretically placed
the entire school at risk. The risk period for
disease development for that school’s population
then begins one incubation period after the first
case is considered to be communicable and ends one incubation period after the last case is
communicable. The termination of
conirnunica-bility of the last case was defined as the last day of
school attendance; in practice this usually
coin-cided with rash onset. The incubation period was
estimated at 12 to 14 days from exposure to rash
onset. The communicable period was estimated at
from four days prior to rash onset to four days
after rash onset.
Thus a given student was considered at risk for
nieasles until removed froii the risk pool either
by
developing the disease or receiving thevaccine, or until the end of the outbreak. The
number of person-weeks-at-risk was compared
with the nuniber of cases occurring across the
various ages of vaccination. The number of years
since vaccination was also analyzed by this
meth-Because nass immunization clinics were exten-sively employed in this outbreak, an attempt was
made to evaluate the efficacy of this method to
reach susceptibles. Licking County had excellent
response to these clinics with approximately 50%
of all school children presenting theniselves for
vaccination. This response was based largely on
the recommendation that because of the presence
of an outbreak, if the parents were uncertain of
vaccine status, revaccination was indicated.
Chil-dren attending the three schools with 5% attack
rates were studied. Parameters evaluated
in-cluded percent of susceptible children vaccinated
and whether susceptible children were more
likely to be vaccinated than those with previously
adequate immunizations.
Through the school-based surveillance system,
35 of 57 schools reported cases. Of the total of 411
Age (yr)
No. of Cases
Population % Att(1(’k Rate (per 1,000)
()-4 13 9,210 3.6 1.4
5-9 113 11,152 31.2 10.1
10-14 155 11,896 42.8 13.0
15-19 77 10,335 21.3 7.5
20+ 4 65,206 1.1 0.1
Total 362 107,799 100.0 3.4
separate cases reported, 31 (7.5%) were reported
only by private physicians, 340 (82.7%) only by
schools, and 32 (7.8%) by both. Six cases were
discovered in siblings of patients when the
patients were called to verify the diagnosis. An
additional two cases were found during the
call-ing of 1 1 1 children not reported as ill.
Age distribution of the 362 patients for whom
the age is known is shown in Table I. Nearly two
thirds were 10 years of age or older. Computation
of attack rate using 1970 census data shows that
the highest attack rate of 13.0/1,000 occurred in
the 10 to 14 age group. No serum samples were
collected from children in this county, but
samples were collected from suspected cases in
neighboring counties in order to plan possible
immunization campaigns there. Of 25 paired sera
from children with rash illness in these counties,
15 (60%) showed at least a fourfold rise in titer.
Vaccine Analysis
Vaccine efficacy was calculated based on the
results of the investigation of children at three
elementary schools with a 5% or greater attack
rate. The total enrollment of the three schools was
953. They reported 78 suspected cases of whom 67 met the predefined clinical case definition for a specificity of 85.8%. ,From Ohio Department of
Health surveys, an additional seven cases meeting
the case definition were discovered.
Of the remaining 879 children, adequate
records were obtainable on 829. Twenty-two had
a history of measles and were excluded from the analysis; 70 had a history of multiple vaccinations
with measles vaccine and also were excluded from
the analysis. Three of the 74 children were
excluded; in one, we were unable to verify the
exact date of vaccination. The remaining 2
chil-dren were vaccinated during the outbreak and ten
days
after vaccination developed clinically#{176}Vaccineefficacy =
incidence rate unvaccinated - incidence rate vaccinated
ilicidence rate unvaccinated
TABLE III
RF;l...TIvE RISK CosII’AREo BY NUMBER OF “tEARS SINcE
VAC:1NATI0N#{176}
Cases (12 no) Person weeks (PW) Incidence rate (per
I ,0()0 PW)
Relative risk
ox = 2.0; P = >.1.
Iear.s’ Since ‘s’(zccination Duration of Immunity
r- k Relative risk of contracting disease was
-- 4-6 -9 10-12 analyzed by number of years since vaccination
2 6 5 4
using
only
those
patients
and
classmates
immu-499 1,420 924 343 nized at 12 or more months of age to control for
40 4.2 5.4 11.7 .
the age effect on vaccine efficacy (Table III). This
1 0 1.1 1.4 2.9 shows a gradual increase in relative risk with
--.---.---
-..--.--
number of years since vaccination, but this trendis not significant
(x2
= 2.0, P > .1).TABLE II
MEASLES ATTA(;K RATE, RELATiVE RiSK, ANI) VACCINE EFFIcAcY Co\IPA1IEo \VITII A(;E AT
VACCINATION
1I1lt’O(’-(‘ill(It(’(I
,,,g(.(It V(I(’(’ill(ItU)ll
A.
(1110)
,._
<11 11 12 1-3
-“
14
Cases :34 16 4 4 1 12
Person-weeks (PW) 219 404 266 567 191 2,558 Incidence rate (per 155.3 39.6 15.0 7.1 5.2 4.7
1,000 PW)
Relative risk 33.0 8.5 3.2 1.5 1.1 1.0
Vaccine efficac”(%) . .. 74.5 90.3 95.5 96.6 96.9
as either natural illness or as a vaccine reaction.
Forty (54.1%) of the 74 children with measles
visited a physician who made the diagnosis.
Seventy (94.6%) reported a cough, 59 (79.7%) had
a ninny nose, and 72 (97.3%) had either conjunc-tivitis or photophobia or both. The average of the
highest
temperatures recorded was 39.7#{176}C(103.5#{176}F). The
average duration of the rash was6.67 days.
Age at Vaccination
Analysis
of vaccine efficacy by age at vaccina-tiolTi (Table II) shows that the incidence rate andrelative risk decrease with increased age at
vacci-nation. Relative risk of disease is calculated by
setting the rate of illness in children immunized at
14 months of age or older as 1.0 and comparing
the rates of illness in the other ages to it. Vaccine
efficacy increases with increased age at
vaccina-tiOIl. Vaccine efficacy is high and relative risk low
in children vaccinated at younger ages.
Determi-nation of confidence limits on the relative risks
shows that 1 1 months is the oldest age group to
differ substantially from those vaccinated at 14
months of age or later. Similarly
x2
analysis withthe Yate’s correction comparing separately those
vaccinated at 12 months vs. those vaccinated at
younger and older ages shows a significant
differ-ence to exist between those vaccinated at 12
months and those vaccinated at a younger age
(x2
6.9, P < .01). However, no significantdifference exists between those vaccinated at 12
months and those vaccinated at older ages
(x2
0.4, P > 0.2).Because vaccine efficacy by age at vaccination
might
be
confounded
by
a decreasing
efficacy
according to time since vaccination we
deter-mined the mean number of years since
vaccma-tion for each of the age groups. The differences in
these means were within 1.6 years except for those children vaccinated at 14 months of age or
older. That these children were vaccinated
rela-tively more recently than the other children is not
surprising since the children vaccinated at 14
months or older includes children vaccinated just
prior to school entry and children immunized
during a previous outbreak. If vaccine efficacy
does decrease with time since vaccination, the net
effect would he to artificially increase the efficacy
for children vaccinated at 14 months of age or
Clinic Efficacy
TABLE IV
In the three schools studied, a total of 60 (6.7%)
of the 903 children for whom a record search was
successful were without previous immunization.
Of these, 26 had either developed measles or were
in the prodromal period at the time the niass
clinics were held. The remaining 34 were eligible
for vaccination. Of these, 16 (47.0%) were
vacci-nated at the clinic. In addition, 131 (14.5%) had a
history of vaccination prior to 12 months of age.
Fourteen had developed measles by the time of
the clinic leaving 117 eligible for immunization.
Of the 1 17, 74 (63.2%) were vaccinated. Thus, as a
measure of clinic efficacy, 90 (59.6%) of the 151
children with inadequate immunization status
who were free of disease at the time of the clinic
were vaccinated (Table IV). Conversely, clinic
efficiency can be evaluated by determining what
percentage of those vaccinated in the mass
inimu-nization clinics were inadequately vaccinated
prior to the clinics. Of 442 total students
vacci-nated, only 90 (20.4%) were in need of
vaccina-tion.
Since 352 of 671 adequately protected children
also attended these clinics, vaccine status of those
who attended the clinics was compared to those
who did not attend. This was to determine if those
who attended the clinics were more likely to be in
need of vaccination than those who did not. No
significant difference was found
(x2
= 2.5,P > .1) in rates of attendance by adequacy of
vaccination status.
DISCUSSION
This outbreak illustrates several important
features. Of the 71 children who developed
measles and for whom prior immunization status
was documented, 37 (52.1%) had been previously
vaccinated. However, even though the majority
of cases occurred in vaccinated children, vaccine
efficacy was more than 95% for those vaccinated
at 12 months of age or older. Adequacy of measles
vaccine cannot be properly addressed by
propor-tion of cases occurring in previously vaccinated
children, but rather systematic measurement of
vaccine efficacy is required according to age at
vaccination.
Despite our failure to demonstrate a
statistical-ly significant difference in vaccine efficacy in
children immunized at 12 months of age
compared to children immunized at older ages, a
small difference may exist between these groups.
However, our sample size is large enough to
detect as significant a relative risk of 3. The
ATTENDANCE AT MASS IMMUNIZATION CLINIcS, BY
ADEQUACY OF PRIOR IMMUNIZATION STATUS#{176}
Mass Climi ics Inadequatet Adequate Total
Attended 90 352 442
Not attended 61 319 380
Total 151 671 822
ox = 2.5; P > .1. Clinic efficacy 90/151 59.6%.
Clinic efficiency = 90/442 = 20.4%.
t”Inadequate” includes unvaccinated children and children
vaccinated before 12 months of age.
differences between the clinical vaccine efficacy
developed from this outbreak and the rates of
seropositivity described by Yeager et al.,”
Krug-man,1’ and Shasby et al.’ may be fundamental to
the different methods. Seroconversion data tend
to exaggerate the rates of susceptibility.
Krug-man” has described the cases of seven
seronega-tive children in whom prior seroconversion had
been demonstrated. Vaccine challenge was
followed by an anamnestic serologic response
indicating the likelihood of persistent immunity
despite seronegativity. Serologic studies would
classify these children as susceptible whereas an
outbreak-based vaccine efficacy study would
show them to be protected. Outbreak-based
vaccine efficacy does not have this bias. However,
exposure has to be random by vaccination status
for this method to be valid. It is likely that a few
susceptible subjects even in large outbreaks are
not adequately exposed and so fail to develop
measles. They would appear to be protected
despite being susceptible, yet this will not affect
the determination of vaccine efficacy as long as
exposure is random. In this study we attempted to
control for exposure by studying only schools with
a 5% or greater attack rate and by adjusting our
risk period according to case attendance. In this
outbreak no differential susceptibility was seen
between those immunized at 12 months of age
and those vaccinated at older ages.
Evaluation of the duration of vaccine
effective-ness showed a low level increase in relative risk.
This analysis was hampered by the small number
of children vaccinated at 12 or more months of
age who developed disease. Because a possible
decrease in efficacy over time is important to
document or disprove, further study of this
prob-tern is indicated.
A difficulty in conducting a study of this
ten years ago may have received either the killed
vaccine or live further attenuated vaccine with
gaiiima globulin. Since these would only have
been used prior to ten years ago their decreased
effectiveness could artifactually suggest a
de-crease in efficacy over time. Most vaccination
records fail to indicate the type of vaccine or
whether gamma globulin was used. In this study
in only one child did the record state that killed
vaccine was used. Future research efforts will
need to take this problem into account.
In the schools surveyed, children vaccinated at
12 months of age comprised 12.4% of all children.
Routine revaccination of these children would
lead to a very small increase in protection relative
to the number of doses administered. Therefore, it
would seem to he premature to recommen#{231}l
alterations in existing recommendations for
routine revaccination which are to revaccinate
children previously vaccinated at less than 12
months of age. The recent change in
recommen-dations for primary immunization is probably
justifiable since the risk of contracting disease
during the period froni 12 to 15 nionths is low
relative to the possible improvement in efficacy
over this time as documented by serologic studies
to date. When a local outbreak is in progress,
revaccination of children previously vaccinated
at 12 months of age may be justifiable since they
may l)e at a small increased risk of being
suscep-til)le.
Clinic Efficacy
The role of mass immunization clinics in
outbreaks is difficult to document. Even though
60% of the inadequately immunized were reached
this was not due to selective attendance by those
in need. Children did not attend the clinic on the
basis of age at prior vaccination, the factor most
clearly associated with adequacy of vaccination.
It is likely that many parents forget the age at
previous vaccination, especially if it was a
number of years in the past. Alternatively, they
may feel that measles immunization is effective
for a limited period of time similar to the
diph-theria, pertussis, tetanus (DPT). Undoubtedly
these perceptions contributed to the low
percent-age of the total vaccine delivered via the mass
clinics that went to high-risk children. It seems
likely that, if good school records exist,
prescreen-ing for those inadequately immunized and
notify-ing only those parents would lead to an increase
in the efficiency of clinics. This would be
espe-cially true in areas where rates of vaccination are
relatively high and records are well kept.
Howev-er, because of limitation of personnel for such
record checks and variability in adequacy of
school records, this approach is frequently not
feasible.
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6. Linnemann CC, Rotte TC, Schiff GM, et al: A
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antibody ill previously illimunized ch ildreri : The need for revaccination. Anl I Di-s’ C/hid 124:53, 1972.
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1 1. ‘merican Academy of Pediatrics (news release), Mea-s’le,s’
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ACKNOWLEDGMENT
This article was awarded the 1978 Alexander D. Langmuir
Prize given by the Center for Disease Control Epidemic
Intelligence Service Alumni.
The authors wish to acknowledge the extensive help of the
Licking County and Newark City Health Departments in
conduct of the control program and collection of case
reports. Especially helpful were Mrs. Frances Benner and Mrs. Pearl Deeds of the Licking County Health Department
and Mrs. Jean Batchelor of the Newark City Health
Depart-ment. In addition we wish to acknowledge the efforts of Mr. Jack McSorley, Mr. Kevin Sullivan, Ms. Sarah Sharp, Mr. Leonard Payton, and Mr. Henry Butler of the Ohio InlIrnini-zation Unit. Special thanks must go to Mrs. Donna Ketner who typed and retyped and retyped the manuscript. \Ve also wish to acknowledge the extensive help of Drs. Alan Hinman, Neal Halsey, and Lyle Conrad in the technical
