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Partial Uptake of Varicella Vaccine and the Epidemiological Effect on Varicella Disease in 11 Day-Care Centers in North Carolina
Dennis A. Clements, MD, PhD;
Jeffrey I. Zaref, MD;
Christine L. Bland, RN;
Emmanuel B. Walter, MD, MPH;
Paul M. Coplan, PhD
Arch Pediatr Adolesc Med. 2001;155:455-461.
ABSTRACT
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Background The increasing use of varicella vaccine in children attending day care
has rapidly decreased the incidence of wild-type varicella disease. The herd
immunity noted is significant and will have an effect on the epidemiology
of natural varicella.
Objective To monitor the change in varicella incidence in day-care attendees after
the licensure of varicella vaccine.
Design A prospective observational cohort study design.
Setting Eleven private day-care centers and preschools in North Carolina participated
in the study from January 1, 1995, through December 31, 1999.
Participants All children in the 11 centers were eligible for participation. Some
participated more actively, supplying information on a regular basis. Others
participated passively. Day-care personnel provided information about all
cases of varicella.
Interventions None.
Main Outcome Variables The change in the incidence of varicella disease was documented as the
use of varicella vaccine increased.
Results Varicella vaccine coverage increased substantially from 4.4% in 1995
to 63.1% in December 1999. The vaccination rate accelerated dramatically in
1996 and 1997, leveled off in 1998, and rose again in 1999. Cumulative varicella
incidence decreased from 16.74 cases per 1000 person-months in July 1996 to
1.53 cases per 1000 person-months in December 1999 in unvaccinated children.
Conclusions The varicella vaccination rate continued to increase slowly in the day-care
population after an initial rapid uptake. The decrease in varicella disease
is greater than the increase in varicella vaccination. This herd effect is
welcome and even apparent in the unvaccinated children younger than 1 year.
INTRODUCTION
VARICELLA IS often viewed as a common and benign illness of childhood.
Serologic evidence has shown that by 20 years of age, 90% of the US population
is exposed to the varicella-zoster virus.1
Most disease occurs in children younger than 10 years,2
with the highest incidence rates from 3 to 6 years of age.3
It has also been suggested that increased use of day-care services has lowered
the average age of varicella illness.4, 5, 6
Despite the perception of varicella as a mostly benign disease, potential
complications exist, including secondary bacterial infection, pneumonia, cerebellar
ataxia, encephalitis, Reye syndrome, glomerulonephritis, arthritis, and, in
the immunocompromised host, disseminated disease.7
The rate of hospitalization due to varicella has been shown to be 5 to 10
times higher among adults older than 20 years.8
However, because of the high prevalence of disease in younger groups, children
still account for the largest percentage of total complicated cases.2 Before 1995, approximately 100 deaths per year were
attributed to varicella, with more than half occurring in adults.5, 9 After the licensing of Haemophilus influenzae type b vaccine and until the licensing of conjugate
pneumococcal vaccine, varicella was the leading cause of death in US children
preventable by childhood vaccination.10
The live attenuated varicella vaccine (VARIVAX; Merck & Co, Inc,
West Point, Pa) was licensed by the US Food and Drug Administration in March
1995 for use in healthy individuals aged at least 12 months without history
of varicella.11, 12 Research has
demonstrated this vaccine (and a similar product by Oka/Biken in Osaka, Japan13, 14) to be highly effective in the clinical
setting, preventing 100% of severe clinical disease and more than 80% of all
disease.13, 15, 16, 17, 18
One Oka/Biken long-term study demonstrated no waning of immunity during 20
years of follow-up.14 When varicella occurs
in vaccinated individuals after exposure to individuals with wild-type disease,
it has been shown to be a milder, modified varicella-like syndrome occurring
at a rate of 1% to 3% annually.16, 17, 18, 19, 20, 21, 22, 23
Since the vaccine was licensed more than 4 years ago, uptake has increased
steadily. The National Immunization Survey has reported national coverage
among children aged 19 to 35 months of 26.0%, 43.2%, and 59.4% in the years
1997, 1998, and 1999, respectively.10
This study considers the effect of varicella vaccination on a North
Carolina day-care population when vaccine is administered to only a portion
of the day-care participants. Specifically, we seek to highlight the potential
effects on the health of the public as vaccine use reshapes the epidemiology
of the disease and potentially affects the childhood population at risk for
disease.
MATERIALS AND METHODS
STUDY DESIGN
This study used a prospective, dynamic observational cohort design.
We studied subjects in 11 North Carolina day-care centers or preschools between
January 1, 1995, and December 31, 1999. These 11 centers serve a total of
1100 to 1500 children younger than 5 years, and are located in Durham, Raleigh,
Cary, Asheville, and Youngsville. All children attending these 11 centers
were eligible for inclusion in the study. Enrollment in the study began in
1995 and is ongoing. Subjects were followed up from the time of enrollment
in the center until completion of the study or withdrawal from the center.
DATA COLLECTION
Data were collected strictly through observational techniques. Information
regarding varicella vaccination status and disease status was collected through
brief questionnaires sent to the parents of all children enrolled in one of
the participating centers. These questionnaires were distributed 2 to 4 times
per year throughout the study.
To monitor varicella outbreaks within the day-care centers and preschools,
close varicella surveillance was maintained at each of the 11 sites. Passive
surveillance was performed by asking the parents and day-care center or preschool
staff to report all suspected cases of varicella to the study coordinator
(C.L.B.). In addition, active surveillance was performed by the study coordinator,
who visited or called each participating center on a weekly basis to ascertain
cases. If a case of varicella was identified, a thorough investigation was
initiated to determine the varicella vaccination status and case status of
all children within that center. Then, the study coordinator made a visit
to that center to ascertain additional cases. In addition, a letter was sent
to parents to inform them of the case of varicella in the center and instruct
them to call the study coordinator if they suspected that their child had
varicella. The study coordinator maintained daily contact with that center
to ascertain other possible cases of varicella and recorded information in
a surveillance log.
In addition, the study coordinator contacted the parents or guardians
of all children suspected of having varicella. If informed consent had already
been obtained, the study coordinator directly contacted the parents by telephone.
If consent had not been obtained, a letter was sent to parents requesting
consent to contact them by telephone. During the telephone interview, the
study coordinator obtained a detailed clinical history to determine exposure
history, date of onset of illness, number and type of lesions, location of
lesions, history of fever or respiratory symptoms, history of physician visit,
and medications given. If a telephone interview was not adequate for assessment,
the study coordinator or one of the principal investigators made an attempt
to examine the child at the Duke Children's Primary Care Clinic, Durham, or
in the day-care centers. A follow-up telephone call was made 10 to 14 days
after the initial assessment, to determine possible complications and the
number of days of day care or preschool missed by that child. If a child was
suspected of having varicella disease but had declined to participate in the
study, his/her parents were asked to complete a brief questionnaire regarding
symptoms and varicella vaccination status. In addition, the center staff provided
anonymous information regarding the vaccination status of nonparticipating
children for whom we had no information.
STUDY DEFINITIONS
Varicella Case
A case described an eligible child presenting
with a typical varicella rash or modified varicella-like syndrome as determined
by the study coordinator.
Vaccination Status
Vaccination history was determined by a parental
yes response to the question, "Has your child ever received the chickenpox
vaccine?"
Susceptibility
A child was regarded as susceptible if there
was no history of vaccination and a parent responded no to the question, "Has
your child ever had the chickenpox?" If the study coordinator subsequently
confirmed a case of varicella, the child was no longer considered susceptible.
Vaccinated children were considered nonsusceptible
after the recorded date of vaccination.
Varicella Vaccine Coverage
Vaccine coverage was defined as the number
of children vaccinated divided by the number of children ever eligible for
vaccine. Eligibility was defined as at least 12 months
of age and no history of varicella or vaccination before 12 months of age.
Varicella Vaccine Uptake
Uptake percentage was calculated by dividing
the number of children who received the varicella vaccine between survey periods
by the number of children eligible for vaccine. Monthly
uptake was obtained by dividing the percentage by the number of months
in the previous interceding interval.
Cumulative Varicella Incidence
The cumulative incidence of previous varicella disease was determined by dividing the number of children with a history of
disease by the total number of children at a particular observation point.
PERSON-TIME CALCULATIONS
Day-care enrollment records collected at the time of questionnaire distribution
were used to assess person-time contributed between survey periods, stratified
by age. Estimations and calculations were performed as follows. If a child
was verified as enrolled at one of the study day-care centers at 2 consecutive
survey periods (at times t1 and t2), then he/she was
assumed to have been present for the entire survey period, contributing the
entire length of person-time (t2 - t1).
If a child was verified as enrolled at one survey point (t1)
but not at the next survey point (t2), it was assumed that the
child had withdrawn at some point between the surveys. Total observed person-time
was estimated to be one half of the interceding interval, ie, (t2 -
t1)/2.
If a child had not been verified at one survey point (t1)
but was present at the next survey point (t2), it was assumed that
he/she had enrolled at some point between the surveys. Total observed person-time
was estimated to be one half of the interceding interval.
Total person-time contributed since the beginning of observation in
January 1995 was then stratified into the following 4 mutually exclusive categories.
Unvaccinated Nondiseased
If a child had no history of vaccination or varicella disease according
to our definitions, the total person-time of observation was classified as unvaccinated and nondiseased. This is equivalent to susceptible
or at-risk person-time. If a child subsequently experienced varicella illness
or vaccination, he/she was considered immune, and all person-time was entered
into a different, appropriate category.
Vaccinated Nondiseased
If a child had previously received varicella vaccine or was given vaccine
at some time during study enrollment but had not yet experienced varicella
illness, the person-time contributed after the date of vaccination was classified
as vaccinated but nondiseased.
Unvaccinated Diseased
If a child had not received varicella vaccine but had already experienced
varicella illness, the person-time contributed was categorized as unvaccinated but diseased from the date of disease forward.
Vaccinated Diseased
A child enrolled in the study with a history of varicella vaccination
and illness could only contribute observed person-time classified as vaccinated and diseased continuing from the date of the
later of the 2 events (normally varicella disease).
For children who enrolled between survey points, the person-time of
observation contributed before the first verified enrollment was classified
according to the child's person-time category status (eg, unvaccinated diseased)
at that initial survey point. Similarly, for children who left a day-care
center between survey points, all person-time contributed after the last verified
enrollment was classified according to the child's person-time category at
that last survey point. Assuming that enrollment or withdrawal from each day-care
center was not related to individual vaccination or varicella status, any
misclassification resulting from these assumptions would be nondifferential.
INCIDENCE RATES
The incidence rates for varicella were defined
as the number of new varicella cases divided by the total person-time at risk
for development of disease. Incidence rates were further stratified by vaccination
status and age group. The incidence rate in those unvaccinated was defined
as the number of new cases of varicella in unvaccinated children, divided
by the total unvaccinated and nondiseased person-time. Incidence rate in those
vaccinated was the number of new cases among vaccinated children, divided
by total vaccinated and nondiseased person-time. Age group for the duration
of an entire interval between observations was determined by the age of the
child at the beginning of the interval.
STATISTICS AND ANALYSIS
Vaccination rates and incidence rates with 95% confidence intervals
(CIs) were calculated using Stata for Windows Version 6.0 (Stata Corporation,
College Station, Tex), and  2 statistics were used for comparison
of proportions or analysis of trends.
If a date of birth for a child was unknown or not available, a value
was imputed by assigning the mean age of all other children in the same classroom
during the first survey point at which the child was verified as enrolled.
RESULTS
A total of 4064 children were observed during the 1995-1999 study. The
mean number of children present at each survey point was 1422, contributing
an average total of 8713.2 person-months per observation period. An average
of 4.8%, 10.6%, 13.0%, 16.6%, and 55.0% of observed person-time in each interval
was contributed by children aged 0 to 11, 12 to 23, 24 to 35, and 36 to 47
months and 48 months or older, respectively. The population consisted of 50.5%
boys for the entire study period. Information regarding vaccination status
and history of varicella disease was obtained on 74.3% and 76.7% of subjects,
respectively.
Vaccine coverage increased substantially in all eligible age groups
during the study period (P<.001) (Figure 1). Overall vaccine coverage increased from 4.4% (95% CI,
3.3%-5.9%) during January through March 1995 to 63.1% (95% CI, 59.8%-66.4%)
in December 1999.
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Figure 1. Varicella vaccine coverage by
age in months and date interval.
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The average monthly vaccine uptake increased from 0.17% per month to
1.57% per month since the beginning of observation (P
= .02). The highest monthly uptake in any group was recorded during 1997 (Figure 1).
Cumulative varicella incidence decreased significantly (2 test for trend, P<.001) in all age groups
(Figure 2). Within the last year
of observation, cumulative incidence continued to decrease significantly among
children at least 36 months of age. Age-related differences in varicella remained
apparent.
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Figure 2. Varicella cumulative incidence
by age in months and date interval.
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Overall varicella incidence rate per 1000 person-months decreased in
the vaccinated children from 5.35 (95% CI, 1.74-12.50) before July 1996 to
1.01 (95% CI, 0.12-3.65) in December 1999. The overall incidence rate also
decreased among the unvaccinated children, from 16.74 (95% CI, 12.77-21.54)
before July 1996 to 1.53 (95% CI, 0.50-3.58) in December 1999 (Figure 3), suggesting strong indirect effects of vaccination at
the current level of partial uptake. Disease in children younger than 1 year
(not eligible for vaccination) has recently disappeared.
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Figure 3. Varicella incidence rate in unvaccinated
children by age in months and date interval.
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Among the oldest children observed (aged  48 months), the distribution
of observed person-time is displayed in Figure
4. The proportion of vaccinated person-time has increased significantly
(P<.001), with a reciprocal decrease in unvaccinated
person-time. As a proportion of the unvaccinated (including diseased and nondiseased
children) person-time, the unvaccinated and diseased person-time has also
decreased significantly (P<.001). This trend has
permitted the susceptible person-time (without a history of disease or vaccination)
to approach about 39.0% of observed person-time in the last observation period.
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Figure 4. Distribution of categorized person-time
among children 48 months or older by date interval. UV indicates varicella
unvaccinated; V, varicella vaccinated; D, past varicella disease; and ND,
no past varicella disease.
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COMMENT
These results demonstrate a significant increase in vaccine coverage
for all eligible age groups in the study period. There is a correlated decrease
in varicella disease in both vaccinated and unvaccinated children. At a partial
uptake of 60%, vaccine has been administered to a high enough proportion of
the children in the population that incidence of varicella disease has decreased
within the unvaccinated population. In the geographically concentrated environment
of the day-care centers, a strong herd immunity24
effect is clearly evident. The indirect effects of vaccine use are important
to consider in evaluating the success of vaccination programs, and they have
undergone extensive mathematical modeling.25, 26, 27
This study shows the varicella vaccine to be extremely effective, given partial
uptake by a limited population.
It is also apparent that vaccine uptake has slowed for our population
after the initial early rise. We believe that as varicella disease becomes
increasingly infrequent, there may be a decreased motivation to obtain an
elective vaccine for eligible children. This trend has already been demonstrated
to occur with respect to the pertussis vaccination program.28, 29
Research has shown in general that as caregivers perceive decreased risk for
disease, the motivation for and likelihood of vaccination also decrease.2 The recent high levels of pertussis (and other) vaccination
is a tribute to the effectiveness of school entry and day-care immunization
requirements.
As vaccine coverage rises and stabilizes, disease becomes increasingly
rare. By 48 months and older, children are immune to varicella due to vaccine
or due to the increasingly rare wild-type disease. Thus, although the unvaccinated
children constitute a continually smaller proportion of the entire population
as assessed by person-time, there remains a large proportion of susceptible
person-time among school-age children. Based on observed trends, it is possible
that the unvaccinated proportion of person-time eventually will be constituted
entirely of susceptible (nondiseased) person-time. If vaccine coverage does
not increase, a large population of children will remain susceptible to varicella.
The unvaccinated children may remain free of disease through indirect
effects of the vaccine only as long as they remain in populations with coverage
levels that are high enough. Day-care centers typically demonstrate higher
levels of vaccine use compared with the national rates for similar-aged children
not enrolled in day care.30 Without school
entry and day-care admission requirements for varicella vaccination, areas
with low vaccine use will always exist. Varicella vaccine coverage rates vary
tremendously, last reported by the Centers for Disease Control and Prevention
to range from 3% to 33% among states from July 1996 to June 199731
and 13% to 40% among various urban areas for all of 1997.10
National Immunization Survey data reported for 1999 suggest that 59.4% of
children in the United States are now immunized against varicella. Even if
children remain free of disease in areas with high vaccine uptake, continued
existence of areas with low vaccine uptake creates the potential for circulating
wild-type virus. A child who remains susceptible and who is placed in a region
with low vaccine coverage and higher levels of circulating wild-type disease
will be at significantly increased risk of contracting disease, with potential
complications. Partial vaccination uptake, with disparate levels of coverage
in different areas, will place an unacceptable number of older children at
risk for complications of varicella.
Physicians previously have demonstrated poor adherence to the recommendations
for varicella immunization by the American Academy of Pediatrics and the Advisory
Committee on Immunization Practices. Several years ago, a Washington State
survey of 574 pediatricians demonstrated that less than 50% of the 434 respondents
recommended immunization in their practices. The main reasons for low adherence
were continued perceptions of varicella as a benign disease and questions
regarding the persistence of immunity from the varicella vaccine.32 A campaign for adding varicella to our already effective
vaccination requirements for school entry is needed to increase physician
adherence and to educate families regarding the advantages of vaccination.
CONCLUSIONS
A distinct shift in the epidemiological susceptibility to varicella
with the use of vaccine is already perceptible because of the compact and
accelerated nature of disease transmission in the day-care setting. There
has been a marked decrease in varicella disease in children attending day
care due to vaccination and significant herd immunity. Rates of vaccination
appear to be continuing to climb, but the elevation may not be sustainable
unless varicella vaccination is incorporated into the school admission requirements.
AUTHOR INFORMATION
Accepted for publication November 16, 2000.
This study was funded in part by Merck Research Laboratories, Inc, Blue
Bell, Pa.
From the Duke Vaccine Unit, Duke Children's Hospital, Durham, NC (Drs
Clements, Zaref, and Walter and Ms Bland); and the Merck Research Laboratories,
Blue Bell, Pa (Dr Coplan).
Corresponding author: Dennis A. Clements, MD, PhD, Campus Box 3810,
Duke University Medical Center, Durham, NC 27710 (e-mail: cleme002{at}mc.duke.edu).
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