MAJOR ARTICLE

Effectiveness of 2 Doses of Varicella Vaccine

in Children
Eugene D. Shapiro,1,3,4 Marietta Vazquez,1 Daina Esposito,1 Nancy Holabird,1 Sharon P. Steinberg,5 James Dziura,1,2
Philip S. LaRussa,5 and Anne A. Gershon5
1Department of Pediatrics; 2Department of Medicine; 3Department of Epidemiology; 4Department of Investigative Medicine, Yale University School of

Medicine and Graduate School of Arts and Sciences, New Haven, Connecticut; and 5Department of Pediatrics, Columbia University College of
Physicians and Surgeons, New York, New York

Background. Because of ongoing outbreaks of varicella, a second dose of varicella vaccine was added to the
routine immunization schedule for children in June 2006 by the Centers for Disease Control and Prevention.
Methods. We assessed the effectiveness of 2 doses of varicella vaccine in a case-control study by identifying

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children >4 years of age with varicella confirmed by polymerase chain reaction assay and up to 2 controls matched
by age and pediatric practice. Effectiveness was calculated using exact conditional logistic regression.
Results. From July 2006 to January 2010, of the 71 case subjects and 140 matched controls enrolled, no cases
(0%) vs 22 controls (15.7%) had received 2 doses of varicella vaccine, 66 cases (93.0%) vs 117 controls (83.6%) had
received 1 dose, and 5 cases (7.0%) vs 1 control (0.7%) did not receive varicella vaccine (P , .001). The
effectiveness of 2 doses of the vaccine was 98.3% (95% confidence level [CI]: 83.5%100%; P , .001). The matched
odds ratio for 2 doses vs 1 dose of the vaccine was 0.053 (95% CI: 0.0020.320; P , .001).
Conclusion. The effectiveness of 2 doses of varicella vaccine in the first 2.5 years after recommendation of
a routine second dose of the vaccine for children is excellent. Odds of developing varicella were 95% lower for
children who received 2 doses compared with 1 dose of varicella vaccine.

The live, attenuated varicella vaccine was developed in care centers occurred, despite high rates of vaccination
Japan in 1974 by Takahashi [1]. Recommendation for [6]. In addition, studies showed that over time the vac-
a single dose of the vaccine as part of the schedule for cines effectiveness was ,90% [7], and in one study of
routine immunization in the United States of suscepti- healthy children the rate of seroconversion after 1 dose of
ble children ages 12 months to 13 years (with 2 doses for the vaccine was only 76% [8]. Therefore, in June 2006,
susceptible older persons) was made after its licensure the Centers for Disease Control and Prevention (CDC)
by the Food and Drug Administration in 1995 [2]. The recommended routine administration of a second dose
incidence of varicella fell by 90%, mortality from vari- of varicella vaccine to children 46 years of age (or at least
cella declined by 66%, and rates of hospitalization for 3 months after the first dose was administered), as well as
varicella decreased by 80% after introduction and rou- administration of catch-up second doses to older chil-
tine use of the vaccine [35]; however, a high frequency dren [9]. Although data show that administration of 2
of breakthrough varicella in immunized children and doses of varicella vaccine is associated with higher anti-
continuing outbreaks of varicella in schools and in day- body titers (and presumably better protection from
varicella) [10], there are no controlled data on the clinical
efficacy of 2 doses of the vaccine in the general pop-
Received 14 July 2010; accepted 23 August 2010.
Potential conflicts of interest: Dr Gershon consults and receives honoraria for ulation. As part of an ongoing case-control study of the
lectures from Merck Laboratories and from GlaxoSmithKline. Dr Vazquez receives effectiveness of varicella vaccine, we conducted an anal-
honoraria for lectures from Merck Laboratories.
Reprints or correspondence: Dr Eugene D. Shapiro, Yale University Dept of
ysis to assess the effectiveness of 2 doses of the vaccine in
Pediatrics, P.O. Box 208064, 333 Cedar St, New Haven, Connecticut 06520-8064 children 4 years of age and older.
([email protected]).
The Journal of Infectious Diseases 2011;203:312315 METHODS
The Author 2010. Published by Oxford University Press. All rights reserved. For
Permissions, please email: [email protected]
1537-6613/2011/2033-0001$15.00
Methods are identical to those previously reported for
DOI: 10.1093/infdis/jiq052 this ongoing study [11, 12]. Informed consent was

312 d JID 2011:203 (1 February) d Shapiro et al.

obtained from all subjects and/or parents, and the study was between groups in continuous variables; the v2 test was used to
approved by Yales Human Investigation Committee. Subjects assess statistical differences between categorical values. All
included in this analysis were children >4 years of age enrolled P values are 2-sided. Results were considered statistically sig-
after 30 June 2006 at one of the 28 pediatric practices in southern nificant if the 2-tailed P value was ,.05.
Connecticut that participated in our surveillance network. Po-
tential case subjects, identified by active surveillance of the par- RESULTS
ticipating practices, were children who were thought by their
practitioners to have varicella. They were excluded if they had Subjects
a contraindication to varicella vaccine, had been previously di- From 1 July 2006 to 8 January 2010 we identified 306 potentially
agnosed with varicella, or had received varicella vaccine in the eligible case subjects. Of these, 247 (80.7%) enrolled, 42 (13.7%)
preceding 4 weeks. On the third to fifth day of the illness, a re- refused, and 17 (5.6%) could not be contacted. For the case
search assistant visited the home of each potential case subject subjects that were enrolled, PCR assay results were positive for
and conducted a brief interview. A suitable lesion from the rash 71 (28.7%), negative for 135 (54.7%), and inadequate for 41
was gently unroofed with a capillary tube that was also used to (16.6%). Of the parents of the 187 potentially eligible matched
collect vesicular fluid, if present. Material also was obtained by controls whom we were able to contact, we enrolled 140
swabbing the underlying skin with a cotton-tipped swab. (74.9%)for 2 of the cases, only 1 matched control was
A polymerase chain reaction (PCR) assay was performed on all enrolled; 47 (25.1%) refused to enroll. Characteristics of the
specimens to detect the presence of DNA of varicella-zoster subjects are shown in Table 1.

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virus (VZV) by investigators who were blind to the vaccina-
tion status of the potential subject. Results were considered Immunization with Varicella Vaccine
positive if the specimen was positive for DNA of VZV and all Vaccination status of the subjects is shown in Table 2. Of the 71
negative controls in the batch were negative. The test results subjects with varicella, 5 (7.0%) had not received varicella vac-
were considered negative if the specimen was negative for cine, 66 (93.0%) had received 1 dose, and none (0%) had re-
DNA of VZV, all positive controls in the batch were positive, ceived 2 doses of the vaccine. By contrast, among the 140
and the specimen was positive for the human b-globin gene matched controls, 1 (0.7%) had not received varicella vaccine,
(indicating the presence of fluid or tissue since there was 117 (83.6%) had received 1 dose, and 22 (15.7%) had received 2
amplifiable human DNA in the specimen). If the result was doses (P , .001). Nearly all case subjects and controls had re-
negative for DNA of both VZV and the b-globin gene, the ceived 2 doses of measles, mumps, and rubella (MMR) vaccine.
specimen was considered inadequate. No statistically significant demographic differences were shown
For each PCR-positive case subject, we selected 2 controls between subjects who had received 2 doses of varicella vaccine
who had not had varicella, matched by both date of birth and those who had received fewer doses. All of the vaccinated
(61 month) and pediatric practice. Controls were selected from case subjects and controls received monovalent varicella vaccine
a list of potential controls by using a table of random numbers to for their first dose (combined measles-mumps-rubella-varicella
select the order in which potential controls were contacted. The
medical records of the subjects (both case and control) were Table 1. Characteristics of the Subjects
reviewed, and all information about previous immunizations
and about significant medical illnesses was recorded. Records of Case Subjects Controls
all health care practitioners (including previous practitioners) n 5 71 n 5 140
(%) (%) P value
were reviewed. Subjects were considered vaccinated if there was
Age, years .905
written documentation that varicella vaccine had been received
Mean 6 SD 10.7 6 2.7 10.7 6 2.7
at least 4 weeks before the date of onset of varicella for each case
Median 11 11
subject. Only written documentation of receipt of vaccines was
Range 418 418
accepted as evidence of prior immunization. Male sex 40 (56.3) 77 (55.0) .853
Data were analyzed using SAS software, version 9.1.3, for Caucasian race 62 (87.3) 126 (90.0) .556
Windows (SAS Institute) and LogExact statistical software Parent education .185
packages (Cytel). Matched odds ratios (ORs),with both their High school or less 22 (31.9) 48 (34.3)
associated statistical significance and their 95% confidence in- Some college 18 (25.4) 21 (15.0)
tervals (CIs), as well as adjustments for potential confounding, College/postgraduate degree 31 (43.7) 71 (50.7)
were calculated using exact conditional logistic regression. The Weekday location .015
vaccines effectiveness was calculated as 1 the matched OR 3 Home 3 (4.2) 22 (15.7)
100% [13]. Student t test or Wilcoxon rank-sum test was used as School or day-care 68 (95.8) 118 (84.3)
Diagnosis of asthma 4 (5.6) 17 (12.1) .136
appropriate to assess statistical significance of differences

Varicella Vaccine in Children d JID 2011:203 (1 February) d 313

Table 2. Vaccination Status of Subjects DISCUSSION

Case Subjects Controls Results from this controlled study of the effectiveness of 2 doses of
n 5 71 n 5 140 varicella vaccine indicate that administration of 2 doses was highly
(%) (%) P value
effective in preventing varicella in the first 2.5 years after im-
Varicella vaccine ,.001
plementation of the 2-dose schedule to prevent disease. There has
0 doses 5 (7.0) 1 (0.7)
been controversy about whether the suboptimal effectiveness of
1 dose 66 (93.0) 117 (83.6)
a single dose of varicella vaccine is due to primary vaccine failure,
2 doses 0 (0.0) 22 (15.7)
Months since dose 1 .151
waning immunity, or both [8, 12,1416]. Whatever the cause,
Mean 6 SD 103.2 6 24.1 97.4 6 28.2 however, initial assessment indicates that administration of 2 doses
Median 106 101 of the vaccine has been highly effective in preventing varicella;
Range 35139 17161 none of the 71 children with PCR-confirmed varicella had received
Months since dose 2 N/A 2 doses of the vaccine, although many had received 1 dose.
Mean 6 SD 14.8 6 13.3 The effectiveness of a vaccine is defined as 1 the odds of
Median 12 disease in vaccinated vs unvaccinated individuals 3 100% [13].
Range 050 In a matched analysis, only groups in which there is discordance
Received MMRa .1 dose 71 (100.0) 139 (99.3) 1.000 in the number of doses of vaccine between the case subjects and
Received MMR 2 doses 70 (98.6) 137 (97.9) 1.000
any of the controls contribute information to the analyses [17].

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NOTE. a MMR, Measles, mumps, and rubella vaccine; N/A, not applicable. Because of the small number of discordant groups in which
subjects had received either no dose or 1 dose of the vaccine, our
statistical power to assess the effectiveness of 1 dose of the
[MMRV] vaccine was not yet on the market at the time these vaccine was poor. Consequently, the confidence interval around
children received their first dose of varicella vaccine). Two of the this estimate is wide, although the point estimate is similar to
controls received their second dose as MMRV vaccine (it was no previous estimates of the effectiveness of 1 dose of the vaccine
longer available beginning in late 2007). [7, 12]. By contrast, we were able to show that administering
2 doses of the vaccine was very effective and that the odds of
Effectiveness of the Vaccine developing disease after 2 doses were significantly lower than
The distribution of vaccination by matched groups is shown in after 1 dose. No similar difference was seen between subjects and
Table 3. The effectiveness of 1 dose of the vaccine was 86.0% controls in receipt of the MMR vaccinenearly all subjects and
(95% CI: 244.5%99%; P 5 .124). The effectiveness of 2 doses controls had received 2 doses of this vaccine. Since MMR vac-
of the vaccine was 98.3% (95% CI: 83.5%100%; P , .001). cine is recommended to be administered at the same ages as
The matched odds ratio for 2 doses versus 1 dose of the vaccine varicella vaccine, this demonstrates the specificity of our results
was 0.053 (95% CI: 0.0020.320; P , .001), indicating that, in and suggests that they are not attributable to selection bias [18].
the first 2.5 years after introduction of the second dose, the odds The United States was the first country to recommend uni-
of developing varicella for children who had received 2 doses of versal immunization with 1 dose of varicella vaccine, and the
the varicella vaccine were 95% lower than for those who had first to introduce a 2-dose schedule. Two doses were recom-
received 1 dose. Results of all of the analyses were virtually mended although there were no data to demonstrate that ad-
unchanged after adjusting for potential confounding (ie, site of ministering 2 doses would reduce the incidence of breakthrough
weekday care, home vs school or day care). varicella, though one uncontrolled study suggested there might

Table 3. Receipt of Varicella Vaccine by Dose and Matched Groups

Doses Received by Matched Control Subjects

One Control
Doses Received by Neither Control One Control One Control Both Controls Received 1 Dose, Both Controls
Case Subject Received Vaccine Received 1 Dose Received 2 Dosesa Received 1 Dose One 2 Doses Received 2 Doses
0 0 0 1 3 1 0
1 0 1 1 48 13 3
2 0 0 0 0 0 0
NOTE. Matched odds ratio, 1 dose vs 0 dose of vaccine: 0.14 (95% CI: 0.0031.445; P 5 124)
Matched odds ratio, 2 doses vs 0 dose of vaccine: 0.017 (95% CI: 00.165) P , .001
Matched odds ratio, 2 doses vs 1 dose of vaccine: 0.053 (95% CI: 0.0020.320; P , .001)
a
Both cases in this category had only one control.

314 d JID 2011:203 (1 February) d Shapiro et al.

be a decrease in incidence after 2 doses [10]. Currently, many Laura Marks, Laura McGrimley, Jonathan Miller, Jennifer Moore, James L.
Morgan, Pamela Murtagh, Robert Nolfo, Jeffrey Owens, Kathy Pae,
other countries, including Australia, Japan, China, and Spain,
Christine Patterson, Lisa Pavlovic, Erin Rice, Marie Robert, Lynn Rudich,
are carrying out universal immunization programs with a single Margaret Sanyal, Raymond Seligson, Lucille Semeraro, Michael J. Sheehan,
dose of the vaccine. Simone Simon, Stephanie Slattery, Jonathan Sollinger, Sydney Spiesel,
The experience in the United States demonstrated that al- Dena Springer, Erin Springhorn, Jonathan H.R. Stein, Elsa Stone, Gordon
Streeter, Craig P. Summers, Dawn Torres, Mark H. Vincent, Lisa Visscher,
though a single dose of the vaccine had a substantial impact on Linda Waldman, Kirsten Wallis, Gary R. Wanerka, Elizabeth Wiesner,
the burden of disease, breakthrough varicella continued to Janet Woodward, Edward Zalitis, Joseph Zelson; PAs Joan Alfiero, Heather
occur. Breakthrough varicella is generally a much milder illness Buccigross, Sue Marie DeMellis, Lisa Keyes, John Roney; APRNs Elyse
Borsuk, Michael Corjulo, Meredith Cowperthwait, Diane Fahey, Brooke
than varicella in unimmunized children and may be difficult to
Fleit, Jennifer Hill, Linda Jacobson, Kathryn Krauser, Paula Masto, Betsy
differentiate from other common skin conditions such as insect Parke, Patricia Ryan-Krause, Cindy Wechsler; CPNPs Jennifer M. Carlson,
bites or impetigo. This likely is the explanation for the lower Patricia B. Davis, Nicole Langan, Elizabeth Perrone; PNPs Ellen Fahey,
proportion of potential subjects with a positive VZV PCR result Claire McKegney, Stephanie Perkins, Lynda Romita; PA-Cs Susan Amster,
Kristen Baker; CFNP Cheryl Savoca.
in this study than in our previous reports [1112]. However,
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