Varicella Vaccine Effectiveness in Preventing Community Transmission in the 2-Dose Era

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2016

Varicella Vaccine Eectiveness in Preventing

Community Transmission in the 2-Dose Era

Dana Perella

Philadelphia Department of Public Health

Chengbin Wang

Centers for Disease Control and Prevention

Rachel Civen

Los Angeles County Department of Public Health

Kendra Viner

Philadelphia Department of Public Health

Karen Kuguru

Los Angeles County Department of Public Health

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Perella, Dana; Wang, Chengbin; Civen, Rachel; Viner, Kendra; Kuguru, Karen; Daskalaki, Irini; Schmid, D. Sco>; Lopez, Adriana S.;

Tseng, Hung Fu; Newbern, E. Claire; Mascola, Laurene; and Bialek, Stephanie R., "Varicella Vaccine E<ectiveness in Preventing

Community Transmission in the 2-Dose Era" (2016). Public Health Resources. 447.

h>p://digitalcommons.unl.edu/publichealthresources/447

Authors

Dana Perella, Chengbin Wang, Rachel Civen, Kendra Viner, Karen Kuguru, Irini Daskalaki, D. Sco> Schmid,

Adriana S. Lopez, Hung Fu Tseng, E. Claire Newbern, Laurene Mascola, and Stephanie R. Bialek

=is article is available at DigitalCommons@University of Nebraska - Lincoln: h>p://digitalcommons.unl.edu/

publichealthresources/447

ARTICLE

PEDIATRICS Volume 137 , number 4 , April 2016 :e 20152802

Varicella Vaccine Effectiveness

in Preventing Community

Transmission in the 2-Dose Era

Dana Perella, MPH,

Chengbin Wang, PhD,

Rachel Civen, MD, MPH,

Kendra Viner, PhD, MPH,

Karen

Kuguru, MPA,

Irini Daskalaki, MD,

D. Scott Schmid, PhD,

Adriana S. Lopez, MHS,

Hung Fu Tseng, PhD,

MPH,

E. Claire Newbern, PhD, MPH,

Laurene Mascola, MD, MPH,

Stephanie R. Bialek, MD, MPH

abstract

OBJECTIVES: We examined overall and incremental effectiveness of 2-dose varicella

vaccination in preventing community transmission of varicella among children aged 4 to

18 years in 2 active surveillance sites. One-dose varicella vaccine effectiveness (VE) was

examined in those aged 1 to 18 years.

METHODS: From May 2009 through June 2011, varicella cases identified during active

surveillance in Antelope Valley, CA and Philadelphia, PA were enrolled into a matched

case–control study. Matched controls within 2 years of the patient’s age were selected from

immunization registries. A standardized questionnaire was administered to participants’

parents, and varicella vaccination history was obtained from health care provider,

immunization registry, or parent records. We used conditional logistic regression to

estimate varicella VE against clinically diagnosed and laboratory-confirmed varicella.

RESULTS: A total of 125 clinically diagnosed varicella cases and 408 matched controls were

enrolled. Twenty-nine cases were laboratory confirmed. One-dose VE (1-dose versus

unvaccinated) was 75.6% (95% confidence interval [CI], 38.7%–90.3%) in preventing

any clinically diagnosed varicella and 78.1% (95% CI, 12.7%–94.5%) against moderate or

severe, clinically diagnosed disease (≥50 lesions). Among subjects aged ≥4 years, 2-dose

VE (2-dose versus unvaccinated) was 93.6% (95% CI, 75.6%–98.3%) against any varicella

and 97.9% (95% CI, 83.0%–99.7%) against moderate or severe varicella. Incremental

effectiveness (2-dose versus 1-dose) was 87.5% against clinically diagnosed varicella and

97.3% against laboratory-confirmed varicella.

CONCLUSIONS: Two-dose varicella vaccination offered better protection against varicella from

community transmission among school-aged children compared with 1-dose vaccination.

Philadelphia Department of Public Health, Philadelphia, Pennsylvania;

Centers for Disease Control and

Prevention, Atlanta, Georgia;

Los Angeles County Department of Public Health, Los Angeles, California; and

Southern California Permanente Medical Group, Kaiser Permanente, Pasadena, California

Ms Perella, Dr Wang, Dr Viner, Dr Daskalaki, Dr Schmid, Ms Lopez, Dr Newbern, and Dr Bialek

conceived and designed the initial study protocol for implementation in Philadelphia, PA.

Dr Civen, Ms Kuguru, Dr Tseng, and Dr Mascola adapted and revised the protocol for

implementation in Antelope Valley, CA. Ms Perella, Dr Viner, and Dr Daskalaki coordinated

and supervised data acquisition in Philadelphia, and Dr Civen, Ms Kuguru, and Dr Tseng were

responsible for these activities in Antelope Valley. Dr Wang, Ms Perella, Dr Viner, and Ms Kuguru

analyzed the study data, and all authors contributed to the interpretation of study analyses for

the manuscript. Ms Perella, Dr Wang, and Dr Bialek drafted the manuscript. All authors critically

revised the manuscript's content and approved the ﬁ nal manuscript as submitted.

To cite: Perella D, Wang C, Civen R, et al. Varicella Vaccine Effectiveness

in Preventing Community Transmission in the 2-Dose Era. Pediatrics.

2016;137(4):e20152802

WHAT’S KNOWN ON THIS SUB JECT: Declines in varicella

incidence since 2006 and vaccine effectiveness estimates

from outbreak investigations indicate that 2-dose

varicella vaccination provides improved protection

against varicella. Limited data exist on the performance

of 2-dose varicella vaccination in preventing community

transmission outside outbreak settings.

WHAT THIS STUDY ADDS: Two-dose varicella vaccination

improved protection against community transmission of

varicella among school-aged children in 2 geographically

and demographically diverse areas compared with 1-dose

vaccination. Our study provides more direct evidence on

the protective effect of a 2-dose varicella vaccine regimen.

This document is a U.S. government work and

is not subject to copyright in the United States.

PERELLA et al

Between 1995 and 2005, the 1-dose

varicella vaccination program in

the United States greatly reduced

varicella incidence, hospitalizations,

and deaths.

1–4

However, between

2001 and 2006, varicella outbreaks

in school settings with high 1-dose

vaccination coverage (>80% among

students without varicella history)

continued to be reported.

5–11

Clinical

trial data had demonstrated that the

immune response produced 6 weeks

after 2-dose varicella vaccination

was 12 times higher than levels after

1-dose vaccination, which translated

into a threefold reduction in

breakthrough varicella over a 10-year

period.

Therefore, in 2006 the

Advisory Committee on Immunization

Practices recommended

implementation of a routine 2-dose

varicella vaccination program for

children aged 4 to 6 years.

Declines in varicella incidence

reported since 2006 along with

varicella vaccine effectiveness

(VE) estimates from a case–control

study conducted as part of active

surveillance of outbreaks in West

Virginia indicate that the 2-dose

regimen provides improved

protection against varicella.

14–18

However, limited field data exist

on the performance of a 2-dose

varicella vaccination program in

preventing community transmission

other than in outbreak settings that

may underestimate the true vaccine

effectiveness.

18, 19

A community-based

case–control study in Connecticut

found 2-dose varicella VE was 98.3%,

but no 2-dose cases were identified

in the study.

As this study

demonstrates, obtaining precise 2-dose

varicella VE estimates is challenging

because of the lower varicella

incidence in the 2-dose era, particularly

among recipients of both doses.

To evaluate the 2-dose varicella

VE, we conducted a matched

case–control study to examine

the overall and incremental VE of

the 2-dose varicella vaccination

regimen in preventing varicella

among school-aged children (4–18

years) in 2 geographically and

demographically diverse areas under

active surveillance for varicella.

Secondary study objectives were

to estimate 1-dose VE among

children aged 1 to 18 years during

the 2-dose era and determine risk

factors associated with breakthrough

varicella among 2-dose recipients.

METHODS

Study Population and Setting

From May 2009 through June

2011, investigators from Antelope

Valley (AV) and West Philadelphia

Varicella Active Surveillance Project

(VASP) conducted this matched

case–control study in collaboration

with the Centers for Disease Control

and Prevention (CDC). Institutional

review boards at all 3 participating

institutions approved the study

protocol. The target populations for

case and control subject recruitment

were residents aged 1 to 18 years

from AV and Philadelphia. AV spans

~2200 square miles of northern Los

Angeles County and has a population

of >370 000 residents.

Philadelphia

is a large and densely populated

metropolis with 1.5 million

residents.

During the study, the

majority of AV residents <20 years

of age were either Hispanic (51%) or

non-Hispanic white (30%).

Among

those of same age in Philadelphia,

48% were non-Hispanic black, 28%

were non-Hispanic white, and only

16% were Hispanic.

Case Recruitment

In AV and Philadelphia, varicella

cases were identified prospectively

through population-based active

surveillance methods. More than 300

participating community-based sites

(eg, schools, health care provider

offices) in each surveillance area

reported suspected varicella cases or

informed project staff that no cases

occurred at their facility biweekly.

15,

During the 2010 to 2011 academic

year, active surveillance was

expanded from West Philadelphia

to include an additional 232

schools that were located in other

areas of Philadelphia. Eligible case

subjects in Philadelphia were also

identified through citywide passive

surveillance. All case reports were

investigated with the standardized

VASP questionnaire.

15, 23

After investigation, a case subject

was defined as a person residing in

AV or Philadelphia with no previous

history of varicella and acute onset

of a diffuse maculopapulovesicular

rash or, for previously vaccinated

people, modified maculopapular

rash with few or no vesicles that

a medical provider definitively

diagnosed as varicella without any

other apparent cause.

15, 24

In May

2009 through July 2010, enrollment

was limited to children aged 5 to 14

years with laboratory confirmation

of varicella-zoster virus (VZV) by

polymerase chain reaction (PCR)

testing. During August 2010 through

June 2011, enrollment was expanded

to include people 1 to 18 years

of age with laboratory or clinical

diagnosis of varicella by a health care

provider. Laboratory confirmation

was expanded to include positive

VZV-specific PCR, direct fluorescent

antibody assay, or culture results.

Control Selection

Control subjects were selected from

the Kaiser Permanente Southern

California membership database

and the Philadelphia Department of

Public Health’s Kids Immunization

Database/Tracking System

registry in AV and Philadelphia,

respectively. Kaiser Permanente

Southern California, an integrated

health care system, provides

comprehensive health services

to 30% of AV residents aged 1 to

19 years; vaccine administration

data for its members are stored in

the Kaiser Immunization Tracking

System and include information

on vaccine doses administered by

PEDIATRICS Volume 137 , number 4 , April 2016

providers inside and outside the

Kaiser network or verified through

school or provider records for

vaccinations given before enrollment.

Kaiser Permanente also was an active

surveillance reporting site in AV. The

Philadelphia Department of Public

Health immunization registry has

used health department birth records

and vaccine administration reporting

from health care providers to

establish and maintain immunization

records for all children aged ≤6

years in Philadelphia since 1995. The

registry expanded to include children

aged ≤18 years in 2007.

For each varicella case identified

that met study inclusion criteria,

we selected potential controls using

incidence density sampling by

extracting age-matched (±2 years)

records for all children from the pool

of eligible controls aged 1 to 18 years

who did not have a previous varicella

history documented in historic

surveillance data or immunization

registry.

A 2-year age range for

controls was chosen, because the

routine 2-dose varicella vaccination

recommendation spans ages 4 to 6

years.

Moreover, because routine

1-dose coverage reached higher

levels (>80%), protection from

1-dose varicella vaccination appears

to remain consistent during the

first few years after vaccination.

Between 5 and 60 potential control

subjects were randomly selected

from the corresponding control pool

for each incident case. To be able to

analyze VE among the age groups for

which the first and second doses of

varicella vaccine are recommended,

controls selected for cases aged 1

to 3 years had to be <4 years of age,

and controls selected for cases ≥4

years of age had to be ≥4 years of

age. Study staff sent an invitation

letter and contacted parents or

guardians of eligible control subjects

via telephone. The first 3 eligible

respondents who consented to

participate were the controls for each

incident case. Recruited controls

were eligible to be controls for

subsequent incident cases, and if she

or he developed varicella at a later

time point, the subject was eligible

for the study as a case subject.

Data Collection

Study staff obtained verbal consent

and collected data from a parent or

guardian of each subject by telephone

by using a standard questionnaire.

Given limited study resources, we

did not recruit cases and controls

with non-English-speaking parents

or guardians who could not provide

consent because of the language

barrier. The questionnaires captured

information on demographics,

varicella vaccination history, recent

VZV exposures, underlying medical

conditions, and use of immune-

suppressing medications. The case

questionnaire, which has been

described previously, included

additional disease-specific questions

and standardized prompts to obtain

the number of lesions.

VASP staff

scheduled home visits to collect

lesion specimens from eligible cases

reported before their rashes had

resolved. The CDC National VZV

Laboratory performed PCR testing

26,

on lesion specimens collected

from suspected varicella cases. For

a few cases, VZV-specific testing was

conducted by hospital or commercial

reference laboratories. Participating

families received a $10–$20 gift

card after completion of study-

related activities, and AV health care

providers were offered a $20 gift

card for every case reported with

lesion specimens collected.

For case and control subjects,

varicella vaccination administration

dates were collected from the

registries used for control selection,

parental records, and the subject’s

health care provider. Study staff

made efforts to validate vaccination

information for all subjects with the

immunization registry or health care

provider records. If a discrepancy

existed between these 2 sources,

the source with the most complete

information (ie, highest number of

doses) was used. We considered

1-dose varicella vaccination to be

valid when given 4 days before a

child’s first birthday or later. Second-

dose varicella vaccination was

considered valid when administered

≥4 weeks after the first dose. The

last dose also needed to be given

>42 days before rash onset for cases

(breakthrough varicella) or the

matched incident case’s onset for

controls. Those given doses within 42

days were excluded.

Data Analysis

For our main analysis, we combined

data from both sites, because

varicella vaccine coverage and risk

for breakthrough varicella have not

differed between sociodemographic

subgroups,

13, 28

and the directions

of estimates from each site were

similar. We used 2 case definitions

for varicella: clinically diagnosed

and laboratory confirmed. Varicella

severity was categorized based on

the number of lesions reported as

mild (<50 lesions), moderate (50–500

lesions), or severe (>500 lesions).

The following VE estimates were

calculated to examine protection

against any varicella or moderate or

severe disease alone (≥50 lesions):

incremental 2-dose VE (2 doses

versus 1 dose), overall 2-dose VE

(2 doses versus unvaccinated), and

overall 1-dose VE (1 dose versus

unvaccinated). All VE estimates were

calculated with Greenwood and Yule’s

formula: VE = 1 − relative risk (RR).

In our study, RR refers to the risk

of developing varicella among the

subgroup with the higher number

of varicella vaccine doses compared

with the subgroup with fewer or no

doses and was estimated with an

odds ratio (OR) from conditional

logistic regression to account for the

matching variable (age). We were

able to adjust for other potential

confounders when examining VE

against clinically diagnosed disease

PERELLA et al

using the combined site data. Changes

in VE by time since vaccination (rash

onset date minus the date of most

recent varicella vaccination) were

calculated via previously described

methods.

The distribution of

categorical or continuous variables

between cases and controls was

examined with Mantel–Haenszel

test, Fisher’s exact test, Mann–

Whitney U test, or Kruskal–Wallis test

where appropriate. All analyses were

conducted in SAS 9.3 (SAS Institute,

Inc, Cary, NC).

RESULTS

Case and Control Subject

Characteristics

A total of 125 clinically diagnosed

varicella cases and 408 matched

controls were enrolled. Of the

44 (35.2%) cases that had lesion

specimens tested for VZV, 29 were

laboratory-confirmed cases (all PCR

positive), 11 were PCR negative

(median lesion collection day: 5

[range: 2–21]), 2 had inadequate

specimens, and 2 were culture

negative. The median age of clinically

diagnosed cases was 2.1 years

among those aged <4 years and

9.5 years among those aged ≥4

years (Table 1). For each case, 2 to

7 matched controls (median = 3)

were recruited after we approached

a median of 5 (range: 5–15) and

29 (range: 5–60) eligible people in

AV and Philadelphia, respectively.

The distribution of demographic

characteristics did not differ

significantly between clinically

diagnosed case and control subjects,

except day care attendance among

those aged ≥4 years (P = .03). Most

controls aged ≥4 years from AV and

Philadelphia had received ≥1 dose of

varicella vaccine (98.8% vs 95.5%,

P = .05), and the majority in each

site had received 2 doses (78.5%

vs 83.6%, P = .31). Although the

proportion of vaccinated cases aged

≥4 years from each site was similar

(91% to 92%), the proportion of

cases aged ≥4 years who were 2-dose

recipients was slightly lower in AV

than Philadelphia (41.1% vs 59.5%,

P = .08).

Among clinically diagnosed cases

≥4 years of age, rash severity

and characteristics differed

significantly by vaccination status,

with the majority of breakthrough

cases reporting mild and mostly

TABLE 1 Demographic and Vaccination Characteristics of Clinically Diagnosed Varicella Case and Control Subjects From Philadelphia, Pennsylvania and

Antelope Valley, California, 2009–2011

Aged 1–3 y

Aged ≥4 y

Cases (n = 32),

n (%)

Controls (n = 103),

n (%)

P Cases (n = 93),

n (%)

Controls (n = 305),

n (%)

Median age 2.1 (1.0–3.9) 2.2 (1.1–3.9) .53 9.5 (4.0–18.9) 9.3 (4.1–18.9) .58

Surveillance site .68 .48

Antelope Valley, CA 9 (28.1) 33 (32.0) 56 (60.2) 171 (56.1)

Philadelphia, PA 23 (71.9) 70 (68.0) 37 (39. 8) 134 (43.9)

Vaccination status <.001 <.001

Unvaccinated 9 (28.1) 4 (3.9) 8 (8.6) 8 (2.6)

1-dose 22 (68.8) 98 (95.1) 40 (43.0) 50 (16.4)

2-dose 1 (3.1) 1 (1.0) 45 (48.4) 247 (81.0)

Race .09 .43

White 12 (37.5) 46 (44.7) 59 (63.4) 171 (56.1)

African American 9 (28.1) 40 (38.8) 25 (26.9) 95 (31.1)

Other 11 (34.4) 17 (16.5) 9 (9.7) 39 (12.8)

Ethnicity .18 .20

Hispanic 14 (45.2) 33 (32.0) 40 (43.0) 109 (35.7)

Non-Hispanic 17 (54.8) 70 (68.0) 53 (57.0) 196 (64.3)

Gender .41 .87

Male 16 (50.0) 60 (58.3) 47 (50.5) 157 (51.5)

Female 16 (50.0) 43 (41.7) 46 (49.5) 148 (48.5)

Born in United States >.999 >.999

Yes 31 (100.0) 103 (100.0) 91 (97.8) 296 (97.0)

No 0 (0.0) 0 (0.0) 2 (2.2) 9 (3.0)

Immunosuppressing condition >.999 >.999

Yes 0 (0.0) 0 (0.0) 0 (0.0) 2 (0. 7)

No 32 (100.0) 103 (100.0) 92 (100.0) 303 (99.3)

Asthma .99 .26

Yes 6 (18.8) 19 (18.6) 19 (20.4) 47 (15.5)

No 26 (81.3) 83 (81.4) 74 (79.6) 257 (84.5)

Attend day care .62 .03

Yes 13 (40.6) 47 (45.6) 6 (4.5) 47 (15.4)

No 19 (59.4) 56 (54.4) 87 (93.5) 258 (84.6)

Missing and unknown responses excluded. Valid percentages presented.

PEDIATRICS Volume 137 , number 4 , April 2016

maculopapular rashes, whereas

most unvaccinated cases had 50–500

lesions that were mostly vesicular

(Table 2). There was no severe

varicella among 2-dose cases. Only

2 cases had >500 lesions; both were

otherwise healthy adolescents, of

whom, 1 was a 1-dose recipient and

the other unvaccinated. None of

the cases were hospitalized due to

varicella or developed complications

of varicella. Among breakthrough

cases aged ≥4 years, 2-dose cases

were more likely to have rashes that

resolved in <1 week (P = .01) and

were less likely to have vesicular

rashes (P = .01) than 1-dose cases.

Presence and duration of fever did

not differ significantly between

breakthrough and unvaccinated

cases.

Varicella Vaccine Effectiveness

Among all unvaccinated and 1-dose

participants, the effectiveness

of 1-dose of varicella vaccine

compared with no vaccine was

75.6% (95% confidence interval

[CI], 38.7%–90.3%) against all

clinically diagnosed varicella and

78.1% (95% CI, 12.7%–94.5%)

against moderate or severe disease

(Table 3). The effectiveness of 2

doses of varicella vaccine compared

with no vaccine among subjects

aged ≥4 years was 93.6% (95% CI,

75.6%–98.3%) against all clinically

diagnosed varicella and 97.9% (95%

CI, 83.0%–99.7%) against moderate

or severe varicella. The incremental

effectiveness of 2-dose varicella

vaccination compared with 1-dose

among participants ≥4 years of age

was 87.5% (95% CI, 74.9%–93.7%)

in preventing any clinically diagnosed

varicella and 94.1% (95% CI, 72.4%–

98.8%) in preventing moderate or

severe clinically diagnosed disease.

VE estimates were higher but not

significantly in AV than Philadelphia.

Among subjects aged ≥4 years from

AV, 2-dose VE and incremental VE

against any clinically diagnosed

varicella were 98.4% and 92.4%,

respectively. In Philadelphia, 2-dose

VE and incremental VE among

subjects ≥4 years old were 92.7%

and 79.8%, respectively. Two-

dose VE estimates did not differ

significantly between sites (P =

0.20); however, the small number of

unvaccinated cases (≤5) and controls

(≤6) may have led to unstable VE

estimates by site.

Among the 26 laboratory-confirmed

cases aged ≥4 years and their

matched controls, 2-dose varicella VE

was 95.9% (95% CI, 23.2%–99.8%),

and incremental VE was 97.3% (95%

CI, 88.9%–100%). Because data

were sparse, we could not assess

effectiveness of 1-dose of varicella

vaccine against laboratory-confirmed

varicella.

Risk Factors for Breakthrough

Varicella Among 2-Dose Varicella

Vaccine Recipients

Among 2-dose varicella vaccine

recipients, there was no association

between time since receiving dose

2 and breakthrough varicella (P =

.17; Table 4). However, those who

received the second dose after 6

years of age were 60% less likely

to have breakthrough varicella

than those who had received the

second dose at an earlier age (P

= .009). A longer time interval

TABLE 2 Varicella Disease Severity by Vaccination Status for Clinically Diagnosed Varicella Case-Subjects Aged ≥4 y in Philadelphia, Pennsylvania and

Antelope Valley, California, 2009–2011

Varicella Vaccination Status Overall P 2- vs 1-Dose P

Unvaccinated (n = 8),

n (%)

1-Dose (n = 40), n (%) 2-Dose (n = 45),

n (%)

Rash severity

.01 .81

Mild (<50 lesions) 1 (12.5) 26 (65.0) 31 (68.9)

Moderate or severe (50–500 lesions) 6 (75.0) 13 (32.5) 14 (31.1)

Severe (>500 lesions) 1 (12.5) 1 (2.5) 0 (0.0)

Fever .36 .11

Yes 2 (25.0) 16 (41.0) 11 (24.4)

No 6 (75.0) 23 (59.0) 34 (75.6)

Most lesions are vesicular <.001 .01

Yes 3 (60.0) 9 (23.1) 2 (4.5)

No 2 (40.0) 30 (76.9) 42 (95.5)

Days of fever: median (IQR) 2 (0–3) 1.5 (1–2.5) 2 (1–2) .86 .57

Rash duration .01 .01

<1 wk (<7 d) 2 (25.0) 10 (25.6) 24 (53.3)

≥1 wk (≥7 d)

6 (75.0) 29 (74.4) 21 (46.7)

School missed .17 .89

≤1 school wk (≤5 d)

2 (33.3) 3 (8.6) 3 (7.7)

>1 school wk (>5 d) 4 (66.7) 32 (91.4) 36 (92.3)

IQR, interquartile range.

Missing and unknown responses excluded. Valid percentages presented.

Rash severity was deﬁ ned as follows: <50 or the total number of spots could be counted in 30 s; 50–249 or you could place the child’s hand between the spots without touching a spot;

250–500 or you could not place a child’s hand between the spots without touching a spot; or >500 spots or the spots were so close you could hardly see normal skin.

PERELLA et al

between receiving 1- and 2-dose

varicella vaccine (>5 vs ≤5 years)

was associated with lower odds of

developing breakthrough varicella

(OR = 0.5, P = .03; Table 4). Subjects

receiving dose 2 after 6 years of age

were older than those receiving the

second dose varicella vaccine earlier

(12.7 vs 7.0 years, P < .001), as were

subjects with a time interval between

1- and 2-dose varicella vaccine >5

years compared with those having a

shorter interval between doses (13.0

vs 7.4 years, P < .001).

DISCUSSION

During the first 5 years after

implementation of 2-dose varicella

vaccination program, we found that

2 doses conferred significantly better

protection against varicella disease

from community transmission among

school-aged children compared with

the 1-dose regimen. By 2010, AV and

West Philadelphia reported >60%

2-dose varicella vaccination coverage

among 5-year old children and 67%

to 78% reductions in overall varicella

incidence since 2006.15 Our study

provides more direct evidence of

the protective effect of a 2-dose

regimen of varicella vaccine for

children. Incremental effectiveness

of the 2-dose varicella vaccination

regimen among all subjects aged

≥4 years was 88% to 97% against

all forms of disease and also highly

protective against moderate and

severe varicella (94%). The reduction

in community circulation of VZV

as a result of high 2-dose coverage

will also protect children who are

immunocompromised and not

eligible for varicella vaccination.

Additional benefits of routine

childhood varicella vaccination may

include reduced risk of herpes zoster

among vaccinated children.

In 2006, concerns about the

effectiveness of the 2-dose regimen

were raised after a varicella

outbreak in an Arkansas elementary

school with 97% 1-dose varicella

vaccination coverage and 41%

2-dose coverage.

Consistent

with our findings, incremental

effectiveness estimates from all but

1 subsequent outbreak investigation

and epidemiologic studies in the

United States have been much higher

(>90% vs 28% from the Arkansas

outbreak).

18, 20, 31, 32

Incremental

effectiveness estimates from school

varicella outbreak surveillance in

Indiana and West Virginia during

2009 to 2010 were 86% and 64%,

respectively.

18, 32

Among ~2800

patients who were recruited into a

prospective cohort study in 1995 at

2 years of age and received a second

dose through catch-up vaccination,

no cases of breakthrough varicella

were observed through 2009.

TABLE 3 Varicella VE Against All Varicella and Moderate or Severe Varicella in Philadelphia, Pennsylvania and Antelope Valley, California, 2009–2011

Unvaccinated and 1-Dose Participants

Regardless of Age

Participants ≥4 y Old

Cases Controls VE (95% CI) Cases Controls VE (95% CI)

n = 79 n = 160 n = 93 n = 305

VE against any clinically diagnosed

varicella

Unvaccinated 17 (21.5) 12 (7.5) Reference 8 (8.6) 8 (2.6) Reference

1-dose 62 (78.5) 148 (92.5) 75.6 (38.7–90.3) 40 (43.0) 50 (16.4) 49.1 (0–85.7)

2-dose — — — 45 (48.4) 247 (81.0) 93.6 (75.6–98.3)

Incremental VE (2-dose vs 1-dose) — — — — — 87.5 (74.9–93.7)

VE against moderate or severe

clinically diagnosed varicella (≥50

lesions)

n = 28 n = 49 — n = 35 n = 119 —

Unvaccinated 10 (35.7) 6 (12.2) Reference 7 (20.0) 5 (4.2) Reference

1-dose 18 (64.3) 43 (87.8) 78.1 (12.7–94.5) 14 (40.0) 20 (16.8) 64.2 (0–93.1)

2-dose — — — 14 (40.0) 94 (79.0) 97.9 (83.0–99.7)

Incremental VE (2-dose vs 1-dose) — — — — — 94.1 (72.4–98.8)

—, no value for category available.

Adjusted for ethnicity given signiﬁ cant differences between cases and controls aged ≥4 y in Philadelphia. Although day care attendance differed between cases and controls aged ≥4 y,

only a small proportion of each group attended day care (<16%), and adding this variable to the model produced VE estimates similar to those presented.

TABLE 4 Risk Factors Associated With Breakthrough Varicella Among 2-Dose Varicella Vaccinees

Aged ≥4 y

Cases, n (%) (n = 45) Controls, n (%) (n = 247) OR (95% CI) P

Time since 2-dose varicella vaccination

<1 y 6 (13.3) 46 (18.6) Reference

1–3 y 19 (42.2) 118 (47.8) 1.2 (0.5–3.3) .67

>3 y 20 (44.4) 83 (33.6) 1.8 (0.7–4.9) .22

Age at receiving 2-dose varicella vaccine

≤6 y

33 (73.3) 128 (51.8) Reference

>6 y 12 (26.7) 119 (48.2) 0.4 (0.2–0.8) .009

Time interval between receiving 1- and 2-dose varicella vaccine

≤5 y

34 (75.6) 144 (58.3) Reference

>5 y 11 (24.4) 103 (41.7) 0.5 (0.2–0.9) .03

PEDIATRICS Volume 137 , number 4 , April 2016

Similarly, no 2-dose breakthrough

varicella cases were identified in a

community-based case–control study

conducted by Shapiro et al

between

2006 and 2010.

Given the excellent protection

provided by the 2-dose regimen in

preventing moderate and severe

disease, it is not surprising that the

majority of 2-dose breakthrough

cases (69%) had mild rashes

with <50 lesions, and none had

severe varicella. These findings

were consistent with 2-dose era

active surveillance data and other

epidemiologic studies.

15, 18, 20, 31

cases in our study were hospitalized

or fatal. Likewise, additional declines

in varicella-related hospitalizations

since implementation of the 2-dose

varicella vaccination era have also

been documented in the literature.

15,

Although there was no difference

in rash severity observed between

1- and 2-breakthrough cases,

average illness duration for 2-dose

breakthrough cases was slightly

shorter than for 1-dose cases, and

fewer 2-dose cases developed

mostly vesicular rashes. The shorter

duration of mild breakthrough illness

among 2-dose recipients may add

to the cost savings from use of this

regimen, and infectiousness may be

lowered, given the lower proportion

of vesicular rashes among 2-dose

breakthrough cases.

In our study and as reported by

others,

1, 18, 34

breakthrough varicella

generally has a modified appearance

with few or no vesicular lesions,

making it challenging to diagnose

clinically. PCR testing of lesion

specimens to detect VZV is highly

sensitive and specific.

However,

as demonstrated during the

investigation of a suspected varicella

outbreak in a Texas school district

in 2011, the utility of VZV-specific

PCR testing can be limited when

only macular lesions are present or

lesion specimens are not collected

early in the course of illness. In the

absence of better laboratory tools,

clinical and epidemiologic data will

remain necessary to support the

confirmation of varicella disease.

the Texas outbreak, the incremental

effectiveness of 2-dose varicella

vaccination against any form of

clinically diagnosed varicella varied

widely across the 2 involved schools

(21% and 72%).

We therefore

chose to examine 2-dose varicella VE

by using 2 different case definitions

for breakthrough varicella: one based

on clinical and epidemiologic criteria

and the other using laboratory

confirmation alone. Both definitions

produced similar estimates for

1-dose and 2-dose varicella VE when

unvaccinated people were used as

the comparison group. Although

incremental effectiveness against

laboratory-confirmed disease was

slightly higher compared with the

incremental effectiveness against

clinically diagnosed disease (97% vs

88%), both estimates demonstrate

that the 2-dose varicella vaccine

regimen is highly effective in

preventing varicella due to sporadic

VZV circulation in the community.

Data on risk factors for 2-dose

breakthrough varicella are limited.

Similar to Thomas et al,

we did not

find a significant association between

time since 2-dose vaccination and

the development of breakthrough

varicella; however, in both studies

findings may have been affected by

the low number of varicella cases

among 2-dose recipients. We were

surprised that those who were older

at time of 2-dose varicella vaccination

or had >5 years between dose 1

and dose 2 had lower likelihood

of breakthrough varicella. These

findings may reflect a lower risk of

VZV exposure or shorter exposure

durations among older subjects

in middle school and high school,

because they are less likely to spend

several hours with the same class of

students throughout the school day.

Our findings are subject to the

following limitations. Given high

1-dose varicella vaccine coverage

among children ≥4 years of age,

very few unvaccinated subjects

were identified, which resulted in

wide confidence intervals for our

estimates of varicella VE. Similarly,

the small number of laboratory-

confirmed 2-dose breakthrough

varicella cases limited our ability to

identify risk factors for or describe

the characteristics of breakthrough

disease in 2-dose vaccinees. Lastly,

although we used the best available

sources of case and control subjects

for our study, ascertainment of

mild varicella cases was probably

incomplete. The data source used

to identify controls in the Antelope

Valley area represented only

30% of the source population,

and the response rate among

potential controls selected from the

immunization registry was low in

Philadelphia because of incomplete

or outdated contact information.

Despite these potential limitations,

the distributions of demographic

characteristics (ie, gender, race, and

ethnicity) among control subjects

were similar to population estimates

for residents <18 years of age in

each site. In AV, 2-dose varicella

vaccination coverage was moderately

high (84%) among kindergarten

students during the 2009 to

2010 school year and 98% to 99%

among Kaiser members aged 5 to 6

years in 2010.

The use of Kaiser

members only as controls probably

did not affect 2-dose varicella

VE but may have resulted in slightly

higher incremental effectiveness

estimates.

With superior protection provided

by the 2-dose varicella vaccination

compared with the 1-dose regimen

as demonstrated in our study and

others, it will be important to expand

school immunization requirements to

include 2-dose varicella vaccination.

By 2012, 36 states had a 2-dose

varicella vaccination elementary

school entry requirement, and 2-dose

varicella vaccine coverage among

PERELLA et al

7-year-olds in 6 sentinel sites had

reached moderate to high levels

(79.9%–92.0%).

Catch-up varicella

vaccination will be particularly

important for 1-dose vaccinees at

increased risk for exposure to people

with varicella or herpes zoster (ie,

international travelers, health care

workers). Continued monitoring of

2-dose varicella VE is also warranted,

to ensure that protection is sustained

over time.

ACKNOWLEDGMENTS

We gratefully acknowledge the

following staff members from the

Philadelphia Department of Public

Health, the Los Angeles County

Department of Public Health, and

the Centers for Disease Control and

Prevention who contributed to the

study: Salini Mohanty, Christina

Jackson, Niya Spells, Michael

Borquez, Rodrerica Thermitus,

Elizabeth Taggert, Perri Alpay,

Kathryn Gevitz, Sabrina Chen,

Jimmy John, and Kay Radford.

We also acknowledge Dr Barbara

Watson for her guidance with

protocol development. Lastly, we

thank community-based sites in

Philadelphia, PA and Antelope

Valley, CA that participated in active

varicella surveillance during the

study period.

REFERENCES

1. Chaves SS, Zhang J, Civen R, et al.

Varicella disease among vaccinated

persons: clinical and epidemiological

characteristics, 1997–2005.

J Infect Dis. 2008;197(suppl 2):

S127–S131

2. Guris D, Jumaan AO, Mascola L, et al.

Changing varicella epidemiology in

active surveillance sites: United States,

1995–2005. J Infect Dis. 2008;197(suppl

2):S71–S75

3. Lopez AS, Zhang J, Brown C, Bialek S.

Varicella-related hospitalizations in the

United States, 2000–2006: the 1-dose

varicella vaccination era. Pediatrics.

2011;127(2):238–245

4. Marin M, Zhang JX, Seward JF. Near

elimination of varicella deaths in

the US after implementation of the

vaccination program. Pediatrics.

2011;128(2):214–220

5. Centers for Disease Control and

Prevention (CDC). Outbreak of varicella

among vaccinated children: Michigan,

2003. MMWR Morb Mortal Wkly Rep.

2004;53(18):389–392

6. Centers for Disease Control and

Prevention (CDC). Varicella outbreak

among vaccinated children: Nebraska,

2004. MMWR Morb Mortal Wkly Rep.

2006;55(27):749–752

7. Lopez AS, Guris D, Zimmerman L, et al.

One dose of varicella vaccine does not

prevent school outbreaks: is it time for

a second dose? Pediatrics. 2006;117(6).

Available at: www. pediatrics. org/ cgi/

content/ full/ 117/ 6/ e1070

8. Nguyen MD, Perella D, Watson B, Marin

M, Renwick M, Spain CV. Incremental

effectiveness of second dose varicella

vaccination for outbreak control at

an elementary school in Philadelphia,

Pennsylvania, 2006. Pediatr Infect Dis

J. 2010;29(8):685–689

9. Parker AA, Reynolds MA, Leung J,

et al. Challenges to implementing

second-dose varicella vaccination

during an outbreak in the absence

of a routine 2-dose vaccination

requirement: Maine, 2006. J Infect Dis.

2008;197(suppl 2):S101–S107

10. Tugwell BD, Lee LE, Gillette H, Lorber

EM, Hedberg K, Cieslak PR. Chickenpox

outbreak in a highly vaccinated school

population. Pediatrics. 2004;113(3 pt

1):455–459

11. Civen R, Lopez AS, Zhang J, et al.

Varicella outbreak epidemiology in an

active surveillance site, 1995–2005. J

Infect Dis. 2008;197(suppl 2):S114–S119

12. Kuter B, Matthews H, Shineﬁ eld H, et

al; Study Group for Varivax. Ten year

ABBREVIATIONS

AV: Antelope Valley

CDC: Centers for Disease Control

and Prevention

CI: confidence interval

OR: odds ratio

PCR: polymerase chain reaction

RR: relative risk

VASP: Varicella Active

Surveillance Project

VE: vaccine effectiveness

VZV: varicella zoster virus

The ﬁ ndings and conclusions in this report are those of the authors and do not necessarily represent the ofﬁ cial position of the Centers for Disease Control and

Prevention, US Department of Health and Human Services, or the Philadelphia Department of Public Health.

DOI: 10.1542/peds.2015-2802

Accepted for publication Dec 21, 2015

Address correspondence to Dana Perella, MPH, Acute Communicable Disease Program, Philadelphia Department of Public Health, 500 S Broad St, 2nd Floor,

Philadelphia, PA 19146. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

FINANCIAL DISCLOSURE: The authors have indicated they have no ﬁ nancial relationships relevant to this article to disclose.

FUNDING: Supported by the American Recovery and Reinvestment Act (ARRA), Section 317 Immunization Program: Strengthening the Evidence Base Measuring

Effectiveness of Two Doses of Varicella Vaccine, U01 (RFA-IP04-11601ARRA09).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conﬂ icts of interest to disclose.

PEDIATRICS Volume 137 , number 4 , April 2016

follow-up of healthy children who

received one or two injections of

varicella vaccine. Pediatr Infect Dis J.

2004;23(2):132–137

13. Marin M, Güris D, Chaves SS, Schmid

S, Seward JF; Advisory Committee

on Immunization Practices, Centers

for Disease Control and Prevention

(CDC). Prevention of varicella:

recommendations of the Advisory

Committee on Immunization

Practices (ACIP). MMWR Recomm Rep.

2007;56(RR-4):1–40

14. Centers for Disease Control and

Prevention (CDC). Evolution of varicella

surveillance: selected states, 2000–

2010. MMWR Morb Mortal Wkly Rep.

2012;61(32):609–612

15. Bialek SR, Perella D, Zhang J, et al.

Impact of a routine two-dose varicella

vaccination program on varicella

epidemiology. Pediatrics. 2013;132(5).

Available at: www. pediatrics. org/ cgi/

content/ full/ 132/ 5/ e1134

16. Daly ER, Anderson L, Dreisig J,

Dionne-Odom J. Decrease in varicella

incidence after implementation of the

2-dose recommendation for varicella

vaccine in New Hampshire. Pediatr

Infect Dis J. 2013;32(9):981–983

17. Kattan JA, Sosa LE, Bohnwagner

HD, Hadler JL. Impact of 2-dose

vaccination on varicella epidemiology:

Connecticut—2005–2008. J Infect Dis.

2011;203(4):509–512

18. Thomas CA, Shwe T, Bixler D, et

al. Two-dose varicella vaccine

effectiveness and rash severity in

outbreaks of varicella among public

school students. Pediatr Infect Dis J.

2014;33(11):1164–1168

19. Chen RT, Orenstein WA. Epidemiologic

methods in immunization programs.

Epidemiol Rev. 1996;18(2):99–117

20. Shapiro ED, Vazquez M, Esposito D, et

al. Effectiveness of 2 doses of varicella

vaccine in children. J Infect Dis.

2011;203(3):312–315

21. Population Estimates: Walter R.

McDonald & Associates, Inc. (WRMA)

for Urban Research. Los Angeles

County ISD. 2009;2010(April):26

22. 2010 Population Estimates.

Philadelphia, PA: Claritas Inc.; 2010

23. Seward JF, Watson BM, Peterson

CL, et al. Varicella disease after

introduction of varicella vaccine in

the United States, 1995–2000. JAMA.

2002;287(5):606–611

24. Leung J, Harpaz R, Baughman A, et

al. Evaluation of laboratory methods

for diagnosis of varicella. J Infect Dis.

2010;202(10):1486–1491

25. Niccolai LM, Ogden LG, Muehlenbein

CE, Dziura JD, Vázquez M, Shapiro ED.

Methodological issues in design and

analysis of a matched case–control

study of a vaccine’s effectiveness. J

Clin Epidemiol. 2007;60(11):1127–1131

26. Loparev VN, McCaustland K, Holloway

BP, Krause PR, Takayama M, Schmid

DS. Rapid genotyping of varicella-

zoster virus vaccine and wild-type

strains with ﬂ uorophore-labeled

hybridization probes. J Clin Microbiol.

2000;38(12):4315–4319

27. Loparev VN, Argaw T, Krause PR,

Takayama M, Schmid DS. Improved

identiﬁ cation and differentiation of

varicella-zoster virus (VZV) wild-type

strains and an attenuated varicella

vaccine strain using a VZV open

reading frame 62-based PCR. J Clin

Microbiol. 2000;38(9):3156–3160

28. Estimated vaccination coverage

with 1+ varicella among children

19–35 months of age by state and

immunization action plan area.

National Immunization Survey.

Available at: www. cdc. gov/ vaccines/

imz- managers/ coverage/ nis/ child/

index. html. Accessed September 30,

2014

29. Weinmann S, Chun C, Schmid DS, et al.

Incidence and clinical characteristics

of herpes zoster among children in

the varicella vaccine era, 2005–2009. J

Infect Dis. 2013;208(11):1859–1868

30. Gould PL, Leung J, Scott C, et al. An

outbreak of varicella in elementary

school children with two-dose varicella

vaccine recipients: Arkansas, 2006.

Pediatr Infect Dis J. 2009;28(8):

678–681

31. Baxter R, Ray P, Tran TN, et al. Long-

term effectiveness of varicella vaccine:

a 14-year, prospective cohort study.

Pediatrics. 2013;131(5). Available at:

www. pediatrics. org/ cgi/ content/ full/

131/ 5/ e1389

32. Hazen D, Baker L. Vaccine efﬁ cacy

estimates during institutional-based

outbreaks, Indiana 2010. In: 45th

National Immunization Conference.

Washington, DC; 2011

33. Baxter R, Tran TN, Ray P, et al. Impact

of vaccination on the epidemiology

of varicella: 1995–2009. Pediatrics.

2014;134(1):24–30

34. Watson BM, Piercy SA, Plotkin SA,

Starr SE. Modiﬁ ed chickenpox in

children immunized with the Oka/

Merck varicella vaccine. Pediatrics.

1993;91(1):17–22

35. Weinmann S, Chun C, Mullooly JP,

et al. Laboratory diagnosis and

characteristics of breakthrough

varicella in children. J Infect Dis.

2008;197(suppl 2):S132–S138

36. Mahamud A, Wiseman R, Grytdal S,

et al. Challenges in conﬁ rming a

varicella outbreak in the two-dose

vaccine era. Vaccine. 2012;30(48):

6935–6939

37. Lopez AS, Cardemil C, Pabst LJ, Cullen

KA, Leung J, Bialek SR; Division of

Viral Diseases; Centers for Disease

Control and Prevention (CDC). Two-

dose varicella vaccination coverage

among children aged 7 years: six

sentinel sites, United States, 2006–

2012. MMWR Morb Mortal Wkly Rep.

2014;63(8):174–177