Human Vaccines & Immunotherapeutics

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Effectiveness of vaccination against varicella in

children under 5 years in Puglia, Italy 2006–2012

Silvio Tafuri, Francesca Fortunato, Maria Giovanna Cappelli, Vanessa Cozza,

Angela Bechini, Paolo Bonanni, Domenico Martinelli & Rosa Prato

To cite this article: Silvio Tafuri, Francesca Fortunato, Maria Giovanna Cappelli, Vanessa
Cozza, Angela Bechini, Paolo Bonanni, Domenico Martinelli & Rosa Prato (2015) Effectiveness of
vaccination against varicella in children under 5 years in Puglia, Italy 2006–2012, Human Vaccines
& Immunotherapeutics, 11:1, 214-219, DOI: 10.4161/hv.36153

To link to this article: https://doi.org/10.4161/hv.36153

Published online: 01 Nov 2014.

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Research Paper
Research Paper

Human Vaccines & Immunotherapeutics 11:1, 214–219; January 2015; © 2015 Landes Bioscience

Effectiveness of vaccination against varicella in

children under 5 years in Puglia, Italy 2006–2012
Silvio Tafuri1, Francesca Fortunato2, Maria Giovanna Cappelli1, Vanessa Cozza2,3, Angela Bechini4, Paolo Bonanni4,
Domenico Martinelli2, and Rosa Prato2,*
1
Department of Biomedical Science and Human Oncology; University of Bari Aldo Moro; Bari, Italy; 2Department of Medical and Surgical Science; University of Foggia; Foggia,
Italy; 3European Programme for Intervention Epidemiology Training (EPIET); European Centre for Disease Prevention and Control (ECDC); Stockholm, Sweden;
4
Department of Health Sciences; University of Florence; Florence, Italy

Keywords: Varicella, vaccine effectiveness, screening method, breakthrough, vaccine failure, universal routine vaccination

©2014 Landes Bioscience. Do not distribute.

Abbreviations: 95% CI, 95% Confidence Interval; ACIP, Advisory Committee on Immunization Practices; CDC, Centers for
Disease Control and Prevention; ECDC, European Centre for Disease Prevention and Control; EU/EEA countries, European
Union /European Economic Area countries; FDA, U.S. Food and Drug Administration; GIAVA, Gestione Informatizzata Anagrafe
Vaccinale - Regional Immunization Registry; HRR, Hospitalization Risk Ratio; HDR, Hospital Discharge Registry; ICD9-CM,
International Classification of Diseases, Ninth Revision, Clinical Modification; IRR, Incidence Rate Ratio; MMR, Measles-
Mumps-Rubella vaccine; MMR+V, Measles-Mumps-Rubella + Varicella vaccines; MMRV, Measles-Mumps-Rubella-Varicella
vaccine; PCV, Proportion of the Cases Vaccinated; PPV, Proportion of the Population Vaccinated; PNPV 2012–2014, Piano
Nazionale Prevenzione Vaccinale 2012-2014 - National Immunization Plan 2012–2014; SAGE, Strategic Advisory Group of
Experts on Immunization; SIMI, Sistema informatizzato malattie infettive - Computerised surveillance system for communicable
diseases; STIKO, German Standing Committee on Vaccination; URV, Universal Routine Vaccination; US, United States; VC,
Vaccination Coverage; VE, Vaccine Effectiveness; WHO, World Health Organization

In Italy, between 2003 and 2010, 8/21 Regions recommended varicella routine vaccination (URV). The National Immu-
nization Plan (PNPV) 2012–2014 scheduled the introduction of URV nationwide in 2015, following the results achieved by
the eight Regions.
Puglia adopted varicella URV in 2006. This study describes epidemiology and costs of varicella in Puglia between 2003
and 2012. One-dose Vaccine Effectiveness (VE) against varicella of any severity and severe hospitalized cases in children
was also evaluated.
Vaccination coverage (VC) was estimated from the regional immunization registry. Incidence and hospitalization
rates were calculated from computerised surveillance system for communicable diseases and hospital discharge registry
(ICD9-CM codes: 052.x), respectively. URV impact was assessed by Incidence Rate Ratios (IIRs) and Hospitalization Risk
Ratios (HRRs). Hospitalization costs were also evaluated. VE was estimated using the screening method, where PPV was
VC in children aged <72 months and PCV was the proportion of cases vaccinated among notified or hospitalized cases,
respectively.
One-dose VC in children aged ≤ 24 months increased from 49% in the birth cohort 2006 to 91.1% in the cohort 2010;
2-dose VC was 64.8% and 28.8% in the 2005 and 1997 cohort, respectively. Comparing pre and post-vaccination era,
incidence declined from 122.5 ×100 000 in 2003–2005 to 13.7 in 2009–2012 (IRR = 0.11, 95% CI = 0.10–0.12), hospitalization
rate from 3.9 ×100 000 to 1.1 (HRR = 0.29, 95% CI = 0.21–0.4), hospitalization costs from 319 000 Euros/year to 106 000.
One-dose VE against varicella of any severity and severe hospitalized disease was 98.8% and 99%, respectively.
Our findings strongly support varicella URV introduction into the Italian Essential Health Interventions, as scheduled
by 2015.

Background Committee on Immunization Practices (ACIP) of the US Centers

for Disease Control and Prevention recommended that children
A live attenuated varicella vaccine was available since 1974.1 aged 12–18 mo and all susceptible subjects by their 13th birthday
In 1995, the Food and Drug Administration (FDA) licensed should receive one dose of vaccine.2
the currently used varicella vaccine and in 1996 the Advisory

*Correspondence to: Rosa Prato; Email: [email protected]

Submitted: 06/28/2014; Accepted: 07/12/2014; Published Online: 08/27/2014
http://dx.doi.org/10.4161/hv.36153

214 Human Vaccines & Immunotherapeutics Volume 11 Issue 1

 In the first five years after the introduction of universal rou- Germany, Spain) observed a rapid reduction in the incidence of
tine vaccination (URV) in USA (1996–2001), the overall number cases, varicella complications, hospitalization rates and deaths in
of cases and deaths attributable to varicella decreased by 83% and all age groups, both in vaccinated and unvaccinated individuals. A
66%, respectively. In children, the number of deaths declined by relative increase in the age of infection has also been reported.15-17
90% and the number of hospitalizations by 88%.3 In Uruguay, ECDC report concluded that more evidences on different aspects
where varicella URV was introduced in 1999, the burden of dis- of varicella vaccination are needed and recommended countries
ease decreased substantially since 2005, with an 81% reduction to assess epidemiological and socioeconomic state, as well as the
in the proportion of hospitalizations among children and 87% in capacity to achieve high VC for varicella.14
the incidence of outpatient visits.4 In Italy, between 2003 and 2010 eight out of 21 regions rec-
Seven studies conducted from 1996 to 2002 in USA showed ommended varicella URV.18 The National Immunization Plan
a vaccine effectiveness (VE) of 71–100% against varicella of any 2012–2014 has scheduled the introduction of URV at country
severity and 95–100% against mild and severe disease.5-10 level in 2015, starting from the birth cohort 2014, in light of the

©2014 Landes Bioscience. Do not distribute.

High vaccination coverage (VC) was reached also in other results achieved by the Regions which had already introduced
countries, notwithstanding outbreaks of varicella still occurred. varicella vaccination.19
In 2002, in UK, an outbreak of varicella was reported in children A rapid reduction of the incidence of varicella cases was
attending a day-care centre with an attack rate among vaccin- reported in Sicily region where vaccination was introduced
ees of 48%. VE was 44% against varicella of any severity and in 2003 targeting children in the second year of life.20 A large
86% against mild or severe disease.11 In 2006, in US, an outbreak reduction of both incidence and hospitalization rates was also
occurred in a school where 1-dose VC was 96%, suggesting that documented in Veneto region where vaccination is provided to
the disease remained highly contagious also among vaccinated children aged 14 mo with a second dose for 6 y olds and a catch-
subjects and that one dose of varicella vaccine could not be suffi- up dose for 12 y olds since 2005.21,22
cient to prevent outbreaks.12 Findings from these studies encour- In 2006, Puglia region introduced 1-dose varicella URV for
aged the adoption of routine 2-dose schedule, as subsequently children aged 15 mo.23 In 2009, tetravalent measles-mumps-
recommended by CDC in 2007.13 rubella-varicella vaccine (MMRV) replaced MMR and V vac-
In the recent “Preliminary guidance on varicella vaccine in the cines for children aged 13 mo, with a second dose of MMRV or
European Union” (2014), ECDC reported how “heterogeneous” MMR+V at 5–6 or 11–12 y of age.24
were the current recommendations on the vaccination in the EU/ In light of the Italian National Vaccination Plan 2012–2014
EEA countries. Between 2003 and 2010, URV has been recom- recommendations and according to ECDC indications,14,19 this
mended in five countries at national level (Germany, Latvia, study aims to describe changes in epidemiology and costs of
Greece, Cyprus, Luxemburg) and in two countries at regional varicella since the introduction of the vaccination programme
level (Spain and Italy); in 17 countries, vaccination is currently in Puglia region. One-dose varicella VE in preventing disease of
recommended only for susceptible teenagers and/or suscepti- any severity and severe hospitalized cases in children was also
ble risk groups.14 Countries that have implemented URV (i.e., estimated.

Table 1. Vaccination coverage for varicella in children and adolescents

(birth cohorts 1996, 1997, 2004, 2005 and 2006–2010), Puglia, Italy Results
2-dose VC 2-dose VC
1-dose VC (%) Impact of varicella URV
Birth cohort (%) 5–6 y (%) 11–12
≤24 mo of age
of age y of age Vaccination coverage for one dose in children ≤24 mo of age
1996 - - 12%†† progressively increased from 49% in the birth cohort 2006 to
89.7% and 91.1% in the cohorts 2009 and 2010, respectively
1997 - - 28.8%††
(average VC in birth cohort 2006–2010 = 75%). VC for the sec-
ond dose was 45.7% in the cohort 2004 and 64.8% in the cohort
2004 - 45.7%† - 2005 (5–6 y of age); it was 12% and 28.8% in the cohorts 1996
2005 - 64.8%† - and 1997, respectively (11–12 y of age; Table 1).
The number of reported cases dramatically decreased from
7330 in 2004 to 234 in 2012 (Fig. 1A). Comparing the pre and
2006 49%* post vaccination era, incidence declined from 122.5 × 100 000
2007 70%* (no. of cases = 4953/year) in 2003–2005 to 85.3 × 100 000 (no.
2008 75.6%* of cases = 3474/year; IRR = 0.7, 95% CI = 0.67–0.73) in 2006–
2008 and to 13.7 × 100 000 (no. of cases = 560/year; IRR = 0.11,
2009 89.7%**
95% CI = 0.10–0.12) in the 2009–2012 period. In the vaccina-
2010 91.1%** tion era, a significant reduction was recorded in subjects aged
<49 y, mainly in the age group 1–4 y (Table 2A).
*VC for one dose of V vaccine in children aged 15 mo; **CV for one dose
of MMRV in children aged 13 mo; †CV for the second dose of MMRV (or Hospitalizations for varicella fell from 216 in 2004 to
MMR+V) at 5–6 y of age; †† CV for the second dose of MMRV (or MMR+V) 22 in 2012, similarly to the trend in incidence (Fig. 1B).
at 11–12 y of age.

www.landesbioscience.com Human Vaccines & Immunotherapeutics 215

Hospitalization rate decreased from 3.9 × 100 000 (no. of cases using a combined vaccine seems to have facilitated the adop-
= 159/year) in 2003–2005 to 2.9 × 100 000 (no. of cases = 118/ tion of URV by simplifying vaccine administration, reducing
year; HRR = 0.74, 95% CI = 0.58–0.94) in 2006–2008 and to the number of accesses to Vaccination Services and lowering the
1.1 × 100 000 (no. of cases = 47/year; HRR = 0.29, 95% CI = rate of delayed or missed vaccinations.26 The acceptance of vari-
0.21–0.4) in 2009–2012. In the early vaccination era, a signifi- cella vaccination depending on the use of combined MMRV was
cant decrease was recorded in children 1–4 y old (HRR = 0.71, recently showed in Germany. A reduction in vaccine uptake was
95% CI = 0.66–0.76). In the late vaccination era, hospitaliza- reported after the German Standing Committee on Vaccination
tion rates significantly declined in children (HRR = 0.16, 95% (STIKO) recommended concomitant but separate first dose vac-
CI = 0.08–0.33), in the age group 5–14 y (HRR = 0.25, 95% cination for MMR and V in September 2011 due to a slightly
CI = 0.12–0.5) and in young adults (HRR = 0.41, 95% CI = increased risk of febrile convulsions after first-dose application of
0.21–0.79; Table 2B). combined MMRV.16
In the pre-vaccination period, the total costs of hospitaliza- Our findings showed a large impact of varicella URV in

©2014 Landes Bioscience. Do not distribute.

tion due to varicella amounted to nearly 319 000 Euro/year. Puglia. Incidence declined more than 90% and hospitalization
This value progressively decreased in the following years, from rate >75%, similarly to what happened in USA in the late 1990s
nearly 267 000 Euro/year in 2006–2008 to 106 000 Euro/year and in Germany, Spain and some other Italian regions where
in 2009–2012, especially in the age group 1–4 y (−78 000 Euro / URV was introduced in the last decade.3,15-18,20-22 Recently, a
year), followed by 5–14 y (−55 000 Euro/year), 15–24 y (-21 000 series of 5 cross-sectional studies performed from 1995 to 2009
Euro/year) and <1 y (-19 000 Euro /year) age group. A large in Northern California showed a decline of the incidence of vari-
reduction was also recorded in adults aged 25–49 y (−48 000 cella in 5–19-y-olds ranging from 90% to 95% and a reduction
Euro/year), whereas a small increase of 4000 Euro/year occurred of the age-adjusted varicella hospitalization rates in the general
in subjects >50 y.
Varicella vaccine effectiveness
PPV in the birth cohorts 2006–2010 was
75%.
From 2006 to 2012, 1178 cases of varicella
were notified among children aged <72 mo,
41 of them had received one dose of vaccine
≥42 d before the disease onset (PCV = 3.4%
-- vaccination failures). One-dose VE against
varicella of any severity was 98.8%.
In the 2006–2012 period, 73 children aged
<72 mo were hospitalized with a diagnosis of
varicella. Two children had received one dose
of vaccine ≥42 d before the hospital admission
(PCV = 2.9% -- vaccination failures). One-
dose VE against severe varicella was 99%.

Discussion

A substantial decrease in incidence and

hospitalization rates for varicella has been
documented in an Italian region that adopted
URV since 2006 and reached high VC few
years after its introduction. One-dose VE was
98.8% against varicella of any severity and
99% against severe cases.
WHO advocates routine childhood
immunization against varicella in countries
where high (>80%) and sustained VC can
be achieved, since low coverage could theo-
retically increase the number of cases in older
children and adults for whom the disease is
more severe.25 In Puglia, VC > 90% has been
reached, especially after the introduction of Figure 1. Trends in notified (A) and hospitalized (B) varicella cases. Puglia, Italy, 2003–2012
tetravalent MMRV vaccine. The choice of

216 Human Vaccines & Immunotherapeutics Volume 11 Issue 1

population of 90%.27 No shift to older age groups was reported, reporting that a single-dose had an approximate median effec-
as in our study. tiveness of 95% for preventing moderate or severe disease and
The 1-dose VE for varicella of any severity appears consistent 100% for preventing severe disease.32
with the finding of 96.8% (95% CI = 96.3–97.2%) reported Despite the URV impact and effectiveness in countries where
by Cenoz et al. in Navarra (Spain) in the years 2006–2012.28 it was introduced, some concerns remain about the possible shift
A recently published case-control study conducted in the same in the age at infection or breakthrough varicella cases, but also,
setting (Navarra, years 2011–2012) among children aged 15 mo to a large extent, about a possible increase of HZ incidence due to
to 10 y showed a lower VE: 93% in the first 12 mo after vac- the reduction of immunological boosting caused by the varicella
cination, 95% between 12 and 35 mo, and 61% after 35 mo vaccination.14 Our data showed that URV rapidly modified the
(overall VE = 87%, 95% CI = 60–97%). The administration of circulation of the virus in Puglia and no shift in the age at infec-
a second dose helps to re-establish very high levels of effective- tion was put in evidence.
ness and to reduce the risk of breakthrough varicella.29 Other A significant reduction of cases and hospitalizations was

©2014 Landes Bioscience. Do not distribute.

previous studies conducted in Puglia between 2009 and 2012 recorded in adults <49 y, with saving of direct costs. Data recently
showed lower VE, ranging from 59% to 82%. These studies, reviewed by Unim B et al. showed that the implementation of
performed in close settings, could be influenced by factors such varicella URV in all Italian regions by 2015 could save the society
as the proportion of subjects who contracted varicella before the from nearly 638 000 Euros (infant strategy) to 53 million annu-
outbreak, the age of subjects and the force of infection.30,31 One- ally (combined infant and adolescent strategy).33
dose VE for severe hospitalized disease in our study appears in Health economic models also suggest that the introduction of
accordance with data from the last systematic review by WHO the vaccine may be cost-effective if there is no associated increase
SAGE Working Group on Varicella and Herpes Zoster Vaccines, in HZ incidence, and may even be cost-saving if indirect societal

Table 2. Incidence rates, IRRs with 95% CIs (A), hospitalization rates, HRRs with 95% CIs (B) of varicella in pre-vaccination era, in one-dose V vaccination
era, and in two-doses MMRV vaccination era. Puglia, Italy, 2003–2012
A
2003–2005* 2006–2008** 2009–2012***
Age
Rate Rate Rate
groups N N IRR 95% CI N IRR 95% CI
(×100 000) (×100 000) (×100 000)
(years)
<1 245 618.4 184 485.7 0.79 0.65–0.95 39 104.4 0.17 0.12–0.24
1–4 2148 1315.2 1479 932.3 0.71 0.66–0.76 161 105.5 0.08 0.07–0.09
5–14 2201 487.1 1570 359.7 0.74 0.69–0.79 289 68.8 0.14 0.12–0.16
15–24 139 26.2 84 16.6 0.63 0.48–0.83 25 5.1 0.19 0.12–0.3
25–49 211 14.2 151 10.1 0.71 0.58–0.88 43 2.9 0.20 0.15–0.29
50–64 6 0.9 4 0.6 0.69 0.20–2.39 2 0.3 0.34 0.07–1.59
>64 4 0.5 2 0.3 0.60 0.12–3.09 1 0.2 0.30 0.04–2.31
Overall 4953 122.5 3474 85.3 0.70 0.67–0.73 560 13.7 0.11 0.10–0.12

2003–2005* 2006–2008** 2009–2012***

Age
Rate Rate Rate
groups N N HRR 95%CI N HRR 95%CI
(×100 000) (×100 000) (×100 000)
(years)
<1 14 35.4 15 39.7 1.12 0.54–2.33 5 12.8 0.36 0.13–1.03
1–4 57 35.1 35 22.3 0.63 0.42–0.97 9 5.6 0.16 0.08–0.33
5–14 42 9.4 29 6.6 0.71 0.44–1.14 10 2.3 0.25 0.12–0.5
15–24 11 2.0 11 2.1 1.05 0.45–2.44 6 1.1 0.57 0.20–1.58
25–49 30 2.0 24 1.6 0.80 0.46–1.36 12 0.8 0.41 0.21–0.79
50–64 2 0.3 2 0.3 0.96 0.15–5.92 3 0.4 1.09 0.19–6.17
>64 2 0.3 2 0.2 0.78 0.1–6.13 3 0.4 1.36 0.22–8.02
Overall 159 3.9 118 2.9 0.74 0.58–0.94 47 1.1 0.29 0.21–0.4

*Pre-vaccination era; **One-dose V vaccination era; ***Two-doses MMRV vaccination era.

www.landesbioscience.com Human Vaccines & Immunotherapeutics 217

costs are included. If the HZ boosting hypothesis is assumed, and 2005, “pre-vaccination era”) were compared with average
then models predict a net increase in morbidity and healthcare rates in 2006–2008 (“1-dose V vaccination era”) and 2009–2012
costs for up to 50 y in some countries, after which net morbidity (“2-doses MMRV vaccination era”) period. The impact of vari-
and healthcare costs will decrease.14 A recent model by Poletti et cella URV was assessed calculating the Incidence Rate Ratios
al. showed that after varicella immunization an increase of HZ (IIRs) and the Hospitalization Risk Ratios (HRRs) with 95%
incidence is not a certain fact, rather depends on the force of Confidence Interval (95% CI) by using Poisson regression mod-
boosting and which might or not be heavily affected by changes els. Costs of hospitalization in the examined period were also
in varicella circulation due to mass immunization.34 evaluated.
A limitation in our study can be related to the analysis of data Varicella vaccine effectiveness
in the infectious disease surveillance system, commonly affected VE against varicella of any severity and severe hospitalized
by low sensitivity and underreporting.35 The methodology we disease in children < 72 mo was estimated using the screening
used appears simple and reliable to assess impact and VE against method as follows:

©2014 Landes Bioscience. Do not distribute.

varicella in other regions where URV was adopted. The screen-
ing method is a rapid approach for the preliminary assessment of
vaccine effectiveness that can be used for monitoring purposes
both during the first years after the introduction of a vaccination
program and when high coverage levels are reached.36
Our findings strongly support the introduction of routine
varicella vaccination into the national list of Essential Health (See ref. 37)
Interventions, as scheduled by the National Immunization Plan where, PPV (proportion of the population vaccinated) was the
by 2015. average coverage for varicella in the birth cohorts 2006–2010 and
PCV was the proportion of cases vaccinated among all notified or
hospitalized cases, respectively (the proportion of varicella cases
Methods among children adequately vaccinated -- vaccine failures).
Cases notified in the period 2006–2012 were selected from
Impact of varicella URV SIMI using the following criteria: age at the onset of symptoms <
The number of children vaccinated against varicella was 72 mo, children residing in Puglia region.
obtained from the Regional Immunization Registry (GIAVA). Cases hospitalized in the same period were extracted from
Coverage rates for one dose were estimated in the birth cohorts HDR following the criteria: age at hospital admission < 72 mo,
2006–2010, for two doses in the birth cohorts 2004–2005 and children residing in Puglia region, main diagnosis of “chicken-
1996–1997. pox” (ICD9-CM: 052.x).
Incidence rates, overall and specific by age, between 2003 Cases and hospitalizations were linked with data from GIAVA
and 2012 were calculated by using data collected in the Apulian (linkage key: personal ID number) to classify them as “vacci-
computerised surveillance system for communicable diseases nated” or “non vaccinated.” A vaccine failure was defined as
(referred as SIMI). Hospitalization rates, overall and specific by varicella disease in a child vaccinated ≥ 42 d before the date of
age, were calculated on data extracted from the regional hospital disease onset or hospital admission.38
discharge registry (HDR), selecting all hospital admissions with
a main diagnosis of chickenpox or its complications (ICD9-CM Disclosure of Potential Conflicts of Interest
codes: 052.x) in the same period. No potential conflicts of interest were disclosed.
Both incidence and hospitalization rates before the introduc-
tion of URV (calculated as the average annual rate between 2001

218 Human Vaccines & Immunotherapeutics Volume 11 Issue 1

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