Varicella vaccination in Italy and Germany – different routes to success: a systematic review

Figures & data

Figure 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram of eligible studies from initial identification to inclusion in qualitative data synthesis

Table 1. Seroprevalence of varicella infection before and after universal varicella vaccination

Citation	Year(s)	Data source	Age group	Seropositive (95% Confidence interval)
Pre-vaccination era
Italy, nationwide
Gabutti et al 2001 [79]*	1996–1997	Serosurvey/sera analysis	All ages	<1 YOA: maternal immunity; 2–4 YOA: 26.0%; 5–9 YOA: 61.8%; 10–14 YOA: 82.1%
De Donno et al 2017 [91]*	1996–1997 2003–2004 2013–2014	National serosurvey	All ages	National seroprevalence: 1996–1997: 73.2%; 2003–2004: 77.8%; 2013–2014: 84.0%
Ciofi Degli Atti et al 2002 [100]*	1996–1997	Surveillance/ seroprevalence	6 MOA–20 YOA	Overall: 64%; 6 MOA–4 YOA: 22.2%; 5–9 YOA: 61.6%; 10–14 YOA: 82.3%; 15–20 YOA: 83.3%
Nardone et al 2007 [38]*	1996–2003	Serosurvey/sera analysis	All ages	5 YOA: 38% Seronegative, % (n): <5 YOA: 78.3 (443); 5–9 YOA: 38.9 (543); 10–14 YOA: 18.3 (519); 15–19 YOA: 18.1 (524)
Gabutti et al 2008 [98-99]*	2003–2004	Serosurvey/sera samples	2–20 YOA	2–4 YOA: 32.9%; 5–9 YOA: 67.0%; 10–14 YOA: 84.6%; 15–19 YOA: 85.4%
Bollaerts et al 2017 [36]***	1995–2015	Systematic literature search/analysis	All ages	<5 YOA: 40.1% (36.5–43.5); <10 YOA: 80.7% (78.0–83.2); <15 YOA: 85.3% (83.9–86.6); <20 YOA: 88.8% (88.0–89.6); <40 YOA: 96.2% (95.1–97.1); <65 YOA: 99.0% (98.3–99.4)
Germany
Wutzler et al 2001 [88]*	1995 (0–19 YOA) 1997–1999(20 – >70 YOA)	Serosurvey/sera analysis	All ages	0–3 MOA: 79.4% (62.3–91.0); End of year 1: 8.6% (4.4–15.2); 2–3 YOA: 33.6% (28.0–40.0); 4–5 YOA: 62.5% (56.0–68.5); 10–11 YOA: 94.2% (91.0–96.0); >40 YOA: >99%; Seroprevalence in East vs West Germany 5–8% higher (p = 0.06)
Nardone et al 2007 [38]*	1996–2003	Serosurvey/sera analysis	All ages	Seronegative, % (n): <5 YOA: 67.4% (457); 5–9 YOA: 13.8% (668); 10–14 YOA: 4.4% (661); 15–19 YOA: 5.9% (630); 20–29 YOA: 2.3% (400)
Bollaerts et al 2017 [36]***	1995–2015	Systematic literature search/analysis	All ages	<5 YOA: 59.4% (55.3–63.2); <10 YOA: 94.7% (93.3–95.8); <15 YOA: 95.9% (95.0–96.7); <20 YOA: 96.8% (96 · 2–97 · 5); <40 YOA: 98.9% (98 · 5–99 · 3); <65 YOA: 99.7% (99 · 4–99 · 9)
Wiese-Posselt et al 2017 [53-54]*	2003–2006	Serosurvey/sera analysis	1–17 YOA	80.3% (79.3–81.3)^#
Post-vaccination era
Italy, nationwide
De Donno et al 2017 [91]*	1996–1997 2003–2004 2013–2014	National serosurvey	All ages	UVV regions vs non-UVV: no significant difference (p = 0.853); 1 YOA: higher prevalence in UVV regions: p = 0.045; 2–4 YOA: higher prevalence in UVV regions: p = 0.0009 5–9 YOA: lower prevalence in UVV regions: p = 0.023 10–14 YOA: lower prevalence in UVV regions: p < 0.0001
Puglia, Italy
Tafuri et al 2014 [121]*	2011–2012	Regional serosurvey	18–65 YOA	Proportion of seropostive adults increased with age. All samples: 93% (91.7–94.1); 18 YOA: 95.1% (86.3–99.0); 19 YOA: 92.0% (74.0–99.0); 20 YOA: 93.3% (77.9–99.2); 18–26 YOA: 90.4% (86.8–93.2); 27–35 YOA: 94.1% (91.7–96.0); 36–45 YOA: 94.8% (92.1–96.8); 46–55 YOA: 97.1% (92.8–99.2); 55–65 YOA: 97.1% (77.9–99.2)
Generalized Italian regions
Gabutti et al 2014 [116-117]* (8 Italian regions)	2013–2014	Regional serosurvey	0–90 YOA	0–11 MOA: 48.6% (33–65); 1 YOA: 36.8% (22–52); 2–4 YOA: 59.8% (51–69); ≥40 YOA: 99% (98–100). Greatest increases between 1 to 2–4 YOA and from 5–9 to 10–14 YOA Compared with pre-vaccination data, seropositivity increased in 1 YOA, 2–4 YOA, 5–9 YOA groups following UVV All samples: 83.9% (2013–2014) versus 75% (1996–1997) and 76.2% (2003–2004)

MOA/YOA, months/years of age; UVV, universal varicella vaccination; *, low risk of bias; **, unclear risk of bias; ***, high risk of bias; ^#data from non-vaccinated individuals.

Vaccine introduction: Germany 2004 (1-dose), 2009 (2-dose); Italy 2017 (nationwide); Basilicata 2010 (2-dose), Calabria 2010 (2-dose); Friuli-Venezia-Giulia 2013 (2-dose); Puglia 2006 (1-dose), 2009 (2-dose); Sardinia 2011 (2-dose); Sicily 2003 (1-dose), 2010 (2-dose); Tuscany 2008 (2-dose); Veneto 2005 (2-dose)

Table 2. Varicella incidence before and after universal varicella vaccination

Citation	Year(s)	Data source	Age group	Annual incidence/100,000^a	Cases, %	Effectiveness
Pre-vaccination era
Italy, nationwide
Fornaro et al 1999 [102]*	1997	Surveillance/ sentinel network	0–14 YOA	51.0 per 1,000 children
Ciofi Degli Atti et al 2002 [101]*	2000	Surveillance/ sentinel network	<15 YOA	Overall: 5,345; <1 YOA: 2,505; 1–4 YOA: 8,960; 5–9 YOA: 5,062; 10–14 YOA: 2,283	Overall: 19,865; <1 YOA: 824; 1–4 YOA: 9,869; 5–9 YOA: 7,199; 10–14 YOA: 1,973
Ciofi Degli Atti et al 2002 [100]*	1976–1997	Surveillance/ seroprevalence survey/database (ISTAT)	6 MOA–20 YOA	Lifetime cumulative incidence: 6 MOA–4 YOA: 2.9%; 5–9 YOA: 10.5%; 10–14 YOA: 10.8%; 15–20 YOA: 8.9%
Giaquinto et al 2002 [103-106]*	1997–1998	Epidemiological/ PEDIANET	≤14 YOA with varicella	≤14 YOA: 8.03%; 3–4 YOA: 16%; 10–12 YOA: 2–4%
Servizi Sociali Sanita. Official bulletin of the Lombardy region 2002–2003 [137]*	2001–2003	Epidemiological/ population database Surveillance (SPES, ISS)	<14 YOA	2001: 5,741; 2002: 5,459; 2003: 5,635	2001: 16,924; 2002: 15,331; 2003: 13,744
Nicolosi et al 2003 [83]***	1997–1998	Epidemiological/ PEDIANET	<14 YOA	0–2 YOA: from 2.9 to 8.5%; 3–4 YOA: from16.2 to 16.4%; 0–14 YOA: 8.0% (7.7–8.4)	1,749/33,430
Gabutti et al 2008 [98]*	1991–2005	Epidemiological/databases (ISTAT, SPES)	All ages	ISTAT data, overall: 1991–2004: 164.4 to 244.2; 0–14 YOA: 1991–1995: 996; 2001–2004: 1,164 SPES data, 2000–2005: from 4,053 to 6,655
Baldo et al 2009 [112]*	2000–2007	Epidemiological/mandatory notification/database (SPES)	All ages	Per 1,000, 2004–2007: from 40.5 to 66.6
EUVAC.net ECDC 2010 [107]*	2000–2007	Epidemiological/ EUVAC mandatory notification	All ages	From 119 to 220	From 69,328 to 126,051
EUVAC.net ECDC 2010 [108]*	2008–2009	Epidemiological/ EUVAC mandatory notification	All ages	2008: 132; 2009: 94	2008: 78,617; 2009: 56,502
EUVAC.net ECDC 2011 [109]*	2009–2010	Epidemiological/ EUVAC mandatory notification	All ages	2009: 94; 2010: 66	2009: 56,502; 2010: 39,649
Bollaerts et al 2017 [36]***	1995–2015	Systematic literature review/analysis	All ages	<5 YOA: 8,020; 5–9 YOA: 8,118; 10–14 YOA: 916; 15–19 YOA: 698; 20–39 YOA: 371; 40–64 YOA: 112
Riera-Montes et al 2017 [6]***	1995–2015	Systematic literature review/analysis	All ages	<5 YOA: 8,020; 5–9 YOA: 8,118; 10–14 YOA: 916; 15–19 YOA: 698; 20–39 YOA: 372; ≥40 YOA: 113
De Donno et al 2017 [91]*	2000–2014	Epidemiological/ population and hospital discharge databases	All ages	2004: 214.4; 2014: 77.3; 2003–2014: 129.4
Pezzotti et al 2018 [93]***	1925–2002	Surveillance/ISTAT and MoH databases	All ages	Morbidity rate: 86.91
Emilia-Romagna, Italy
Gatti et al 2013 [142]*	2006–2011		0–17 YOA	Per 10,000 vaccine doses: from 0 to 19.0
Florence, Italy
Moretti et al 2000 [130]*	1997–1998	Epidemiological/ sentinel and notification systems	<14 YOA	Per 1,000: sentinel system: 41.6; notification system: 23.7	2,043
Lombardy, Italy
Servizi Sociali Sanita. Official bulletin of the Lombardy region 2002–2003 [137]*	2000–2003	Epidemiological/ databases (SPES, ISS)	All ages	2000–2003: 0–4 YOA: 2,182.5–2777.5; 5–9 YOA: 1904.4–2269.4; 10–14 YOA: 228.2–271.8; 15–19 YOA: 54.8–85.1; 20–29 YOA: 43.5–55.5; 30–39 YOA: 47.2–55.5; ≥40 YOA: 4.3–5.7
Piedmont, Italy
Zotti et al 2002 [135]**	1995–2000	Epidemiological/ databases (SIMI, SPES)	All ages	Children: 5,452; Adults: 41
Bollettino Epidemiologico Anno 2005 [146]**	2005	Epidemiological/ population database	All ages	261	427
Dipartimento di Prevenzione. EpiCentro.iss [143]*	2010–2016	Epidemiological/ population database	All ages		From 5,017 to 6,286
Dipartimento di Prevenzione. EpiCentro.iss[139-140]*	2015	Epidemiological/ population database	All ages		5,049
Marinaro et al. [148]*	2003	Epidemiological/ population database	All ages	279.31	<1 YOA: 15; 1–5 YOA: 251; 6–14 YOA: 134; 15–24 YOA: 14; 25–64 YOA: 37; ≥65 YOA: 0
Agnelli. EpiCentro.iss [149]*	2006	Epidemiological/ population database	All ages	352	564
Dipartimento di Prevenzione. EpiCentro.iss [145]*	2011	Epidemiological/ population database	All ages	246	<1 YOA: 16; 1–5 YOA: 271; 6–14 YOA: 102; 15–24 YOA: 10; 25–64 YOA: 22; ≥65 YOA: 0
Dipartimento di Prevenzione. EpiCentro.iss [151]**	2012	Epidemiological/ population database	All ages	342	0–14 YOA: 551; 15–24 YOA: 8; 25–64 YOA: 23; ≥65 YOA: 1
Dipartimento di Prevenzione. EpiCentro.iss [152-153]**	2013	Epidemiological/ population database	All ages	488	839
Borello et al. [147]*	2014	Epidemiological/ population database	All ages	415	714
Sicily, Italy
Amodio et al 2015 [29]*	2003–2012	Surveillance/database (SIMI)	All ages		2003: 5,290
Puglia, Italy
Tafuri et al 2015 [133]*	2003–2005	Surveillance/ database (SIMI)	All ages	122.5	2004: 7,330; 2003–2005: 4,953/year
Sardinia, Italy
Assessorato Dell’igiene E Sanita’ E Dell’assistenza Sociale Servizio Prevenzione. [144]*	2006–2009	Epidemiological/ population database			From 1,299 to 2,306
Tuscany, Italy
Bonsignori et al 2007 [127]*	1997–2003	Surveillance/hospital and healthcare records	0–14 YOA	Per 1,000: 19.68	6,406
Frenos et al 2007 [129]*	1997–2004	Surveillance/medical records	0–14 YOA		1997–2004: from 6,809 to 9,585
Boccalini et al 2016 [114]*	2004–2012	Surveillance/ hospital and regional databases	All ages	Per 1,000, 2004–2007: 2.30	2004: 11,445; 2004–2007: 33,114
Veneto, Italy
Russo et al. [138]**	1999–2009	Epidemiological/ population database	All ages	1999–2004: Overall: 248.4–330.6; <12 MOA: 429–660; ≤14 MOA: 698–1,003; 1–3 YOA: 1,923–2,922; 4–14 YOA: 1,662–2,103	1999–2004: from 11,209 to 15,536
Russo et al. [141]**	1999–2013	Epidemiological/ population database	All ages	1999–2004: All: 247.6–327.9; ≤14 MOA: 623.2–896.3; >14 YOA: 27.8–38.1	1999–2004: All: 11,169 to 15,413 ≤14 MOA: 5.1–5.9
Baldo et al 2009 [112]*	2000–2007	Epidemiological/mandatory notification/databases (SPES)	All ages	Per 1,000, 2000–2004: <1 YOA: 4.3–6.3; 1–4 YOA: 30.0–39.0; 5–9 YOA: 22.6–27.4; 10–14 YOA: 3.3–4.6; 15–19 YOA: 1.0–1.6; >20 YOA: 0.3–0.3; Total: 2.6–3.3	2000–2004: <1 YOA:179–291; 1–4 YOA: 5,094–6,926; 5–9 YOA: 4,561–5,871; 10–14 YOA: 674–949; 15–19 YOA: 201–316; >20 YOA: 952–1,225; Total: 11,871–15,283
Pozza et al 2011 [132]*	2000–2008	Surveillance systems/database analyses (RDP, SPES)	All ages	RDP: 2000: 289.2, 2004: 325.6 0–14 YOA, RDP (SPES): 2000: 1,939.3 (6,136.8), 2004: 2,211.4 (7,712.7)	RDP: 2000: 13,206, 2004: 15,532
Generalized Italian regions
EpiCentro.iss [150]*	2000	Epidemiological/ population database	0–14 YOA	Sentinel surveillance/Obligatory notification: 5,34/976 North Italy: 6,034/1,529 Central Italy: 5,234/2,517 South Italy: 4,825/351
Servizi Sociali Sanita. Official bulletin of the Lombardy region 2002–2003 [137]* (North Italy)	2001–2003	Epidemiological/ databases (SPES, ISS)	<14 YOA	From 5,605 to 7,053	From 6,189 to 8,098
Alfonsi et al 2011 [95]*** (21 Italian regions)	2006–2009	Surveillance/ mandatory notifications and questionnaire	Children eligible for vaccinations	2006: 164; 2009: 101 (p < 0.01) UVV regions: 380; Non-UVV regions: 404 (p < 0.01)
Trucchi et al 2015 [134]* (nationwide, Sicily, Veneto, Puglia)	2001–2010	Surveillance/ mandatory notification/databases (hospital records, ISTAT)	All ages	2001–2003: incidence remained stable
Germany
Wagenpfeil et al 2004 [86]*	1999	Epidemiological/ medical records	Unvaccinated children (mean age: 7.4 YOA)	9.3/1000 person	<8 YOA: 82.4%
Bollaerts et al 2017 [36]***	1995–2015	Systematic literature review/analysis	All ages	<5 YOA: 11,884; 5–9 YOA: 7,048; 10–14 YOA: 246; 15–19 YOA: 190; 20–39 YOA: 103; 40–64 YOA: 32
Riera-Montes et al 2017 [6]***	1995–2015	Systematic literature review/analysis	All ages	<5 YOA: 11,884; 5–9 YOA: 7,048; 10–14 YOA: 246; 15–19 YOA: 190; 20–39 YOA: 103; ≥40 YOA: 32
Post-vaccination era
Italy, nationwide
Pezzotti et al 2018 [93]*** (8 Italian regions)	1900–2015	Surveillance/ISTAT and MoH databases	All ages	2003–2015, prevented cases: 679,512
Puglia, Italy
Tafuri et al 2013 [122]**	2011	Epidemiological/patient records	Children (mean age: 5.2 ± 1.4 YOA)		BV: 14	1-dose: Day care center: 59.9% (48.3–69.8); Elementary school: 69.2% (50.5–88.1)
Tafuri et al 2014 [154]***	2006–2011	Regional serosurvey	1–15 YOA			Time from vaccination (1-dose) to varicella virus exposure Cases: 797 days (±445) Controls: 638 days (±439 days) p = 0.018 BV was associated with the time (in months) from vaccination to varicella virus exposure OR: 1.02 (CI 95%: 1.001–1.04; p = 0.04)
Tafuri et al 2015 [133]*	2006–2012	Surveillance/database (SIMI)	All ages	2006–2008: 85.3; 2009–2012: 13.7	2006–2008: 3,474/year; 2009–2012: 560/year; 2012: 234 BV 2006–2012, <72 MOA: 3.4% (any severity); 2.9% (hospitalizations with varicella diagnosis)	1-dose: 98.8% (any severity)
Sicily, Italy
Giammanco et al 2009 [118]*	2003–2007	Surveillance/ sentinel network	0–14 YOA	Per 1,000, 2007: 9.0	BV: 22
Amodio et al 2015 [29]*	2003–2012	Surveillance/database (SIMI)	All ages	From 2007: <0.1/1,000 inhabitants/year (0–14 YOA: 94% of all cases)	2012: 207
Tuscany, Italy
Pieri et al 2015 [131]*	2010–2013	Surveillance	24 MOA		Cases: 2008 BC: 459; 2009 BC: 292; 2010 BC: 218; 2011 BC: 111. BV, 1-dose: 26.6% BV, 1-dose per BC: 2008: 40.5%; 2009: 21.6%; 2010: 15.1%; 2011: 4.5%	1-dose: Overall: 90.8%; BC 2008: 77.8%; BC 2009: 94.0%; BC 2010: 96.6%; BC 2011: 98.6%
Boccalini et al 2016 [114]*	2004–2012	Surveillance/ hospital and regional databases	All ages	Per 1,000:0.89	2009–2012: 13,184 2012: 1,502
Bechini et al 2018 [113]*	2004–2016	Surveillance/national and international databases	All ages	Between 2004–2016: decrease in all age groups
Veneto, Italy
Baldo et al 2009 [112]*	2000–2007	Epidemiological/mandatory notification/databases (SPES)	All ages	Per 1,000, 2005–2007: <1 YOA: 3.8–6.0; 1–4 YOA: 24.1–36.4; 5–9 YOA: 15.9–22.3; 10–14 YOA: 1.8–2.9; 15–19 YOA: 0.4–0.8; >20 YOA: 0.2–0.2; Total: 2.0–2.9	2005–2007: <1 YOA: 181–279; 1–4 YOA: 4,511–6,685; 5–9 YOA: 3,505–4,982; 10–14 YOA: 377–615; 15–19 YOA: 98–163; >20 YOA: 632–944; Total: 9,808–13,644
Russo et al. 2011 [138]**	1999–2009	Epidemiological/population database	All ages	2005–2009: 2005: 218.6, 2009: 65.2 <12 MOA: 112–637; 1–3 YOA: 263–2794; 4–14 YOA: 479–1772 Incidence in children ≤14 MOA: 215.3–981.7	2005: 10,358, 2009: 3,187
Russo et al. [141]**	1999–2013	Epidemiological/ population database	All ages	2005: 217.2, 2013: 28.2 Incidence in children ≤ 14 MOA: 2005: 606.6; 2013: 134.0; >14 YOA: 2005: 23.2; 2013: 4.2	2005: 10,291; 2013: 1,379 ≤14 MOA: 2005: 6.1%; 2013: 9.4%
Pozza et al 2011 [132]*	2000–2008	Surveillance systems/ databases (RDP,SPES)	All ages	2008: RDP 123.8 2008, 0–14 YOA: RDP: 813.0; SPES: 4,004.8	2008: RDP 6,054
Giaquinto et al 2018 [119]***	2006–2013	Surveillance/ PEDIANET	Children (2006–2007 BC)	Per 100 person-years, ProQuad-vaccinated children: 0.43		ProQuad, 1-dose: 93% (90–95)
Generalized Italian regions
Bechini et al 2015 [125]* (8 Italian regions)	2003–2012	Epidemiological/database analyses	All ages	Per 1,000, 2003–2012: Notified incidence: 0.42–2.18; Estimated real incidence*: 1.66–8.73; * underreporting rate of 5 for mandatory notification
Trucchi et al 2015 [134]* (nationwide, Sicily, Veneto, and Puglia)	2001–2010	Surveillance/ mandatory notification (hospital discharge, ISTAT)	All ages	2004–2010: 215.6–102.6. 0–14 YOA, 2001–2010: 948.6 (88.8% of total cases) Sicily, 2003–2010: 105.7–9.2 Veneto, 2007–2010: 225.5–55.7 Puglia, 2006–2010: 121.7–13.1
Germany
1-dose UVV vs no UVV
Spackova et al 2010 [64]***	2005–2009	Surveillance/ sentinel data and physicians’ questionnaire	All ages		Decrease by 63% between 2005–2006 and 2008–2009
Siedler et al 2010 [31]*	2005–2009	Surveillance/ sentinel data	All ages	Monthly reported cases: All: 55% decrease (from 2.85 to 1.29); 0–4 YOA: 63% decrease (from 1.85 to 0.69); 5–9 YOA: 38% decrease (from 0.85 to 0.53)	2005–2009: 12,414–32,569; BV cases: 2005/2006: 289, 2008/2009: 1,016
Hagemann et al 2017 [47]*** (Munich and Wurzburg)	2009–2011	Surveillance/ patient questionnaire	18–36 MOA	Munich: 6.9%; Würzburg: 5%
2-dose UVV vs 1-dose UVV
Spackova et al 2010 [44-46]***	2008–2009	Surveillance/ health records and patient questionnaires	Median age: 4 YOA		154 cases (109 with known vaccination status) BV: 40% Compared with 1-dose Varivax: higher risk of BV with 1 dose of Varilrix and 1 dose of Priorix-Tetra 2 doses of Priorix-Tetra: lower risk of BV compared with 1 dose of Varivax Risk for mild or moderate BV: no significant difference by vaccine brand	72% (no difference across age, day care center, gender)
Siedler et al 2013 [41]*	2004–2012	Surveillance/ sentinel network	All ages	Per reporting doctor: 2005: 3.6 cases/month; 2012: 0.6 cases/month Per practice: 1–4 YOA: 91% decrease; 5–9 YOA: 76% decrease
Streng et al 2013 [65]*** (Bavaria)	2006–2011	Surveillance/ parental surveys, pediatric practices, hospital databases	0–16 YOA	Practice surveillance (per 1,000): 2006–2007: 6.6; 2010–2011: 2.2	Practice surveillance: 2006–2007: 6,079; 2010–2011: 1,464 2006–2011: cases reduction: <1 YOA: 71%; 1–4 YOA: 75%; 5–9 YOA: 63%; 10–16 YOA: 63%
Neuhauser et al 2014 [59]***	2003–2006 2009–2012	Surveillance/ telephone survey	0–17 YOA		2003–2006: 0–2 YOA: 12.8; 3–6 YOA: 60.5; 7–10 YOA: 85.7; 11–13 YOA: 86.8; 14–17 YOA: 85.6 2009–2012: 0–2 YOA: 2.4; 3–6 YOA: 18.0; 7–10 YOA: 62.2; 11–13 YOA: 82.7; 14–17 YOA: 83.4
Streng et al 2014 [85]* (Munich and Wurzburg)	Munich: 2010–2011 Wurzburg: 2010–2012	Surveillance/ pediatric practices (BaVariPro)	0–16 YOA	Munich: 28% decrease (from an average of 1.8 cases per practice and months to 1.3); Würzburg: 24% decrease (from an average of 1.0 to 0.7)	Munich: 2167; Würzburg: 278
Siedler et al 2015 [40]*	2005–2014	Surveillance/ sentinel network	64.0 MOA (mean)		BV: 4,357–80% (3,504) received one dose, 20% (853) received two doses
Siedler et al 2016 [51]*	2009–2014	Surveillance/ National sentinel data and health insurance claims data.	1–4 YOA		Total: 8,153/31,288 (26.1%), all ages; 1-dose vaccination: 403 (4.9%); 2-dose vaccination: 285 (3.5%)	1-dose vaccination: 2009–2014: 86.6%; 2010: 92.0%; 2014: 76.1% VE2-dose vaccination: 2009–2014: 97.3%, 2009: 98.4%, 2013: 96.2%
Rieck et al 2017 [50]*	2006–2015(2006–2013 BC)	Surveillance/ health insurance claims from ASHIP	3.6 YOA (mean)		29,404 (2.0%)	VE, any vaccination: 1^st dose (VE1): 81.9%; 2^nd dose (VE2): 94.4%. VE, time interval between 1^st and 2^nd dose: 1–27 days: 87.3%; 28–365 days: 94.4%; >1 year: 94.8%;>3 years: 95.0% VE over time from vaccination: VE1 > 0.5–1.0 year: 79.4%; VE1 > 7.0–8.0 years: 88.0%; VE2 > 0.5–1.0 year: 93.1% VE2 > 7.0–8.0 years: 92.4% VE, vaccine type: VE1: VAR: 82.0%; MMRV: 81.7%; VE2 for all combinations of VAR and MMRV as 1^st- or 2^nd-dose: between 94.3% and 95.0% VE against complications: VE1:98.2%; VE2:99.5% VE against non-complicated varicella: VE1:65.3%; VE2:89.3%
Liese et al 2013 [57]*	2008–2010	Epidemiological prospective, matched case-control study/according to protocol	1–7 YOA			VE, against PCR-confirmed varicella, any severity: 1-dose OKA/GSK: 71.5%; 1-dose; any vaccine: 86.4% VE, against clinical varicella, any severity: 1-dose, any vaccine: 81.1% (unadjusted) and 81.2% (adjusted) VE, against PCR-confirmed varicella, moderate or severe: 1-dose OKA/GSK: 94.7%; 1-dose any vaccine: 97.7% VE, against PCR-confirmed varicella, any severity: 2-doses, any vaccine: 94.3% (unadjusted) and 94.3% (adjusted)
Hecht et al 2017 [48]***	2002–2014	Surveillance/ mandatory notification across NFS between 2002–2009 and nationwide in 2013; insurance claims database	All ages	2013: >70% decrease 2005–2013: 1–4 YOA: 90% decrease; 5–9 YOA: 59% decrease 2014: increase in all age groups. Cases/practice/month (all ages): 2005: 3.47; 2014: 0.43.
GBE-Bund Federal Statistics Office 2003–2017 [68]*	2014–2017	Epidemiology/ notifiable diseases	<15 YOA	2014–2017: 18,991–21,155

^adata provided as per 100,000 population unless otherwise stated. ^bmajor factor influencing vaccination status. *, low risk of bias; **, unclear risk of bias; ***, high risk of bias; BV, Breakthrough varicella; BC, birth cohort; EUVAC.net, European surveillance network for vaccine-preventable diseases; ISTAT, Italy’s National Institute of Statistics; ISS, Italy’s National Institute of Health; BaVariPro, Bavarian Varicella Surveillance Project; PEDIANET, database from 35 pediatricians; SPES, Italy’s Pediatric Sentinel Surveillance System of Vaccine-Preventable Diseases; CI, confidence intervals; PCR, polymerase chain reaction; SIMI, Italian National Surveillance System of Infectious Diseases; ECDC, European Center for Disease Control and Prevention; MoH, Ministry of Health; RDP, Regional Department of Prevention; UVV, universal varicella vaccination; ASHIP, Associations of Statutory Health Insurance Physicians; VAR, monovalent varicella vaccine; VE, vaccine effectiveness; MMRV, measles-mumps-rubella-varicella vaccine; NFS, New Federal States; OR, odds ratio; MOA/YOA, months/years of age.

Vaccine introduction: Germany 2004 (1-dose), 2009 (2-dose); Italy 2017 (nationwide); Basilicata 2010 (2-dose), Calabria 2010 (2-dose); Friuli-Venezia-Giulia 2013 (2-dose); Puglia 2006 (1-dose), 2009 (2-dose); Sardinia 2011 (2-dose); Sicily 2003 (1-dose), 2010 (2-dose); Tuscany 2008 (2-dose); Veneto 2005 (2-dose)

Table 3. Varicella-related hospitalizations, complications, and vaccine effectiveness before and after universal varicella vaccination

Citation	Year(s)		Data source	Age group	Hospitalization/complications (Average annual incidence/100,000^a [95% CI])	Cases
Pre-vaccination era
Italy, nationwide
Giaquinto et al 2002 [103]*	1997–1998		Epidemiological/ PEDIANET	≤14 YOA with varicella		Hospitalizations: 9 on 2,958 cases Complications: 126 on 2,958 cases (both over 8 months)
EUVAC.net ECDC 2011 [109]*	2010		Epidemiological/ EUVAC mandatory notification	All ages		Hospitalizations, 2010: 273 (0.5% of all cases)
EUVAC.net ECDC 2010 [107]*	2000–2007		Epidemiological/ EUVAC mandatory notification	All ages		Hospitalizations: 2000–2006: 1,062–1,609; 2007: 789
EUVAC.net ECDC 2010 [108]*	2008–2009		Epidemiological/ EUVAC mandatory notification	All ages		Hospitalizations: 2008: 820; 2009: 672 (both 1% of all cases)
Fornaro et al 1999 [102]*	1997		Surveillance/sentinel network	0–14 YOA		Complications: 56 (3.5%)
Gabutti et al 2008 [78]***	1999–2005		Epidemiological/hospital databases	All ages		Hospitalizations: 1,508 Inpatients: 1,456
Sbarbati et al 2014 [110]*	2006–2011		Epidemiology/ hospital database	0–24 MOA	Hospitalizations: 37.5	Hospitalizations/cases: with complications: from 107 to 174 without complications: from 246 to 356
Riera-Montes et al 2017 [6]***	1995–2015		Systematic literature review/analysis	All ages	Hospitalizations (min-max)/Deaths: <5 YOA: 37–NA/0.04; 5–9 YOA: 19–NA/0.01; 10–14 YOA: 5.2–NA/0.01; 15–19 YOA: 2.5–NA/0.0; 20–39 YOA: 2.7–NA/0.01; ≥40 YOA: 0.7–NA/0.01
Trucchi et al 2015 [134]* (Sicily, Veneto, and Puglia)	2001–2010		Surveillance/ mandatory notification/databases (hospital discharge, ISTAT)	All ages		Deaths, 2001–2003: 8
De Donno et al 2017 [91]*	2000–2014		Epidemiological/ population and hospital discharge databases	All ages	Hospitalizations: 2002 and 2004: 4.2 2013 and 2014: 1.9
Gabutti et al 2008 [98]*	1991–2003		Hospital databases/ISTAT	All ages	Mean deaths: 1991–2002: 5.5/year	Hospitalizations, 2000–2003, annual mean: 1,575 (1,521 hospitalizations and 54 day-hospital admissions)
Florence, Italy
Azzari et al 2007 [123]*	2005–2006 (12-month period)		Surveillance/ hospital admissions	0–16 YOA with varicella		Hospitalizations: 47/279 (16.8%) children examined at emergency department <1 YOA: 14 (29.8%); 1–4 YOA: 26 (55.3%); 5–9 YOA: 4 (8.5%); 10–14 YOA: 2 (4.3%); >14 YOA: 1 (2.1%) All children had complications (16.8%).
Piedmont, Italy
Zotti et al 2002 [135-136]**	1995–2000		Epidemiological/ hospital database	All ages		Hospitalizations: 882 <14 YOA: 227 (with 25.7% for ≥15 YOA)
Sicily, Italy
Cuccia et al 2010 [115]*	2002		Epidemiological/ hospital records	All ages		Hospitalizations/Complications: Overall: 346/57; 0–15 MOA: 69/5; 16–48 MOA: 83/21; 5–14 YOA: 100/16; 15–40 YOA: 80/13; >40 YOA: 14/2
Amodio et al 2015 [29]*	2003–2012		Surveillance/hospital discharge database	All ages	Hospitalizations, 2003: 4.8 Median age at hospital admission (2003): 5 YOA	Hospitalizations, 2003: 238
Puglia, Italy
Tafuri et al 2015 [133]*	2003–2005		Surveillance/hospital discharge database	All ages	Hospitalizations: 3.9	Hospitalizations, mean: 159
Tuscany, Italy
Bonsignori et al 2007 [127]*	1997–2003		Surveillance/hospital and healthcare records	0–14 YOA	Varicella: 0.19%/year of pediatric hospitalizations Hospitalizations: 22.66 Complicated VZV: 12.00 Hospitalizations, per 1,000 notified VZV cases: 11.52 Complicated VZV: 6.09	Hospitalizations: total: 650 (1.1% out of 56,406), from 64 to 115 per year. Complications: total: 344 (2.92% of 650), from 37 to 63 per year.
Boccalini et al 2016 [114]*	2004–2012		Surveillance/ hospital and regional databases	All ages	Hospitalizations, 2004: Overall: 5.3; 1–4 YOA: 52.1 Hospitalizations, 2004–2007: Overall: 4.1; <1 YOA: 59.6; 1–4 YOA: 39.5; 5–14 YOA: 9.2; 15–24 YOA: 2.6; 25–49 YOA: 2.7; 50–64 YOA: 0.8; >64 YOA: 0.6	Hospitalizations, 2004: Overall: 189; 1–4 YOA: 60 Hospitalizations, 2004–2007: Overall: 584; <1 YOA: 73; 1–4 YOA: 189; 5–14 YOA: 105; 15–24 YOA: 32; 25–49 YOA: 141; 50–64 YOA: 23; >64 YOA: 21
Frenos et al 2007 [129]*	1997–2004		Surveillance/medical records	1 MOA–14 YOA	Central nervous system complications per 1,000 cases: 1997: 0.80; 2004: 1.51.	Complications: 414 (0.013% of total population) Central nervous system complications: 69 (16.7% of complications)
Veneto, Italy
Pozza et al 2011 [132]*	2000		Surveillance systems/ database analyses (RDP; SPES, hospital discharge)	All ages	Hospitalizations: 4.1 0–14 YOA: 18.7	Hospitalizations: 185
Generalized Italian regions
Bechini et al 2015 [125]* (8 Italian regions)		2003–2012	Epidemiological/database analyses	All ages	Hospitalizations, 2003: 3.3 (3.0–3.5)
Marchetto et al 2007 [120]* (Florence, Ancona, Turin)		2002–2006	Surveillance/hospital discharge records	0–17 YOA		Hospitalizations: 349 (median age: 40 months) Complications: 261 (74.8%, median age: 41 months)
Germany
Liese et al 2006 [69]* (North Rhine-Westphalia)		2003–2004	Surveillance/hospital databases (ESPED+EURODIAB+ICD-10)	0–16 YOA	Hospitalizations: <1 YOA: 96.5; 1–4 YOA: 47.6; 5–10 YOA: 14.3; 11–17 YOA: 2.3	Hospitalizations: ESPED, 2003: 918 (<0.01%)
Liese et al 2008 [58]*		2003–2004	Surveillance/hospital databases (ESPED+EURODIAB)	0–16 YOA	Hospitalizations, ESPED: overall: 3.25; 2003: 2.72; 2004: 3.78	Hospitalizations, ESPED: 2003: 384; 2004: 534 (mean age 3.3 YOA)
Siedler et al 2014 [39]*		1995–2003	Surveillance/ hospital discharge database	All ages	Hospitalizations: <1 YOA: 42.56; 1–4 YOA: 21.76; 5–9 YOA: 6.08; 10–14 YOA: 1.40; 15–19 YOA: 1.27; 20–49 YOA: 1.26; ≥50 YOA: 0.3 Total (age adjusted): 3.3	Hospitalizations (mean per year): <1 YOA: 327.8; 1–4 YOA: 691.9; 5–9 YOA: 264.0; 0–14 YOA: 64.2; 15–19 YOA: 58.0; 20–49 YOA: 450.4; ≥50 YOA: 88.7 Total: 1,948.8
Riera-Montes et al 2017 [6]***		1995–2015	Systematic literature review/analysis	All ages	Hospitalizations (min-max)/Deaths: <5 YOA: 45–NA/0.03; 5–9 YOA:10–NA/0.01; 10–14 YOA: 2–NA/0.01; 15–19 YOA: 1–1/0.0; 20–39 YOA: 1–2/0.0; ≥40 YOA: 0–0/0.0
Ziebold et al 2001 [90]*		1997	Surveillance/ questionnaire	≤16 YOA	Severe complications: 8.5	Neurological complications: 73/119 (61.3%)
Wagenpfeil et al 2004 [86]*		1999	Epidemiological/ medical records	Unvaccinated children (mean age: 7.4 YOA)		Complications: 76/1334 (5.7%)
Grote et al 2008 [55]*		2003–2004	Surveillance/hospital databases	0–17 YOA (median age: 5 YOA)	Deaths: 0.4	Deaths: 2003: 4; 2004: 6
Rack et al 2010 [60]*		2003–2004	Surveillance/hospital databases (ESPED+ICD-10)	0–16 YOA (median age 3.3 YOA)	Neurological complications, ESPED: 0.8	Hospitalizations, ESPED: 918 Neurological complications, ESPED: 232/918 (25.4%)
GBE-Bund Federal Statistics Office 1994–1999 [70]*		1994–1998	Epidemiological/ diagnostic data from hospitals	<15 YOA		Hospitalizations: 1,275–1,558 per year Deaths: 0–2 per year
GBE-Bund Federal Statistics Office 1998–2016 [71]*		1998–2016	Epidemiological/	1–14 YOA		Deaths 1998–2004: from 1 to 4 per year
GBE-Bund Federal Statistics Office 2003–2017 [72]*		2003–2017	Epidemiological/ patients in hospitals with >100 beds	<15 YOA		Hospitalizations/Complications: 2003: 23/3 encephalitis; 2004: 14/2 encephalitis
Post-vaccination era
Puglia, Italy
Tafuri et al 2015 [133]*		2006–2012	Surveillance/hospital discharge database	All ages	Hospitalizations: 2006–2008: 2.9; 2009–2012: 1.1	Hospitalizations: 2006–2008: 118/year; 2009–2012: 47/year (2012: 22)
Sicily, Italy
Amodio et al 2015 [29]*		2003–2012	Surveillance/hospital discharge records	All ages	Hospitalizations, 2012: 0.8 Median age at hospital admission (2009): 20 YOA	Hospitalizations, 2012: 38
Cuccia et al 2010 [115]*		2003–2007	Epidemiological/ hospital database	All ages		Hospitalizations/Complications: 2003: 247/53; 2004: 224/40; 2005: 160/22; 2006: 152/19; 2007: 71/14 Hospitalizations/Complications, 2007: 0–15 MOA: 14/0; 16–48 MOA: 5/3; 5–14 YOA: 14/2; 15–40 YOA: 27/4; >40 YOA: 11/5
Tuscany, Italy
Boccalini et al 2016 [114]*		2004–2012	Surveillance/ hospital and regional databases	All ages	Hospitalizations 2009–2012: Overall: 2.2; <1 YOA: 32.7; 1–4 YOA: 18.9; 5–14 YOA: 4.5; 15–24 YOA: 1.7; 25–49 YOA: 1.3; 50–64 YOA: 0.5; >64 YOA: 0.7 In 2012: 1.2; 1–4 YOA: 4.6	Hospitalizations 2009–2012: Overall: 325; <1 YOA: 42; 1–4 YOA: 99; 5–14 YOA: 55; 15–24 YOA: 21; 25–49 YOA: 67; 50–64 YOA: 16; >64 YOA: 25 Hospitalizations, 2012: 44 Hospitalizations: 77% reduction between 2004 and 2012, 44% reduction (259 fewer cases) between 2009 and 2012
Veneto, Italy
Pozza et al 2011 [132]*		2000–2008	Surveillance systems/ databases (RDP; SPES, hospital discharge)	All ages	Hospitalizations, 2008: 1.7 Hospitalizations, 0–14 YOA: 2006: 16.1; 2007: 10.3; 2008: 8.4	Hospitalizations, 2008: 81
Generalized Italian regions
Bechini et al 2015 [125]* (8 Italian regions)	2003–2012		Epidemiological/database analyses	All ages	Hospitalizations: 2004: 3.8; 2007: 2.4; 2010: 1.6; 2012: 1.0 2004–2012: ~75% decrease
Trucchi et al 2015 [134]* (nationwide, Sicily, Veneto, and Puglia)	2001–2010		Surveillance/ mandatory notification/databases (hospital discharge, ISTAT)	All ages	Hospitalizations: 2001–2010: 3.4; 2004: 4.4 (peak value); 2009–2010: 2.5 (steady decline) Sicily: 2003: 4.8; 2010: 0.8; Veneto: 2006: 3.1; 2010: 0.9; Puglia: 2006: 3.9; 2010: 1.5	Hospitalizations: 2001–2010: 20,295 (mean annual number: 2,030) Sicily: 2003: 238; 2010: 41; Veneto: 2006: 150; 2010: 42; Puglia: 2006: 158; 2010: 63 Deaths: 2006–2010: 25
Germany
Siedler et al 2014 [39]*	2005–2012		Surveillance/ hospital discharge database	All ages	Hospitalizations: <1 YOA: 16.47*; 1–4 YOA: 8.15*; 5–9 YOA: 3.79*; 10–14 YOA: 1.18; 15–19 YOA: 1.13; 20–49 YOA: 1.15; ≥50 YOA: 0.6*; Total (age adjusted): 1.86* *p < 0.05 reduction compared with pre-vaccination	Hospitalizations (mean cases/year): <1 YOA: 112.3; 1–4 YOA: 231.1; 5–9 YOA: 143.8; 10–14 YOA: 47.3; 15–19 YOA: 50.8; 20–49 YOA: 392.4; ≥50 YOA: 193.4; Total: 1,171.0
Siedler et al 2013 [41]*	2004–2012		Surveillance/ sentinel network	All ages		Hospitalizations, 2004/2010: All ages: 2,316/984; <5 YOA: 1,139/175
Siedler et al 2010 [31]*	2005–2009		Surveillance/ sentinel data	All ages		Complications: 2005/2006: 142 (0.4%); 2008/2009: 26 (0.2%)
Spackova et al 2010 [64]***	2005–2009		Surveillance/ sentinel data and physicians’ questionnaire	All ages		Hospitalizations: 25.4% of patients with complications (71/280) Complications: 81% decrease 0–4 YOA: 59.3%; 5–9 YOA: 30.4%; 10–14 YOA: 3.9%; 15–19 YOA: 0.7%
Streng et al 2016 [52]* (Bavaria)	2005–2011		Surveillance (BaVariPro)/ hospital database (ICD-10 code)	<17 YOA (median age: 3 YOA)	Hospitalizations, per 1,000 beds: 2005: 90.5; 2008: 61.5; 2011: 30.5	Hospitalizations: 2005: 239; 2008: 159; 2011: 53
Streng et al 2013 [65]*** (Bavaria)	2006–2011		Surveillance/ parental surveys, pediatric practices, hospital databases	0–16 YOA	Hospitalizations, hospital database: All: 2005: 7.6; 2009: 4.3; <1 YOA: 2005: 60.8; 2009: 14.2; <5 YOA: 2005, 21.0; 2009: 4.7	Hospitalizations, practice surveillance: 2006–2007: 8; 2010–2011: 4 Hospitalizations, 2006–2011: 0.1% of all cases, 17% of 134 patients with complications. Hospitalizations, hospital database, 2005–2009: <11 MOA: 38 (21.3%); 11 MOA–<5 YOA: 78 (43.8%); 5–9 YOA: 47 (26.4%); 10–16 YOA: 15 (8.4%) Complications, pediatric practices: 0.83% (134/16,054)
Streng et al 2017 [42-43]* (Bavaria)	2005–2011		Surveillance/ hospital discharge database (ICD-10)	<17 YOA	Hospitalizations: 2005: 13.3; 2011: 4.8 Neurological complications: 2005: 2.8; 2011: 1.2	Hospitalizations: 2005: 251; 2011: 54 Neurological complications: 2005: 52; 2011: 14
GBE-Bund Federal Statistics Office 1998–2016 [71]*	1998–2016		Epidemiological/	1–15 YOA		Death, 2005–2016: from 0 to 1 per year
Rieck et al 2017 [50]*	2006–2015(2006–2013 BC)		Surveillance/ health insurance claims from ASHIP	3.6 YOA (mean)		Complications: 4.13% (1,213/29,404)
GBE-Bund Federal Statistics Office 2003–2017 [72]*	2003–2017		Epidemiological/ patients in hospitals with >100 beds	<15 YOA		Hospitalizations, 2005–2017: from 0 to 10 per year Complications, 2005–2017: from 0 to 3 encephalitis per year

^adata provided as cases per 100,000 population unless otherwise stated; ^bregions offering vaccination to people at risk and susceptible adolescents. *, low risk of bias; **, unclear risk of bias; ***, high risk of bias; BC, birth cohort; CI, confidence intervals; ASHIP, Associations of Statutory Health Insurance Physicians; BaVariPro, Bavarian Varicella Surveillance Project; ECDC, European Center for Disease Control and Prevention; EUVAC.net, European surveillance network for vaccine-preventable diseases; ESPED, Germany’s Epedemiological Institute for rare pediatric diseases; PEDIANET, database from 35 pediatricians; EURODIAB, a collaboration of European Childhood Diabetes Registers; ISTAT, Italy’s National Institute of Statistics; SPES, Italy’s Pediatric Sentinel Surveillance System of Vaccine-Preventable Diseases; RDP, Regional Department of Prevention; VZV, varicella zoster virus; ICD-10, International Classification of Diseases and Related Health Problems, 10th Revision, MOA/YOA, months/years of age.

Vaccine introduction: Germany 2004 (1-dose), 2009 (2-dose); Italy 2017 (nationwide); Basilicata 2010 (2-dose), Calabria 2010 (2-dose); Friuli-Venezia-Giulia 2013 (2-dose); Puglia 2006 (1-dose), 2009 (2-dose); Sardinia 2011 (2-dose); Sicily 2003 (1-dose), 2010 (2-dose); Tuscany 2008 (2-dose); Veneto 2005 (2-dose)

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