Impact of universal mass vaccination with monovalent inactivated hepatitis A vaccines – A systematic review

Figures & data

Figure 1. Flowchart of the selection procedure.

Table 1. Effect of universal mass vaccination programs for hepatitis A on incidence of acute hepatitis A.

	Vaccination
Author; country	Start UMV; Target age	Vaccine coverage	Vaccine	Data source of hepatitis A cases	Years compared (before vs with UMV)^a	Incidence (95%CI) per 100,000 population	Decline (%)	Comments^b
Single-dose immunization strategy
Vizzotti et al. 2013^27 Argentina	2005 1 yr	96.8% for 2006–2011	Havrix˜ 720EU, Vaqta™ 25U, Avaxim˜ 80U, Virohep-A Junior 12UI	Early Alert Module, National Health Surveillance System; passive clinical surveillance	2000–2002 vs. 2006–2011	66.5 vs. 7.9	88.1	– –Source and year of denominator data n.r. – –COI: none
Two-dose immunization strategy
Mellou et al. 2014^40 Greece	2008 >12 mo	VC with 1 dose among 3 yr old children 80%, with 2 doses 42% in 2013	n.r	National surveillance data	2007 vs. 2013	2–3 vs. 2^c	–^c	COI: none
Chodick et al. 2008^64 Israel	1999 18 mo	Received at least 1 dose:-<5 yrs: 9% (1999), 89% (2007)-5–14 yrs: 15% (1999), 68% (2007)	Havrix˜ 720EU^28	Maccabi Healthcare Services; health maintenance organization	1998 vs. 2007	142.4 vs. 7.6^d	95.0	– –MHS not representative of the general population (higher socio-economic class) (Daniel Shouval, personal communication, February 23, 2015) – –COI: none
Levine et al. 2015^47 Israel	1999 18 mo	VC for vaccines given in 2003–2010 : 92% (dose 1), 88% (dose 2)	Havrix˜ 720EU	Cases reported to the national surveillance system	1993–1998 vs. 2008–2012	50.4 (35.9–64.9) vs. < 1.0	>98	COI: none
Estripeaut et al. 2015^50 Panama	2007 > 12 mo	VC 1 dose 70.7% and 1 dose 40.1% in 2010	Havrix˜ 720EU	National surveillance systems	2000–2006 vs. 2010	51.1 vs. 3.7	93^e	GlaxoSmithKline Biologicals SA
Romero et al. 2012^36 Uruguay	2007 vaccination of children 1–5 yrs old In 2008 >12 mo	VC 1 dose 74%	n.r.	National surveillance system	2005 vs. 2010	69.6 vs. 2.7	96	COI: n.r.
Erhart et al. 2012^49 Arizona, US	1999^c 2 yrs (1999) 1 yr (2006)	VC with 1 dose (by age): −24–59 mo: 36% (2000), 65% (2006) −5–9 yrs: 24% (2000), 77% (2006)	Havrix˜ 720EU, Vaqta˜ 25U^69	Arizona Department of Health Services and local public health departments; passive surveillance	1994–1995 vs. 2006–2007	41 (41–42) vs. 2.6 (2.5–2.7)	94^e	– –Year of denominator data n.r – –COI: n.r.
Ly et al. 2015^45 US	1999^f (vaccinating states^g) 2006 (all) 2 yrs (1999) 1 yr (2006)	n.r.	Havrix˜ 720EU, Vaqta˜ 25U^69	National Notifiable Disease Surveillance System	1999 vs. 2011	6.0 vs. 0.4	93^e	COI: none
Singleton et al. 2010^48 Alaska, US	1999^f 2 yrs (1999) 1 yr (2006)	VC with ≥1 dose among children aged 24–35 mo:-2003: 72.7% (±95%CI 7.4)-2004: 69.9% (±95%CI 7.9)-2005: 66.8% (±95%CI 9.1)-2006: 65.9% (95%CI 57.1–73.7)	Havrix˜ 720EU, Vaqta˜ 25U^69	Alaska Section of Epidemiology; surveillance	1994–1995 vs. 2002–2007	22.2 vs. 0.9	95.9^e	COI: n.r.
Wasley et al. 2005^35 Vaccinating states^g, US	1999^f 2 yrs	VC for 1^st dose among children aged 24–35 mo in 2003, in states in which routine vaccination was: – Recommended: 50% – To be considered: 25%	Havrix˜ 720EU, Vaqta˜ 25U^69	National Notifiable Diseases Surveillance System; passive national surveillance	1990–1997 vs. 2003	10.7 vs. 2.6	76	COI: none

CI: confidence interval; COI: conflict of interest; EU: ELISA units; HA: hepatitis A; MHS: Maccabi Healthcare Services; mo: months; n.r.: not reported; U: antigen units; UI: international unit; UMV: universal mass vaccination; US: United States; VC: vaccine coverage; yr(s): year(s)

^a Years compared as available in the respective article. If more options were available, the most recent pre-vaccination and the most recent post-introduction year were used.

^b Only industry-related conflicts of interest, funding source or financial disclosures reported

^c Numbers read from graph. The incidence dropped to almost 0 in 2011 and rose again after that. Numbers read from graph therefore too imprecise to calculate % decline.

^d Per 100,000 MHS members

^e Calculated based using the formula [1-(HA incidence with UMV/HA incidence before UMV)]*100%

^f Vaccination of American Indian and Alaska Native children started in 1996

^g Vaccinating states: states in which HA childhood vaccination was recommend by the Advisory Committee on Immunization Practices (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, Washington) or considered (Arkansas, Colorado, Missouri, Montana, Texas, Wyoming) as of 1999

Table 2. Effect of universal mass vaccination programs for hepatitis A on other outcome measures.

	Vaccination
Author; country	Start UMV; Target age	Vaccine coverage	Brand, EU, doses	Data source	Outcome	Years compared	Before UMV	With UMV	Comments^a
Single-dose immunization strategy
Vizzotti et al. 2013^27 Argentina	2005 1 yr	96.8% for 2006–2011	Havrix˜ 720EU, Vaqta˜ 25U, Avaxim˜ 80U, Virohep-A-Junior 12UI	4 pediatric centers in Buenos Aires and Unique Central National Institute of Ablation and Implant	Number of cases of HA-associated fulminant hepatic failure cases per year	2000–2003 vs. 2008–2011	∼17.5 ^b	0	– No case definition of fulminant hepatic failure – COI: none
Two-dose immunization strategy
Papaevangelou et al. 2016 [ref] Athens, Greece	2008 1 yr	88% (dose 1), 82% (dose 2) among children aged 6 yrs in 2012	n.r.	Infectious Disease Unit of a Tertiary Pediatric Hospital	HA hospital admission per 1000 admission among children aged 0–14 yrs	1999–2008 vs. 2009–2013	50.5 (95%CI 29.2–67.1)	20.8 (95%CI 19.2–30.1)	–COI: none
Belmaker et al. 2007^41 Negev, Israel	1999 18 mo	Birth cohort 2000, by age 3 yrs: 86.4% (dose 1), 77.3% (dose 2)	Havrix˜ 720EU	Treating physicians, medical laboratories, Ministry of Education, concerned parents	Yearly average of HA cases associated with outbreaks in day care and school settings^c	1993–1999 vs. 2001–2005	45.6	0	– Not clear how complete the notifications of outbreaks are (e.g. Ministry of Health not included as a source) – COI: n.r.
Collier et al. 2014^44 US	1999^e (vaccinating states^f) 2006 (nationwide) 2 yrs (1999) 1 yr (2006)^43	n.r.	Havrix˜ 720EU, Vaqta˜ 25U^69	National Inpatient Survey discharge data (∼20% of all community hospital discharges)	Hospitalizations for HA illness as principal diagnosis per 100,000 persons^d	2004–2005 vs. 2010–2011	0.64	0.29	– Source and year of denominator data n.r. – COI: none
Ly et al. 2014^45 US	1999^e (vaccinating states^f) 2006 (nationwide) 2 yrs (1999) 1 yr (2006)	n.r.	n.r	National Notifiable Disease Surveillance System and Multiple Cause of death	% of HA-cases that was hospitalized; and HA-related mortality per 100,000 population^g	1999 vs. 2011	7.3; 0.1	24.5; 0.02	COI: none
Vogt et al. 2008^43 Vaccinating states^f, US	1999 2 yrs	n.r.	Havrix˜ 720EU, Vaqta˜ 25U^69	CDC's National Center for Health Statistics	Age-adjusted HA mortality rate per 1 million persons^h	1990–1995 vs. 2000–2004	0.51	0.28	– –Denominator data from 2000–2004, but incidence data from 1990–2004 – –Some decline in mortality attributable to temporal trends, as reflected by statistically significant declines in mortality in states in which no large-scale vaccination programs were implemented – –COI: none
Zhou et al. 2007^42 Vaccinating states^f, US	1999 2 yrs	2004, children aged 2 yrs: 30.0%(in-plan vaccination rate)	Havrix˜ 720EU, Vaqta˜ 25U^69	Medstat MarketScan database	HA-related ambulatory visits per 100,000 MarketScan enrollees	1996–1997 vs. 2004	20.9	8.7	– –Causal role for the vaccination program in decline is supported by greater decline in rate of HA ambulatory visits in vaccinating states vs. non-vaccinating states. – –Population somewhat homogeneous and not nationally representative. – –COI: n.r.

CDC: Centers for Disease Control and Prevention; CI: confidence interval; COI: conflict of interest; EU: ELISA units; HA: hepatitis A; NIS: National Inpatient Survey; n.r.: not reported; U: antigen units; UI: international unit; UMV: universal mass vaccination; US: United States; yr(s): years

^a Only industry-related conflicts of interest, funding source or financial disclosures reported

^b Outbreak in 2004, 27 cases of HA-associated fulminant hepatitis failure

^c Outbreak: 2 or more reported cases of HA illness occurring within a month of each other in a day care facility, kindergarten, primary school or junior high school

^d Extrapolated to nationwide hospitalizations using discharge weights

^e Vaccination of American Indian and Alaska Native children started in 1996

^f Vaccinating states: states with hepatitis A vaccination recommendations by the Advisory Committee on Immunization Practices (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, Washington) or considered (Arkansas, Colorado, Missouri, Montana, Texas, Wyoming) as of 1999

^g HA listed as any cause of death in record axis, of HIV as underlying cause of death and HA as any other cause in record or entity axis

^h HA listed as underlying cause of death

Table 3. Decline (%) in hepatitis A incidence by age group (years) before and after the introduction of universal vaccination.^a

			Decline in hepatitis A incidence (%, with p-value or 95%CI when available)
Reference; Country	Years compared (before UMV vs. with UMV)	Target age at 1st dose	Age groups with children younger than target age UMV program	Age groups with most vaccinated children	Other age groups	Oldest age groups
Vizzotti et al. 2014^27 Argentina	2000–2002 vs. 2006–2011	1 yr	Age < 1: n.r.	Age 0–4: 90.5% (p < 0.0001) Age 5–9: 89.1% (p = 0.0004)	Age 10–14: 86.6% (p < 0.0001) Age 15–44: 72.8% (p < 0.0019)	Age > 45: 58.1% (p = 0.0033)
Dagan et al. 2005^28 Israel	1993–1998 vs 2002–2004	1 yr	Age < 1: 84.3% (p < 0.005)	Age 1–4: 98.2% (p < 0.001) Age 5–9: 96.5% (p < 0.001)	Age 10–14: 95.2% (p = 0.01) Age 15–44: 91.3% (p < 0.001)	Age 45–64: 90.6% (p = 0.15) Age ≥65: 77.3% (p = 0.009)
Estripeaut et al. 2015^50 Panama	2000–2006 vs.2010	12–18 mo	Age < 1: 100.0%	Age 1–4: 95.1	Age 5–9: 97.8% Age 10–14: 96.6% Age 15–19:91.7% Age 20–24:90.2% Age 25–49: 88.9%	Age ≥50: 61.8%
Ly et al. 2015^45 All states, US	1999 vs. 2011	1 yr	Age <1: n.r.	Age 0–19: 95.9%	—	Age 20–39: 93.1%
Wasley et al. 2005^35 Vaccinating states^b, US	1990–1997 vs. 2003	2 yrs	Age < 2: 91.4% (95%CI 86.3–94.8)	Age 2–9: 95.6% (95%CI 94.8–96.1%) Age 10–18: 90.6% (95%CI 89.4–91.5%)	—	Age ≥19: 84.5% (95%CI 84.0–85.5)

CI: confidence interval; mo: months; UMV: universal mass vaccination; yr(s): year(s); n.r.: not reported; mo: months

^a Age-specific groups as reported in the articles. Only studies with age-specific data in the main text or tables (rather than graphs) are shown.

^b Vaccinating states: states in which HA childhood vaccination was recommend by the Advisory Committee on Immunization Practices (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, Washington) or considered (Arkansas, Colorado, Missouri, Montana, Texas, Wyoming) as of 1999

Vizotti et al describes a 1-dose vaccination program while the other publications refer to 2-dose vaccination programs.

Table 4. Long-term persistence of anti-hepatitis A antibodies.

Author Country	Intervention	Population	Number of participants	Outcome^a: % (95%CI) seroprotected	Outcome^a: GMC mIU/ml (95%CI)	Comments^b
Espul et al. 2014^52 Argentina	Avaxim˜ 80U Pediatric Gr1: 1 dose Gr2: 2 doses (schedule n.r.) Age at 1^st vacc: 11–23 mo	Healthy children. Ineligible for follow-up analyses if received additional dose of HA vaccine (Gr1: n=8; Gr2: n=1).	Gr1: 435 at 1 yr post-vaccination, 318 at 5 yr FU^c Gr2: 108 at 1 yr post-vaccination, 85 at 5 yr FU^c	At 5 yr FU, %≥10 mIU/mL: Gr1: 99.7% (98.3–100.0) Gr2: 100.0% (95.8–100.0)	At 5 yr FU: Gr1: 122.5 (111.2–135.0) Gr2: 591.7 (479.9–729.4)	Subjects whose anti-HAV IgG titres fell <10 mIU/mL at any of the scheduled visits were offered a booster vaccination. Sanofi Pasteur.
Lopez et al. 2015^68 Argentina	Avaxim˜ 80U Pediatric 2 doses (0, 6 mo)	Healthy children ≤ 15 years of age Ineligible for follow-up analyses if received additional dose of HA vaccine	54 at start, 30 at 14–15 yr FU^c	At 14–15 yr FU, %≥20 mIU/mL 100.0%	At 14–15 yr FU: 253 (181–353)	Sanofi Pasteur
Van Herck et al. 2015^73 Belgium	Gr 1: Epaxal˜ Junior Gr2: Epaxal˜ Gr3: Havrix˜ 720 EU 2 doses (0, 6 mo)	Healthy subjects	Gr1: 121 at start, 85 at 5.5 yr FU^d Gr2: 121 at start, 87 at 5.5 yr FU^d Gr3: 60 at start, 41 at 5.5 yr FU^d	At 5.5 yr FU, %≥10 mIU/mL: 100% At 5.5 yr FU, %≥20 mIU/mL: Gr1: 98.8% Gr2: 100% Epaxal˜ Gr3: 97.6%	At 5.5 yr FU: Gr1: 171 (141–207) Gr2: 241 (201–287) Gr3: 152 (109–213)	Crucell Switzerland
Bian et al. 2010^74 China	Havrix˜ 720 EU 2 doses (0, 6 mo) Mean age at 1^st vacc: 2.1 yrs	Children from Zhenhai District and Beilum District	200 at start, 110 at 10 yr FU^d	At 10 yr FU, %≥5 mIU/mL: 99.09%	At 10 yr FU: 61.59 (51.92–73.07)	Children were “selected” to receive Havrix or live attenuated vaccine, but selection criteria n.r. COI: n.r.
Yu et al. 2016 [ref] China	Gr1: Healive 250 U Gr2: Havrix˜ 720 EU(randomly allocated) 2 doses (0, 6 mo)	Healthy children	Gr1: 300 at start, 230 at 5 yr FU^c Gr2: 100 at start, 79 at 5 yr FU^c	At 5 yr FU, %≥20 mIU/mL: Gr1: 99.1% (96.9–99.9) Gr2: 97.5% (91.2–99.7)	At 5 yr FU: Gr1: 257.1 (226.9–291.4) Gr2: 168.1 (135.6–208.4)	COI: none
Dagan et al. 2016 [ref] Israel	Gr1: Epaxal˜ Jr (day 1) + RCV (day1) Gr2: Epaxal˜ Jr (day 1) + RCV (day 29) Gr3: Havrix˜ 720 EU (day 1) + RCV (day 1) (randomly allocated) 2 doses (0, 6 mo) Age at 1^st vac: 12–15 mo	Healthy children No HA vacc given during follow-up.	Gr1: 112 at start, 50 at 7.5 yr FU^d Gr2: 106 at start, 54 at 7.5 yr FU^e Gr3: 109 at start, 53 at 7.5 yr FU^d	At 7.5 yr FU, % (95%CI) ≥10 mIU/mL: Gr1: 98.0% (89.4–99.9 Gr2: 96.3% (87.3–99.5) Gr3: 96.2% (87.0–99.5)	At 7.5 yr FU: Gr1: 85 (64–111) Gr2: 80 (61–105) Gr3: 61 (47–79)	Janssen Vaccines AG
Raczniak et al. 2013 (JID)^51 US	Havrix˜ 360 EU^d 3 doses (schedule randomly allocated) Gr1: 0, 1, 2 mo Gr2: 0, 1, 6 mo Gr3: 0, 1, 12 mo Age at 1^st vacc: 3–6 yrs	Alaska Native children. Ineligible at 17 year follow-up if received a booster dose of HA vaccine (n=30)	Gr1: 49 at start, 23 at 17.3 yrs FU^d Gr2: 42 at start, 17 at 17.3 yrs FU^c Gr3: 45 at start, 18 at 17.3 yrs FU^c	At 17.3 yr FU, %≥20 mIU/mL: Gr1: 87% Gr2: 100% Gr3: 94%	At 17.3 yr FU: Gr1: 129 (61–270) Gr2: 235 (125–445) Gr3: 354 (143–880)	COI: none
Raczniak et al. 2013 (Vaccine)^56 US	Havrix˜ 720 EU or Vaqta˜ 720 EU 2 doses (0, 6–12 mo) Age at 1^st vacc: 1–4 yrs (50.5%), 5–9 yrs (31.7%), >10 yrs (17.8%)	Alaska Native children	101 at start, 57 at ≥11 yrs FU^d	At ≥11 yrs FU, %≥20 mIU/mL: 95%	≥13 to <15 yrs FU, by age at first dose^f: 1–2 yrs (n=5): 21 (6–77) 3–6 yrs (n=5): 80 (40–159) ≥7 yrs (n=1): 81	Participants were evaluated for follow-up only once (i.e. those evaluated before 11 years not counted in follow-up) COI: none
Spradling et al. 2016 [ref] US	Havrix˜ 720EU 2 doses (0 and 6 mo) Age at 1^st vacc (randomly allocated): Gr1: 6 mo Gr2: 12 mo Gr 3: 15 mo	Children who participated in immunogenicity study; enrolled from prenatal and pediatric clinics in Anchorage. Ineligible for long-term follow-up if received additional dose of HA vaccine (n=11)	Gr1: at start, 38 (20+, 18-) at 15–16 yrs of age Gr2: at start, 26 (17+, 9-) at 15–16 yrs of age Gr3: at start, 31 (19+, 12-) at 15–16 yrs of age	At 15–16 yrs of age, %>20 mIU/mL: Gr1-: 75% Gr1+: 61% Gr2-: 100% Gr+: 67% Gr3-: 100% Gr3+: 67%	At 15–16 yrs of age: Gr1-: 49 (31–77) Gr1+: 27 (16–44) Gr2-: 78 (49–123) Gr2+: 35 (14–87) Gr3-: 58 (37–90) Gr3+: 50 (24–103)	COI: none
Fiore et al. 2003^53 US	Havrix˜ 360 EU^d 3 doses (0, 2, 4 mo) Age at 1^st vacc: 2 mo	Infants in immunogenicity trial who responded to primary series Children who had received additional doses of HA vaccine since the 1991 study excluded (n=n.r.)	78 at start, 48 (31-, 17+) at 6.1 yrs FU^g	At 6.1 yrs FU, %≥33 mIU/mL: -: 68% +: 24%	At 6.1 yrs FU: -: 50 (31–81) +: 18 (10–32)	SmithKline Beecham Biological

CI: confidence interval; COI: conflict of interest; EU: ELISA units; FU: follow-up; Gr: group; HA: hepatitis A; HAV: hepatitis A virus; mo: months; n.r.: not reported; RCV: routine childhood vaccines; U: antigen units vacc: vaccination; yr(s): years;

^a + and – refer to maternal anti-HAV antibody status

^b Only industry-related COI, funding source or financial disclosures reported

^c After first dose

^d After second dose

^e This formulation is no longer available

^f ≥11 to <13 yrs FU, GMC by age at first dose: 1–2 yrs (n=26): 98 (66–147); 3–6 yrs (n=8): 298 (51–1749); ≥7 yrs (n=11): 211 (112–397). ≥15 years FU, age at first dose 3–6 yrs (n=1): 43 mIU/mL

^g After third dose

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