The immunogenicity and safety of GSK’s recombinant hepatitis B vaccine in adults: a systematic review of 30 years of experience

ABSTRACT

Introduction: Engerix B (GSK HepB, GSK, Belgium) was the first recombinant hepatitis B virus vaccine to be licensed, and marked its 30^th anniversary in 2016. Vaccination of adult populations against HBV is usually implemented on a risk-based approach with varying degrees of success. Confirmation of ongoing vaccine effectiveness requires monitoring the performance of HBV immunization as reported in individual studies, using systematic methods.

Areas covered: We conducted a systematic review of the literature to summarize 30 years of immunogenicity and safety data for GSK HepB in adult populations.

Expert commentary: Primary 3-dose vaccination of healthy individuals is generally associated with seroprotection rates of 90% or more, although seroprotection decreases with older age. Accelerated 0, 1, 2-month or 0, 7 and 21-day schedules require the recommended booster dose to achieve similar rates of seroprotection. Lower rates of seroprotection were also observed in adults with underlying chronic disease and with a weakened immune system. GSK HepB had a clinically acceptable safety profile in all of the populations studied, including individuals with underlying co-morbidities and immunosuppression. GSK HepB will continue to contribute to global HBV control for the foreseeable future. Further investigation is needed into how to optimize seroprotection in less immune-competent groups.

KEYWORDS:

• Adults
• hepatitis B
• immunocompromised
• immunogenicity
• seroprotection
• vaccines

1. Introduction

Hepatitis B is the most common liver infection worldwide and one-third of the global population is thought to have been infected [1]. The World Health Organization (WHO) estimates that more than 658,000 individuals die annually from hepatitis B virus (HBV)-related complications, such as fulminant hepatitis, cirrhosis, and liver cancer [2]. Chronic HBV infection is estimated to affect 240 million persons worldwide, most of whom reside in Asia and sub-Saharan Africa [2]. New HBV infections in adults occur via horizontal infection through sexual transmission, or exposure to contaminated blood products or needles. Approximately 2.6 million individuals are coinfected with human immunodeficiency virus (HIV) and HBV, and these individuals are at higher risk of HBV-associated morbidity and mortality [2].

The term ‘hepatitis B’ was first used in 1947. By 1965, the hepatitis B surface antigen (HBsAg) was identified by Blumberg (known initially as the Australia antigen) [3]. In 1971, Krugmen et al. showed that boiled plasma from an HBsAg carrier provided protection against HBV infection when injected into humans [4,5]. Ten years later, the first serum subunit vaccine produced from the blood of HBV carriers was available. A landmark trial conducted in men who have sex with men estimated the efficacy of a subunit vaccine produced by MSD as 92.3%, providing convincing evidence of the means to prevent HBV infection through vaccination [6]. Plasma-based vaccines were used widely more many years and were highly effective. However, the production process was time-consuming, was expensive, and was limited by available human plasma volumes and by the theoretical risk of possible human-to-human disease transmission, stimulating the search for alternative HBV vaccine technologies. To this end, several investigators including Rutter, Hall and colleagues in the United States, simultaneously identified the gene encoding HBsAg [7], and using an existing yeast cell model, successfully produced HBsAg from genetically altered yeast cells [8]. The recombinant HBsAg (a precursor of Recombivax™, MSD) was shown to protect chimpanzees from infection [9], and vaccine development for use in humans rapidly followed. The first recombinant HBV vaccine brought to the European market was Engerix™ B (GSK HepB, GSK, Belgium), closely followed by Recombivax™ in the United States, both licensed in 1986.

Initial immunization strategies for HBV control in industrialized countries were targeted toward high-risk groups (men who have sex with men, intravenous drug users, health-care workers (HCW), relatives of individuals with chronic HBV infection, sex workers). The impact of these programs was limited because high coverage of at-risk populations proved hard to achieve and had little or no impact on transmission, particularly in highly endemic areas. In 1991, the WHO resolved on a global approach to HBV control and recommended HBV vaccines be included into national immunization schedules everywhere, beginning with highly endemic countries [10]. Substantial gains in HBV infection control have been achieved over the last 25 years [11]. Nevertheless, the number of people expected to die between 2015 and 2030 due to HBV-related conditions is about 20 million, unless current response rates to HBV control can be improved or a curative treatment is licensed [2,12].

HBV vaccines have been widely used alone or in combination vaccines in childhood vaccination programs, and the impact of these programs on HBV-associated liver disease can be measured and are published [2–4]. On the other hand, HBV adult vaccination is still implemented on a risk-based approach, with varying degrees of success and coverage in different countries. Because the impact of adult HBV immunization in terms of long-term safety, immunogenicity, and effectiveness cannot be measured in the context of national programs, it is important to continue monitoring the performance of HBV immunization as reported in individual studies using systematic and unbiased methods.

Studies of vaccinated cohorts demonstrated that virtually all subjects with an anti-HBsAg antibody (anti-HBs) level of at least 10 mIU/ml were protected against HBV disease [13,14]. A postvaccination anti-HBs antibody concentration ≥ 10 mIU/ml is associated with the development of immune memory and confers long-term protection [14]. Individuals with low (<10 mIU/ml) or undetectable anti-HBs antibodies many years after vaccination respond robustly to challenge, indicating sustained immune memory responses [15,16]. Because of the long incubation period between exposure and development of HBV infection, immune memory responses are sufficient to provide prolonged protection [14].

GSK HepB has made a substantial contribution to HBV containment globally. Since launch, approximately 1.1 billion doses of GSK HepB have been distributed worldwide. The indicated adult dose of GSK HepB consists of three doses of 20μg HBsAg administered at 0, 1, and 6 months, respectively. Accelerated schedules may be given at 0, 1, and 2 months or at 0, 7, and 21 days, but require a booster dose at 12 months.

We conducted a systematic review of the literature to summarize 30 years of efficacy, effectiveness, immunogenicity, and safety data using GSK HepB in adult populations aiming to collate information in a systematic way for all adult populations in which GSK HepB is used.

2. Methods

2.1. Search strategy

The PubMed and Cochrane databases were searched for relevant literature published between 1980 and 21 September 2016 using a search string combining terms on HBV and immunogenicity (Appendix). The search was limited to articles in English, articles with an abstract available, and the geographical scope was worldwide. The study was based on PRISMA guidelines.

Due to the very large number of available articles, we made decisions that limited the search to a manageable size; we searched for ‘Engerix B’ in the title and abstract but limited key terms (anti-HBs, hepatitis B, vaccine, and immunogenicity) to the title. While this may have led to some articles being missed, the identified articles nevertheless provide a comprehensive overview of GSK HepB immunogenicity and safety.

2.2. Inclusion and exclusion criteria

Articles were included if they contained data relevant to the study objectives and if they were clinical trials or of cohort, case–control, or cross-sectional design. Case reports, editorials, letters, news, commentaries, and congress reports were excluded from the review. Articles were also excluded if they did not report separate data for GSK HepB, if they were genetic, biochemistry, molecular or treatment studies, studies on vaccination coverage, laboratory methods, or economic evaluations. Other exclusion criteria were Phase I/II trials, articles comparing administration routes, articles on a booster dose of GSK HepB after priming with another vaccine, and articles in which the sample size of the GSK HepB group was <100 in studies of the general population and <50 in special populations. Seroprevalence studies estimating vaccine effectiveness were not included if they did not have a control group.

2.3. Selection process and quality control

Titles and abstracts identified through the search strategy were assessed for their relevance to the study objectives. Full text articles were critically appraised and relevant articles underwent data extraction and reference lists were examined for additional articles. The first 30% of titles and abstracts were screened in duplicate by two independent researchers. There was less than 5.0% discrepancy between the two researchers.

2.4. Gray literature

The following sources were also accessed: World Health Organization, United States Centers for Disease Control and Prevention, European Center for Disease Prevention and Control, Eurosurveillance, and The EuroHep.Net project [17–21].

2.5. Quality assessment

Most studies were not of a classical design (for example cohort or case–control studies) which could be critically appraised using existing checklists. Therefore, no checklists were used to assess the quality of the articles or to calculate a total quality score. However, some articles were excluded based on their quality, for example, if the article presented a narrative review with no methods section that described the way the authors collected the literature. All systematic reviews were checked for relevant articles that may have been missed in our search.

2.6. Outcomes and definitions

The humoral antibody response to HBsAg is widely accepted as an immunological correlate of protection against HBV infection. In line with accepted guidelines, we defined seroprotection as being an anti-HBs antibody concentration ≥ 10 mIU/ml [13], but also report other cut-offs (100 and 1000 mIU/ml) when provided. We report anti-HBs for all time points provided in each article: usually 1 or 2 months after the final dose in the primary course, and after booster doses if administered. Long-term antibody persistence was defined as 5 or more years after the last vaccination.

3. Results

The search strategy was used to identify relevant articles across all age groups. In this paper we present immunogenicity and safety data for GSK HepB that pertains to adults. Results for children and adolescents are presented in another report.

We identified 66 unique articles (Figure 1) describing 64 studies of immunogenicity and/or safety data in adults. Eleven of these studies reported combined populations of adults and children, for which we present the adult data if available separately, or the combined results. Twenty-three articles reported on the immunogenicity of GSK HepB in the general population, and 43 in special populations at risk for HBV infection either due to increased exposure or to immunosuppression. Only two articles described long-term follow-up of 5 years or more: one study in a healthy cohort and one in institutionalized adults with an intellectual disability [22,23]. Key study characteristics for all included articles are provided in the supplementary table. No relevant data were found in the gray literature. There were no studies reporting on the effectiveness of GSK HepB in adults.

Figure 1. PRISMA diagram.

3.1. Immunogenicity in the general population

3.1.1. Standard schedule and dose

Fourteen articles reported seroprotection (defined as anti-HBs antibody levels ≥ 10 mIU/ml) rates between 4 weeks and 8 months post-dose 3 following a 0-, 1-, and 6-month schedule (Table 1). In 10 articles, the seroprotection rate post-dose 3 was >90.0%. Very high seroprotection rates and geometric mean antibody concentrations (GMC) were observed in a study conducted in medical students in Italy [24]. The high response may be because the population was young adults, and three-quarters of subjects were women, in whom high responses to HBV have been documented [25]. One study in medical students only reported seroprotection rates before complete vaccination, these were 20.0%, 61.0%, and 82.0% at month 1, 2, and 3, respectively [26]. In one of these studies with long-term persistence data, the rate of seroprotection 6.5 years after vaccination was 85.6% [22].

Table 1. Immunogenicity of GSK HepB in adults in the general population.

Author	Immunized subjects (N) study population; country; Age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b						GMC (mIU/ml)
Standard schedule and dose
Treadwell, 1993 [27]	Healthy adults (N = 199); USA; 39-70y	3 doses at 0, 1, 6 m	20 µg	1	12						6.9
				3	63						37.8
				6	73						54.4
				8	91						836.6
Bock, 1996 [28]	Healthy adolescents or adults (N = 855); Germany; mean: 28.0 y	3 doses at 0, 1, 6 m	20 µg	4–6 wks post-dose-3	97.8						1989
Chiaramonte, 1996 [24]	Healthy medical students (N = 251); Italy; mean (range): 22.1 y (16–35)	3 doses at 0, 1, 6 m	20 µg	7	99.6						22,601
Levie, 2002 [29]	Healthy adults (N = 148); Belgium; mean (range): 22.6 y (16–40)	3 doses at 0, 1, 6 m	20 µg	1	20.4						9
				2	77.0						33
				6	92.6						137
				7	99.3						6274
				12	98.6						1883
Demoraes, 2010 [30]	Policemen (N = 203); Brazil; 31-40y	3 doses at 0, 1, 6m	20 µg	7	95.6						11,673
					>100 mIU/ml				10–100 mIU/ml
					84.7				10.8
Gilbert, 2011 [31]	Healthy, older adults (N = 165); Canada, Denmark, Sweden, UK; mean (range): 59.8 y (50–89)	3 doses at 0, 1, 6m	20 µg	7	≥50 y		50–64 y			≥65 y	≥50 y			50–64 y		≥65 y
					84.0		88.5			67.7	187.9			409.1		86.3
Sablan, 2012 [32]	Healthy adults ≥40 y (N = 204); Korea, the Philippines, Singapore; mean: 49.1 y	3 doses at 0, 1, 6 m	20 µg		≥10mIU/ml				≥100mIU/ml
				Wk 4	3.4				-		-
				Wk 8	24.0				-		-
				Wk 28	73.1				58.0		94.307
				Wk 50	68.6				43.5		33.850
Heyward, 2013 [33]	Healthy adults (N = 359); Canada, USA; mean (range): 54.0 y (40–70)	3 doses at 0, 1, 6 m	20 µg	Wk 4	4.5						-
				Wk 8	20.3						-
				Wk 12	17.0						-
				Wk 18	19.5						-
				Wk 24	21.4						-
				Wk 28	72.8						-
				Wk 32	70.5						61.4
				Wk 36	65.5						-
				Wk 44	59.8						-
				Wk 52	59.0						-
Vermeiren, 2013 [34]	Adults (N = 11,439); The Netherlands; mean (range): 29 y (16–70)	3 doses at 0, 1, 6 m	20 µg	35 days	-								16 y	35 y	65 y	70 y
											Men		793	362	50	-
											Women		883	-	-	235
Rendi-Wagner, 2001 [35]	Healthy adolescents and adults seeking pre-travel immunization advice (N = 155); Austria; mean: 43.4 y	3 doses at 0, 1, 6 m, booster at 12 m	20 µg	4 wks to 5 y post-dose-3	15–30 y	30–50 y		50–60 y	>60 y	Total	15–30 y		30–50 y	50–60 y	>60 y	Total
					95^b	93^b		88^b	73^b	85^b	1437		738	451	96	523
Joines, 2001 [36]	Healthy adults (N = 269); USA; mean (range): 40.4 y (19–83)	3 doses at 0, 1, 6 m (Engerix-B^TM + Havrix^TM)	20 µg	1	7.5						6
				2	50.4						18
				6	75.7						45
				7	92.2						1871
Van der Wielen, 2006 [37]	General population (N = 182); Belgium, Czech Republic, Germany; >40 y	3 doses at 0, 1, 6 m (Engerix-B^TM + Havrix^TM)	NR	23–40 days post-dose-3	79.7						491
Martins, 2004 [38]	Adults (N = 486); Brazil; NR	3 doses at 0, 1, 6 m	20 µg	28–100 days post-dose-3	20–30 y				31–40 y		20–30 y				31–40 y
					95.5 (94.5 male, 97.8 female)				92.4 (91.5 male, 95.6 female)		1369.0				686.2
Tregnaghi, 2010 [39]	Adults 16–45 y (N = 166); Argentina, Uruguay; mean: ±30 y	3 doses at 0, 1, 6 m	20 µg	1	0.0						-
				2	55.0
				6	70.0
				7	95.9
Ayerbe, 2001 [22]	Healthy cohort immunized between 1990 and 1992 (N = 462); Spain; mean (range): 33 (6–90) y	3 doses at 0, 1, 6 m	20 µg/10 µg for children <15 y	7	96.6						411.15
				Y6.5	85.6						101.65
Harries, 1991 [26]	Healthy first-year medical students (N = 120; UK; mean 19.0 y	3 doses at 0, 1, 6 m	20 µg		>10 IU/L				≥100 IU/L		-
				1	20
				2	61
				3	82				8
Wang, 2016 [40]	Healthy adults 25-25 y (N = 293); China; Mean: 41.24 y	3 doses at 0, 1, 6 m	20 µg	8	93.17						1033.38
Standard schedule and alternative dose
Tregnaghi, 2010 [39]	Adults 16-45 y (N = 166); Argentina, Uruguay; mean ±30 y	3 doses at 0, 1, 6 m	10 µg	1	0.0							-
				2	73.9
				6	95.2
				7	99.4
Alternative schedule and standard dose
Young, 2001 [41]	Healthy adults (N = 199); USA; 18-64y	3 doses at 0, 1, 2 m	20 µg		Younger (<40) adults				Older (>40) adults		Younger (<40) adults				Older (>40) adults
				Within 3 m	77				62		116				126
				1	5						-
				2	38						-
				3	71						-
Harries, 1991 [26]	Healthy first-year medical students (N = 132); UK; mean: 18.9 y	3 doses at 0, 2, 6 wks	20 µg		>10 IU/L				≥100 IU/L		-
				1	40
				2	73
				3	87				43
Nothdurft, 2002 [42]	Healthy adults (N = 192); Germany, UK; mean: 26.9 y	3 doses at 0, 7, 21 days, booster at 12 m	20 µg (+Havrix™)	1	83.9						98
				2	84.9						58
				3	90.8						131
				12	91.6						106
				13	100						29,196
Connor, 2007 [43]	Healthy adults (N = 197); Belgium, Czech Republic, Norway, USA; NR	3 doses at 0, 1, 2 m, booster at 12 m	20 µg (+Havrix™)	Day 37	43.5						7.5
				3	76.7						52.2
				12	77.8						-
				13	93.4						4380.9
Rodrigo, 1992 [44]	Family members of intravenous heroin addicts (N = 271); Spain; mean: 24.2 y	3 doses at 0, 1, 2 m	20 µg	3	80.0						69.1
Rustgi, 1995 [45]	Healthy adults (N = 110); USA; mean 29.1 y	3 doses at 0, 1, 2 m booster at 12 m	20 µg	3	~85^c						~100^c
				13	~95^c						~8000^c
Bock, 1995 [46]	Healthy adults (N = 306): Germany; mean: 27.0y	3 doses at 0, 28, 56 days, booster at 12m	20 µg	2	~65^c						~75^c
				13	~96^c						>10,000^c
		0, 14, 28 days, booster at 12 m	20 µg	2	~79^c						~75^c
				13	~99^c						>10,000^c
		0, 7, 21 days, booster at 12 m	20 µg	2	~77^c						~75^c
				13	~98^c						>10,000^c

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; N: number of subjects; NR: not reported; UK: United Kingdom; USA: United States of America; y: years; m: months; wks: weeks; Y; year; Wk: week; -: not reported; Havrix™: hepatitis A vaccine.

^aThe blood sampling time point is given in months unless otherwise indicated; ^bAll rates are seroprotection defined anti-HBs ≥10 mIU/ml unless clearly stated otherwise; ^cResults presented graphically.

Seroprotection rates <90.0% were reported in one study that enrolled 50- to 89-year-old adults (84.0% in ≥50 year olds and 67.7% in ≥65 year olds [31]), and in three studies in adults aged ≥40 years (73.1% in a study conducted in three Asian countries [32], 72.8% in Canada [33], and 79.7% in three European countries [37]). In all studies with data stratified by age or gender, seroprotection rates were lower in men than in women and progressively decreased as age increased [31,34,35,38].

The percentage of subjects with anti-HBs antibody concentrations ≥10 mU/ml after 1 year was reported in two articles; 59.0% in adults aged ≥40 years at the time of vaccination, and 98.6% in adults aged 16–40 years at the time of vaccination [29,33].

3.1.2. Standard schedule with alternative dose

Using a pediatric dose of 10 µg administered at 0, 1, and 6 months of age, 99.4% of 16- to 45-year-old subjects had anti-HBs concentrations ≥10 mIU/ml 1 month after the third dose [39] (Table 1).

3.1.3. Alternative schedule and standard dose

Six articles reported on the immunogenicity of GSK HepB using the accelerated 0-, 1-, 2-month (0, 28, and 56 day) or 0-, 7-, 21-day schedules [41–46] (Table 1). Additional studies also investigated a 0-, 2- and 6-week schedule in medical students [26], and a 0-, 14-, and 28-day schedule in adults [46].

One month after the third vaccine dose, the percentage of subjects with anti-HBs concentrations ≥10 mIU/ml was approximately 65.0–85.0% using the 0-, 1-, 2-month schedule, approximately 77.0–90.8% using the 0-, 7-, 21-day schedule, 87.0% using the 0-, 2-, 6-week schedule, and around 79.0% after the 0-, 14-, 28-day schedule (Table 1). In four studies in which the recommended booster dose was administered after the third priming dose, the seroprotection rate 1 month post-booster was 93.4–100%. In one study with data stratified by age, seroprotection was higher in adults <40 years than in adults 40 years or older [41].

3.2. Immunogenicity in HCW

3.2.1. Standard schedule and dose

Five articles reported on the immunogenicity of GSK HepB in HCW when used according to the standard dose and schedule [47–51] (Table 2). One month (or at an unspecified time) after dose 3, the percentage of subjects with anti-HBs concentrations ≥ 10 mIU/ml was ≥90.0% in four studies. The post-dose 3 seroprotection rate was 86.2% among 666 HCW in Pakistan, and 86.0% in HCW in the United Kingdom. There were 14.0% nonresponders in Pakistan; however, these results are difficult to interpret because anti-hepatitis B core antibody could not be assessed prior to enrolment, and occult HBV infection could not be ruled out [51]. In the UK study, 8.5% were nonresponders and significantly lower post-dose 3 GMCs and lower seroprotection rates were observed in males compared to females [50]. In other studies with data stratified by age or gender, anti-HBs responses were lower as age increased, and in men [47–49]. One year after vaccination of HCW in Germany, 93.0% retained anti-HBs concentrations ≥ 10 mIU/ml.

Table 2. Immunogenicity of GSK HepB in adult HCW.

Author	Immunized subjects (N) study population; country; Age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b				GMC (mIU/mL)
Standard schedule and dose
Rogan, 1991 [50]	HCW who come into contact with blood/blood products (N = 129); UK; mean (range) men: 40.36 y (22–62), mean (range) women: 39.9 y (20–65)	3 doses at 0, 1, 6 m, non- and poor-responders received booster doses	20 µg	Between 8–12 wks post-dose-3	20–29^a	30–39^a	40–65^a	All	Males	Females
					Males 90 Females 100	Males 30 Females 95	Males 80 Females 85	86	317.9	706.2
				8–12 wks after booster	Poor responders (<10 mIU/mL)		Nonresponders (Titer not detected)		Poor responders (<10 mIU/mL)	Nonresponders (Titer not detected)
					100		36		164	41.2
Averhoff, 1998 [47]	HCW (N = 875); USA; mean: 41.2y	3 doses at 0, 1, 6 m	20 µg	NR	<40 y		≥40 y		<40 y	≥40 y
					92		87		2138	1000
Knoll, 2000 [48]	Medical students, staff members (N = 148); Germany; mean (range) anti-HAV negative: 22 y (18–39),mean (range) anti-HAV positive: 26 y (17–39)	3 doses at 0, 1, 6 m	20 µg	7	Anti-HAV negative		Anti-HAV positive		Anti-HAV negative	Anti-HAV positive
					99 Men 99 Women 100		100 Men 100 Women 100		7826 Men 7,280 Women 9783	8813 Men 4406 Women 20,960
Zeeshan, 2007 [51]	HCW (N = 666); Pakistan; 39.4% <25 y, 47.7% 25–34 y, 11.2% 35–49 y, 1.7% ≥50 y	3 doses at 0, 1, 6 m	20 µg	6–8 wks post-dose-3	86.2				-
Hess, 1992 [52]	Medical students, HCW (N = 141); Germany; mean (range): 28 y (18–73)	3 doses at 0, 1, 6 m	20 µg	1	18				8.3
				3	70				40.0
				6	76				55.3
				7	96				2877
				12	93				442
Palmovic, 1994 [49]	HCW (N = 1,250); Croatia; NR	3 doses at 0, 1, 6 m	20 µg	7	10.1-100 mIU/ml	100.1-1000 mIU/ml		>1000 mIU/ml	-
					5	44		45
Alternative schedule and standard dose
Hess, 1992 [52]	Medical students, HCW (N = 143); Germany; mean (range): 28 y (18–73)	3 doses at 0, 1, 12 m	20 µg	1	32				11.6
				2	59				40.0
				3	82				160
				7	90				173
				12	83				97
				13	94				5608
				18–19	92				1889

Anti-HAV +ve/–ve: antibodies to hepatitis A virus positive/negative; Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; HbsAg: hepatitis B surface antigen; HCW: health-care workers; UK: United Kingdom; N: number of subjects; NR: not reported; y: years; m: months; wks: weeks; -: not reported

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

3.2.2. Alternative schedule and standard dose

GSK HepB administered to medical students and HCW at 0, 1, and 12 months induced seroprotective antibodies in 94.0% 1 month post-dose 3 [52] (Table 2).

3.3. Immunogenicity in patients with chronic renal disease (predialysis and patients receiving dialysis)

Patients with chronic renal failure (CRF) and those undergoing dialysis are known to respond suboptimally to HBV vaccines [5]. Current recommendations indicate that these individuals should receive a higher dose and/or more doses of recombinant HBV vaccines than healthy individuals [53,54]. In this section, studies describing immunogenicity after three double doses (40 µg HBsAg) of GSK HepB, which is the indicated dosage in this population, are considered as the standard schedule and dose.

3.3.1. Standard schedule and dose

Using a 3-dose schedule and 40 µg HBsAg, the seroprotection rate in patients with CRF or in patients undergoing hemodialysis ranged from 60.9% to 85.5% (blood sampling time point ranging from 1 to 8–12 months post-dose 3, and unknown in one study) [55–57] (Table 3). One study stratified immunogenicity by the glomerular filtration rate (GFR) and showed that the percentage of subjects with anti-HBs concentrations ≥ 10 mIU/ml decreased as GFR decreased [57]. The seroprotection rate 8–12 weeks post-dose 3 when the GFR was <15 ml/min was 67.0% in patients not receiving dialysis, versus 79.0% in those who had commenced dialysis [57]. In one study, the seroprotection rate was 100% in patients <40 years of age, 75% in 40–60-year-olds, and 74% in those >60 years of age [58].

Table 3. Immunogenicity of GSK HepB in adults with chronic renal disease (predialysis and [hemo]dialysis).

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b					GMC (mIU/ml)
Standard schedule and dose
Fleming, 1991 [59]	Patients with CRF undergoing dialysis (N = 83); Australia; mean (range): 65 y (19–77)	3 doses at 0, 1, 6 m nonresponders received a double dose at month 9	20 µg 40 µg (booster)	6 wks post-dose-3	32.5					-
Standard schedule and alternative dose
Fernandez, 1996 [55]	Patients with end-stage CRF on maintenance hemodialysis (N = 64); Spain; mean responders: 52.9 y, mean nonresponders: 65.3 y	3 doses at 0, 1, 6m	40 µg	NR	60.9					-
Sorkhi, 2008 [56]	Hemodialysis patients (N = 62); Iran; mean (range): 50.95 y (10–79)	3 doses at 0, 1, 6 m	40 µg		10-99 mIU/ml		>100 mIU/ml			-
				7	85.5		49.1
Hashemi, 2011 [57]	Patients with CRF and hemodialysis patients (N = 167); Iran; NR	3 doses at 0, 1, 6 m	40 µg	8–12 wks post-dose-3	78
					Glomerular filtration rate					Glomerular filtration rate
					30–59 ml/min	15–29 ml/min		<15 ml/min		30–59 ml/min	15–29 ml/min		<15 ml/min
					80 (predialysis)	76 (predialysis)		67 (no dialysis) 79 (on dialysis)		150.6 (predialysis)	115.5 (predialysis)		77.9 (no dialysis) 84.4 (on dialysis)
Alternative schedule and dose
Rault, 1995 [60]	Hemodialysis patients (N = 50); USA; mean (range): 51 y (20–93)	4 doses at 0, 1, 2, 6 m nonresponders received a second course of vaccination	40 µg	Post-course 1	74					-
				Post-course 2	84
Peces, 1997 [58]	Stable hemodialyzed patients (N = 80); mean patients: 58.5 y	4 doses at 0, 1, 2, 6 m	40 µg		≥10 mIU/ml		>100 mIU/ml			In responders only (>10 mIU/ml)
				7	77.5		72.5			3466
				13	70.8		61.0			2435
				18	70.0		46.0			1419
				24	66.7		48.7			816
					<40	40–60		>60
					100	75		74
Sezer, 2000 [61]	Hemodialysis patients (N = 50); Turkey; mean: 50.51 y	4 doses at 0, 1, 2, 6 m	40 µg	7		0–10 mIU/ml	10–99 mIU/ml		≥100 mIU/ml	-
						20	36		44
				18	0–10 mIU/ml	90^c	39		4.5
					10–99 mIU/ml	10	61		41
					≥100 mIU/ml	0	0		54.5
Bel’eed, 2002 [62]	Patients with end-stage CRF (N = 247); UK; mean hemodialysis: 59 y, mean peritoneal dialysis: 52.6 y, mean predialysis: 60.5 y, mean failing transplant: 37.7 y	4 doses at 0, 1, 2, 3 m booster doses were given every 3 m to patients not reaching >100 IU/L	40 µg	6		>100 mIU/ml	10–100 mIU/ml	<10 mIU/ml	Undetected	-
						31	33	8	28
				16 (post-booster)	>100 mIU/ml	37^d	43	1	19
					10–100 mIU/ml	0	44	4	52
Tong, 2005 [63]	Pre-dialysis and hemodialysis patients (N = 83); Spain, Czech Republic, Malaysia; mean: 58.6 y	4 doses at 0, 1, 2, 6 m	40 µg		≥10 mIU/ml			≥100 mIU/ml
				1	4.8			2.4		28.7
				2	21.7			7.2		55.8
				3	52.4			15.9		50.1
				6	66.2			35.1		89.5
				7	84.4			67.5		933.0
				12	77.1			54.3		320.8
				24	70.2			47.4		253.8
				30	60.4			37.7		111.9
				36	52.0			36.0		99.6
Lin, 2011 [64]	Dialysis patients (N = 156); China, Taiwan; mean hemodialysis: 60.9 y, mean peritoneal dialysis: 51.7 y	4 doses at 0, 1, 2, 6 m	40 µg	7	70.5					43.3
				Y1	-					13.9
				Y2	-					11.3
				Y3	-					5.8
				Y4	-					4.2
				Y5	-					0.7
Nahar, 2011 [65]	Patients with chronic kidney disease (N = 50); Bangladesh; mean (range): 46.52 y (20–70)	3 doses at 0, 1, 2 m booster dose was given at month 6 if titer was <100 mIU/ml	40 µg		Total response rate	10–100 mIU/ml		>100 mIU/ml		-
				3	44	38		6
				7 (post-booster)	80	32		48
Gilbert, 2014 [66]	Dialysis and predialysis patients (N = 138); Canada, Italy, Spain, UK; mean: 69.2 y	4 doses at 0, 1, 6, 8m	40 µg		Dialysis patients		Predialysis patients			Dialysis patients		Predialysis patients
				7	57.7					48.7
					52.7		62.5			42.3		56.1
				9	69.2					115.8
					64.0		74.1			91.8		146.1
Janssen, 2015 [67]	Chronic kidney disease patients (N = 160); Canada, Germany, USA; mean: 63 y	4 doses at 0, 1, 2, 6 m	40 µg	7	76.7					-
				9	76.4
				11	75.0
				13	73.3
Garcia-Agudo, 2012 [68]	Chronic kidney disease patients evaluated for renal transplantation (N = 155); Spain; mean: 65 y	4 doses at 0, 1, 2, 6 m nonresponders received second vaccination course	40 µg		≥10 mIU/ml	10–99 mIU/ml	100–999 mIU/ml	>1000 mIU/ml		-
				Post-dose 1	5.4	-	-	-
				Post-dose 2	29.5	-	-	-
				Post-dose 3	66.7	-	-	-
				Post-dose 4	75.9	12	30.1	34.9
				Post-dose 5	83.3	-	-	-
				Post-dose 6	87.3	-	-	-
				Post-dose 7	92.5	-	-	-
				Post-dose 8	93.8	7.7	46.2	15.4

Anti-HBs: antibodies to hepatitis B virus; CRF: chronic renal failure; GMC: geometric mean concentration; N: number of subjects; NR: not reported; UK: United Kingdom; USA: United States of America; y: years, m: months; Y; year; -: not reported.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

^cOf the participants who had antibody titers of 10–100 mIU/ml at month 7, 90% had antibody titers of 10–100 mIU/ml at month 18.

^dOf the participants who had antibody titers > 100 mIU/ml at month 6, 37% had antibody titers > 100 mIU/ml at month 16.

3.3.2. Standard dose and alternative schedule

Ten studies reported on the immunogenicity of 40 µg HBsAg (double-dose of GSK HepB) in different multidose schedules (Table 3). Seven of these studies assessed one or two consecutive 4-dose schedules at 0, 1, 2, and 6 months in patients with chronic renal disease and patients undergoing dialysis (peritoneal or hemodialysis) [58,60,61,63,64,67,68]. In five studies, the seroprotection rate after four doses was 70.5–84.4% [58,61,63,64,67]. In two studies, the seroprotection rates were 74.0% and 75.9% after four doses, and increased to 84.0% and 93.8% overall after a second course of four immunizations administered to nonresponders [60,68]. Three studies measured antibody persistence at month 12 or 13; the seroprotection rate ranged from 70.8% to 77.1% [58,63,67], decreasing to 66.7% and 70.2% after 2 years (two studies [58,63]), and 52.0% after 3 years (one study [63]).

Other four-dose schedules using 40 µg HBsAg included a UK study in which patients were immunized at 0, 1, 2, and 3 months, a multi-country study that assessed a 0-, 1-, 6-, 8-month schedule, and a study in Bangladesh that administered three doses at 0, 1, 2 months and a booster dose at month 6 if the antibody concentration was <100 mIU/ml. The percentage of subjects with anti-HBs concentrations ≥10 mIU/ml was 64.0%, 69.2%, and 80.0% (post-booster) in the respective studies [62,65,66].

One study explored three doses of 20 µg HBsAg in patients with CRF undergoing dialysis [59]. The percentage of subjects with anti-HBs concentrations ≥10 mIU/ml was 32.5% (6 weeks post-dose 3) (Table 3).

3.4. Immunogenicity in adults with type 2 diabetes mellitus

One controlled study was conducted in adults with and without type 2 diabetes mellitus [69] (Table 4). Participants had normal renal function and received GSK HepB in a standard dose and schedule. One month post-dose 3, the seroprotection rate was 75.4% in diabetic participants and 82.0% in controls matched for age and body mass index (BMI) (not statistically significant). Subjects were less likely to achieve seroprotection if they had an increased BMI and if they were of older age [69]. Among adults less than 40 years of age, the seroprotection rate was 88.5% in diabetic participants and 100% in controls, versus and 58.2% and 70.2%, respectively, in those aged 60 years or more.

Table 4. Immunogenicity of GSK HepB in adult transplant recipients and adults with type 2 diabetes mellitus.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b				GMC (mIU/ml)
Transplant recipients
Alternative schedule and dose
Arslan, 2001 [70]	Liver transplant recipients who underwent orthotropic liver transplantation (N = 356); USA; mean (range): 48.9 y (3 m–71 y)	4 doses at 0, 2, 4, 24 wks	40 µg		Total response rate	>10 mIU/ml		>100 mIU/ml
				Day of OLT	36	90^c		54^d	86.7
				1Y after OLT	11.6	61^c		47^d	0.32
				2Y after OLT	8	54^c		77^d	0.33
Feng, 2013 [71]	Liver transplant recipients (N = 50 group A, N = 45 group B), liver transplant recipients who received no vaccination (N = 95); China; mean group A: 53.6 y, mean group B: 52.6 y, mean control: 52.7 y	A) 7 doses at 0, 1, 2, 3, 4, 5, 6 m	40 µg (first 4 doses) 20 µg (last 3 doses)	NR	24.6 (responders > 60 mIU/ml)				-
		B) 7 doses at 0, 7, 14, 28 days and 2, 3, 4 m			8.8 (responders > 60 mIU/ml)
Adults with type 2 diabetes mellitus
Standard schedule and dose
Van der Meeren 2016 [69]	Subjects with type-2 diabetes mellitus diagnosed within the past 5 y and healthy controls (N = 378, N = 189 controls); Australia, Canada, New Zealand, USA; Mean (SD) diabetes: 53.7 (12.07) y, Mean (SD) controls: 53.1 (12.88) y	3 doses at 0, 1, 6 m	20 µg	7		Diabetes patients	Controls	Diabetes patients	Controls
					≥6.2 mIU/ml	77.5	84.7	147.6	384.2
					≥10 mIU/ml	75.4	82.0
					≥100 mIU/m	53.7	71.4
					20–39 y	88.5	100
					40–49 y	81.2	86.4
					50–59 y	83.2	82.3
					60+ y	58.2	70.2

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; OLT: orthotropic liver transplantation; USA: United States of America; y: years; m: months; wks: weeks: Y: year; N: number of subjects; -: not reported; NR: not reported; SD: standard deviation.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

^cOf the patients with detectable anti-HBs.

^dOf the patients with anti-HBs > 10 mIU/ml.

3.5. Immunogenicity in transplant recipients

Two studies reported on the immunogenicity of GSK HepB in transplant recipients. Both studies used an alternative schedule and dose [70,71] (Table 4). In patients who underwent orthotropic liver transplantation, four doses (40 µg HBsAg) of GSK HepB at 0, 2, 4, and 24 weeks induced a seroprotection rate of 36.0% prior to transplantation, which decreased to 11.6% and 8.0%, after 1 and 2 years post-transplant, respectively [70]. Multivariate analysis suggested that antibody persistence post-transplant may be influenced by genetic predisposition (HLA type) underlying liver disease and severity of disease. The impact of immunosuppressants was not analyzed [70].

In the second study, liver transplant recipients received a 7-dose rapid schedule (0, 1, 2, 3, 4, 5, 6 months) or an accelerated schedule at 0, 7, 14, 28 days and 2, 3, 4 months (both schedules administered 40 µg HBsAg for the first four doses and 20 µg HBsAg for the last three doses). Response rates (defined as anti-HBs antibody concentrations > 60 IU/L) of the rapid and accelerated schedule were 24.6% and 8.8%, respectively (time point for testing not reported) [71]. Multivariate analysis did not find evidence that demographic features, underlying indication of transplant, donor type, antiviral regimen, immunosuppressant, CD4+ count, or hepatitis B immunoglobulin dose influenced the response to vaccination [71].

3.6. Immunogenicity in adults with liver disease

Two studies assessed GSK HepB in patients with liver disease patients using a 40 µg HBsAg dose administered at 0, 1, and 2 months (Table 5). Nonresponders either received a second vaccination course [72], or a fourth dose of 80µg HBsAg [73]. The first study reported a seroprotection rate of 44.0% after the first three doses and 62.0% after the second vaccination course [72]. In the second study, the seroprotection rate was 62.0% (time point not reported). A total of 61.0% of the group who received a fourth dose seroconverted after the booster [73].

Table 5. Immunogenicity of GSK HepB in adults with liver disease.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b		GMC (mIU/ml)
Alternative schedule and dose
Dominguez, 2000 [72]	Patients with decompensated liver cirrhosis (N = 50); Spain; mean (range): 52 y (18–65)	3 doses at 0, 1, 2 m nonresponders received a second vaccination course	40 µg	3	44		-
				10 (after second vaccination course)	62
Demaria, 2001 [73]	Chronic liver disease patients (N = 222); USA; NR	3 doses at 0, 1, 2 m nonresponders were given a fourth dose	40 µg 80 µg (booster)	NR	>10 mIU/ml	>100 mIU/ml	All patients	Chronic active hepatitis patients	Cirrhosis patients
					All patients
					62	42	39.9	41.7	33.6
					Chronic active hepatitis patients
					74	49
					Cirrhosis patients
					42	30
				Post-booster dose	61^c		-	-	-

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; USA: United States of America; y: years; m: months; N: number of subjects; -: not reported; NR: not reported.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

^cCalculated based on the subjects who received the booster.

3.7. Immunogenicity in adults with inflammatory bowel disease (IBD)

3.7.1. Standard schedule and dose

Using the standard dose and schedule in patients with IBD, a seroprotection rate of 60.0% was reported 1–3 months post-dose 3 in a cohort of whom 70.0% were receiving immunosuppressive drugs [74] (Table 6). Univariate analysis showed that the response rate was lower in patients receiving immunosuppressive therapy, but this was not confirmed in the multivariate analysis.

Table 6. Immunogenicity of GSK HepB in adults with IBD.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b			GMC (mIU/ml)
Standard schedule and dose
Belle, 2015 [75]	Patients with IBD (N = 96), France; 44.9 y	3 doses at 0, 1, 6 m	20 µg	2 m post-dose-3	>10 IU/L	>100 IU/L	253.9
					80.2	45.8
Gisbert, 2012 [74]	Patients with IBD (N = 68); Spain; mean: 40 y	A) 3 doses at 0, 1, 6 m^c	20 µg	1–3 m post-dose-3	41	22
Alternative schedule and dose
Gisbert, 2012 [76]	Patients with IBD (N = 241); Spain; mean: 44 y	3 doses at 0, 1, 2 m. Patients with titers <100 mIU/ml received a second vaccination course	40 µg		>10 IU/L	>100 IU/L	>10 IU/L		10–100 IU/L	>100 IU/L
				1–3 m post-dose-3	59	39	373		47	549
				1–3 m post-dose-6	79	65	-		-	-
Gisbert, 2012 [74]	Patients with IBD (N = 80); Spain; mean: 40 y	B) 3 doses at 0, 1, 2 m^c	40 µg	1–3 m post-dose-3	75	55

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; y: years; m: months; N: number of subjects; -: not reported.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

^cIn the article, it is stated that patients with titers <100 mIU/ml received a second vaccination course; however, these results are not presented.

In a study that enrolled patients with IBD and healthy controls, the seroprotection rate in patients with IBD was 80.2% 2 months post-dose 3 compared with 94.1% in healthy controls [75]. Ileal disease was the only factor associated with a lower vaccine response in the multivariate analysis.

3.7.2. Alternative schedule and dose

Two studies evaluated three doses of 40 µg HBsAg (double-dose of GSK HepB) administered at 0, 1, and 2 months [74,76] (Table 6). The seroprotection rate was 59.0% and 75.0% 1–3 months post-dose 3. In one of the studies, a second course was administered to patients with post-dose 3 concentrations < 100 mIU/ml. The cumulative percentage of patients with anti-HBs concentrations ≥ 10 mIU/ml was 79.0% after the second course [76]. Older age and receipt of anti-tumor necrosis factor agents were associated with a lower response to immunization.

3.8. Immunogenicity in adults with HIV

3.8.1. Standard schedule and dose

In three studies that assessed GSK HepB administered according to the standard schedule and dose to patients with HIV, the seroprotection rate >2 weeks to 2 months post-dose 3 ranged from 34.0% to 62.6% [77–79] (Table 7). One study reported a seroprotection rate of 41.4% at week 72 (48 weeks after the third vaccination) [77]. Pollack et al. identified the CD4 T-cell count at commencement of vaccination as the only predictor of response [79]. The seroprotection rate decreased progressively as the CD4 T-cell count decreased, from 79.7% in patients with a CD4 count ≥300 cells/ml to 37.5% when the CD4 count was <100 cells/ml.

Table 7. Immunogenicity of GSK HepB patients with HIV infection.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a(m)	Anti-HBs response
					% Seroprotection^b	GMC (mIU/ml)
Standard schedule and dose
Fonseca, 2005 [78]	Adults with HIV (N = 94 20 µg, N = 98 40 µg); Brazil; mean 37 y	3 doses at 0, 1, 6 m	20 µg	7–8	34	-
Flynn, 2011 [77]	HIV infected youth age 12–<25 y (N = 106 20 µg, N = 112 40 µg); Bahamas, Brazil, South Africa and the USA; mean 20 µg: 20.49 y, mean 40 µg: 20.82 y	3 doses at 0, 1, 6 m	20 µg	Wk 28	60	52.5
				Wk 72	41.4	-
Pollack, 2016 [79]	HIV-infected patients (N = 302); Vietnam; Mean (range): 36.0 y (16–75)	3 doses at 0, 1, 6 m Patients testing positive for anti-HBc received a single dose. If anti-HBs ≥ 10 IU/L 4 wks post-vaccination no further vaccine was administered	20 µg	>2 weeks after third dose	62.6	-
				CD4 ≥ 300	79.7
				CD4 ≥ 200–299	66.7
				CD4 ≥ 100–199	47.9
				CD4 < 100	37.5
Standard schedule and alternative dose
Fonseca, 2005 [78]	Adults with HIV (N = 94 20 µg, N = 98 40 µg); Brazil; mean 37 y	3 doses at 0, 1, 6 m	40 µg	7–8	46.9	-
Flynn, 2011 [77]	HIV infected youth age 12–<25 y (N = 106 20 µg, N = 112 40 µg); Bahamas, Brazil, South Africa, and the USA; mean 20 µg: 20.49 y, mean 40 µg: 20.82 y	3 doses at 0, 1, 6 m	40 µg	Wk 28 Wk 72	73.2 52.4	77.6 -

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; USA: United States of America; y: years; m: months; N: number of subjects; -: not reported; wks: weeks; Wk: week.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

3.8.2. Standard schedule and alternative dose

Two of these studies also assessed 40 μg GSK HepB administered at 0, 1, and 6 months. The seroprotection rate 1–2 months post-dose 3 was 46.9% and 73.2% in the respective studies [77,78] (Table 7). One of the studies reported that the seroprotection rate was 52.4% 48 weeks after vaccination [77]. Compared to the standard dose, the double-dose of HBsAg improved the immune response in patients with low viral load (<10,000 copies) or CD4+ count ≥ 350 cells/mm³ [78].

3.9. Immunogenicity in adults with cancer

3.9.1. Standard schedule and dose

One study conducted in India in cancer patients who received the standard schedule and dose reported a seroprotection rate of 49.0% 9 months after receiving chemotherapy [80] (Table 8).

Table 8. Immunogenicity of GSK HepB in adults with cancer.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b	GMC (mIU/ml)
Standard schedule and dose
Sodhi, 2015 [80]	Adults with cancer (N = 472); India; median (range): 55 y (2–78)	3 doses at 0, 1, 6 m	10 µg (children <19 y) 20 µg (adults)	3	26.7	28
				6	37.7	42
				9	49	52
Alternative schedule and dose
Sodhi, 2015 [80]	Adults with cancer (N = 454); India; median (range): 52 y (0.45–85)	6 doses at 0, 1, 3 wks prior to chemotherapy followed by 0, 1, 2 m after chemotherapy	20 µg (children <19 y) 40 µg (adults)	3	41.1	64
				6	66.1	78
				9	75.9	102

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; y: years; m: months; N: number of subjects; -: not reported; wks: weeks.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10mIU/ml unless stated otherwise.

3.9.2. Alternative schedule and dose

The same study assessed an alternative schedule and dose in which six 40 µg HBsAg doses were administered 0, 1, and 3 weeks prior to chemotherapy and 0, 1, and 2 months after chemotherapy [80] (Table 8). The seroprotection rate was 75.9% 9 months after chemotherapy [80].

3.10. Immunogenicity in adults with an intellectual disability

3.10.1. Standard schedule and dose

Three articles describing one study reported on the immunogenicity of GSK HepB (standard dose and schedule) in institutionalized children and adults with an intellectual disability [23,81,82] (Table 9). Two articles describe the results up to 2 years after vaccination [81,82], and the third article describes the results up to year 11 [23]. Nonresponders and low responders (anti-HBs antibody concentration < 100 mlU/ml) received a booster dose at month 12, and all subjects received a booster dose at month 60.

Table 9. Immunogenicity of GSK HepB in adults with an intellectual disability.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b						GMC (mIU/ml)
Standard schedule and dose
Van Damme, 1990 and 1989 [81,82]	Intellectually disabled residents (N = 231); Belgium; 1.1 to 60 y	3 doses at 0, 1, 6 m nonresponders and low responders received booster at 12 m	20 µg		All	Down syndrome	Other	10–100 mIU/ml	100–1000 mIU/ml	≥1000 mIU/ml	All	Down syndrome	Other
				1	10.8	21.4	10.1	9	1.7	0	6.4	14.7	6.1
				2	51.8	50.0	51.9	36	13	2.6	23.4	19.6	23.6
				7	92.3	75.0	93.5	10	30	52.4	1033.7	516.3	1078.7
				12	88.3	75.0	89.1	20	47	22	268.8	255.5	269.5
				24^c	93.9	66.7	96.0	36	45	12.9	149.6	40.1	166.3
Vellinga, 1999 [23]	Intellectually disabled residents (N = 67 group A, N = 30 group B, N = 8 group C)^d; Belgium; mean: 34.1 y	A) 3 doses at 0, 1, 6 m, booster at 60m^d	20 µg	36^e							117
				48							75
				60	92.1 (for total population)						60
				61							30,946
				Y11	92.4 (for total population)						1184
		B) 4 doses at 0, 1, 6 m booster dose at 12 m and 60 m^d	20 µg	36^e							87
				48							85
				60							79
				61							3885
				Y11							249
		C) >5 doses^d	20 µg	Y11							Between 2 and 147

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; y: years; m: months; N: number of subjects; -: not reported.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

^cDoes not include data of those who received a booster.

^dIf residents did not meet the anti-HBs requirements of 100 IU/L, they received an extra booster at month 12. All study subjects received a booster dose at month 60. Subsequently, the subjects were divided into three groups: group A, who received four doses in total (0, 1, 6, and month 60), group B (0, 1, 6, 12, and month 60), group C (>5 doses).

^eData before month 36 was retrieved from the articles of Van Damme (1990 and 1989). The presented data in Vellinga et al., 1999 (before month 36) is different from the data in the articles of Van Damme and based on a different sample size; the reason for this is not clear.

One month post-dose 3, the seroprotection rate was 92.3% overall, but was lower in individuals with Down syndrome (75.0%). The seroprotection rate after 1 year was 88.3% and was 93.3% after 2 years [81,82]. Protective antibody levels were still high (92.4%) 11 years after the start of vaccination and 6 years after a booster dose [23].

3.11. Immunogenicity in adults who are drug users

3.11.1. Standard schedule and dose

In current drug users in the United States of America, the anti-HBs seroprotection rate 6 months after the third dose of GSK HepB administered in a standard schedule and dose was 65.0% [83] (Table 10).

Table 10. Immunogenicity of GSK HepB in adults who are drug users.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose	Time point^a (m)	Anti-HBs response
					% Seroprotection^b	GMC (mIU/ml)
Standard schedule and dose
Tran, 2012 [83]	Not-in-treatment current drug users (N = 342) USA; mean: 43 y	3 doses at 0, 1, 6 m	20 µg	12	65	-
Alternative schedule and standard dose
Rodrigo, 1992 [44]	Intravenous heroin addicts (N = 86); Spain; mean drug users: 23.7 y	3 doses at 0, 1, 2 m	20 µg	3	58.0	18.2
Tran, 2012 [83]	Not-in-treatment current drug users (N = 365); USA; mean: 43 y	3 doses at 0, 1, 2 m	20 µg	12	65	-

Anti-HBs: antibodies to hepatitis B virus; GMC: geometric mean concentration; USA: United States of America; y: years; m: months; N: number of subjects; -: not reported.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

3.11.2. Alternative schedule and standard dose

In the same study, the seroprotection rate in USA drug users who received GSK HepB in the accelerated 0, 1, and 2 months schedule was 65.0% 6 months post-dose 3 [83]. In a study in Spain using the same accelerated schedule, the seroprotection rate one month post-dose 3 was 58.0% [44].

3.12. Immunogenicity in other high risk adults

3.12.1. Standard schedule and dose

Four articles reported on GSK HepB immunogenicity in populations at risk of HBV infection (Table 11). These included commercial sex workers, family members of chronic HBsAg carriers, alcoholic patients, and descendants of African slaves living in Remaining Quilombo communities in Central Brazil, where HBV endemicity is moderate-to-high [49,84–86].

Table 11. Immunogenicity of GSK HepB in other at-risk groups.

Author	Immunized subjects (N) study population; country; age (y)	Schedule	Dose		Time point^a (m)	Anti-HBs response
						% Seroprotection^b				GMC (mIU/ml)
Standard schedule and dose
Wouters, 2007 [84]	Commercial sex workers (N = 293); Belgium; NR	3 doses at 0, 1, 6 m	20 µg			10–100 mIU/ml	100–1000 mIU/ml		>1000 mIU/ml	-
				14–90 days post-dose-3		8	28		59
				>90 days post-dose-3		12	40		36
Rosman, 1997 [85]	Alcoholic patients (N = 52); USA; mean 51.7y	3 doses at 0, 1, 6 m	20 µg	12		46.2				39.4
Motta-Castro, 2009 [86]	HBV-susceptible participants^c (N = 708); Brazil; mean (range): 24.8 y (2–95)	3 doses at 0, 1, 6 m	10 µg children 20 µg adults	45 days post-dose-3		83.1				512
						10–100 mIU/ml			>100 mIU/ml
						23.6			59.5
Palmovic, 1994 [49]	Family members of HBsAg chronic carriers (N = 200); Croatia; NR	3 doses at 0, 1, 6 m	20 µg	7		10.1–100 mIU/ml	100.1-1000 mlU/ml		>1000 mIU/ml	-
						4.5	47.5		44.5
Alternative schedule and standard dose
Wouters, 2007 [84]	Commercial sex workers (N = 322); Belgium; NR	3 doses at 0, 1, 4 m	20 µg			10–100 mIU/ml	100–1000 mIU/ml		>1000 mIU/ml	-
				14–90 days post-dose-3		10	23		56
				>90 days post-dose-3		26	39		26
Gupta, 2003 [87]	Pregnant women without complications or recent or past history of jaundice (N = 52 group A, N = 48 group B); India; mean (SD) group A: 22.3 (5.4) y, mean (SD) group B: 23.3 (5.2) y	A) 2 doses at 24, 28–30 weeks gestation	20 µg	At time of delivery		-				73.6
				2-m post delivery						87
				4-m post delivery						87.5
		B) 3 doses at 24 weeks gestation and second/third dose at 4–6 week intervals		At time of delivery						116.8
				2-m post delivery						126.7
				4-m post delivery						125.5
Bayas, 1993 [88]	Male prisoners (N = 705); Spain; NR	3 doses at 0, 15–90 days, 5–12 m	NR^f			>10 mIU/ml	10–99 mIU/ml	100–999 mIU/ml	≥1000 mIU/ml	-
				Prior to dose 3		33	58^d	14^d	2^d
				30–60 days post-dose-3		76	34^d	38^d	23^d
Alternative schedule and dose
Rosman, 1997 [85]	Alcoholic patients (N = 52 group A, N = 48 group B); USA; mean 50.4 y	4 doses at 0, 1, 2, 6 m	40 µg	12		75.0				76.4
Hoebe, 2012 [89]	Nonresponders^e (N = 201 group A; N = 37 Group B); The Netherlands; NR	A) 3 doses at 1-month interval	10 µg	4–8 wks post-dose 3		75.1				41
		B) 1 dose	10 µg	4–8 wks post-dose 3		62.2				22

Anti-HBs: antibodies to hepatitis B virus; HbsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCW: health-care workers; N: number of subjects; NR: not reported; GMC: geometric mean concentration; USA: United States of America; y: years; m: months; wks: weeks; -: not reported.

^aThe blood sampling time point is given in months unless otherwise indicated.

^bAll rates are seroprotection rates defined as anti-HBs ≥ 10 mIU/ml unless stated otherwise.

^cStudy population not further specified.

^dIn seroconverters.

^eSubjects with titer <10 IU/L after standard vaccination (3-dose of 10 µg).

^fAssuming a standard dose was used.

The seroprotection rate 14–90 days post-dose 3 was 95.0–96.5% in sex workers and at-risk family members. The seroprotection rate amongst Quilombo community members was 83.1%, with a lower response significantly associated with male sex and age ≥40 years; the seroprotection rate was 90.0% in those aged <40 years, compared to 66.7% in adults >40 years of age. In alcoholic patients, 46.2% had anti-HBs concentrations ≥ 10 mIU/ml 6 months post-dose 3 [85].

3.12.2. Alternative schedule and standard dose

The seroprotection rate in commercial sex workers 14–90 days after the third dose of GSK HepB administered in a 0, 1 and 4 months schedule was 89.0% and was 91.0% more than 90 days post-dose 3 [84] (Table 11). In male prisoners, a three-dose schedule at 0, 15–90 days, and 5–12 months induced a seroprotection rate 1–2 months post-dose 3 of 76.0% [88].

Pregnant women in India received two GSK HepB doses at 24 and 28–30 weeks gestation, or three doses beginning at 24 weeks of gestation and administered at 4–6 week intervals thereafter. The seroprotection rate, defined in this study as anti-HBs ≥ 15 mIU/ml, was 92.0% and 94.0% at the time of delivery, respectively, although anti-HBs antibody levels were higher in the mothers receiving three doses, and their infants [87].

3.12.3. Alternative schedule and dose

In one study, alcoholic patients received four doses of 40 µg HBsAg (double-dose of GSK HepB) at 0, 1, 2, and 6 months. After 1 year, the seroprotection rate was 75.0% [85]. In another study, subjects not sufficiently responding to three doses of GSK HepB (10 µg) were revaccinated with either three doses administered at 1-month intervals, or with a single dose. After revaccination with three doses, 75.1% were seroprotected compared to 62.2% in the one-dose group [89].

3.13. Safety of GSK Hepb in adults

Twenty-three articles (22 studies) reported on the safety of GSK HepB in different adult populations (Table 12). Four articles (describing three studies) only reported on the occurrence of unspecified adverse events; these ranged from 0.0–12.5% after vaccination [68,78,81,82].

Table 12. Solicited and unsolicited adverse events following immunization with GSK HepB in adults.

Reaction	% reporting the adverse event following GSK HepB, range	Reference
Local reactions, %
Any	<1–40.9	[28,31,32,39,46,52,63,66]
Soreness/pain	1.5–44.7	[28,29,31,32,41,43,45,63,66,69,90]
Redness/erythema	0–24.4	[29,31,32,39,41,43,63,66,69,90]
Swelling	0–12.0	[29,31,32,39,41,43,63,66,69,90]
Induration	0–0.6	[39]
Systemic reactions, %
Any	0.6–34.4	[28,31,32,39,46,52,66]
Diarrhea	0–9.2	[32,39,41,45]
Fever	0–14.8	[28,29,32,39,45,63,66,69,90]
Sweating	2	[41]
Headache	0.7–27.6	[29,32,39,41,45,63,66,69,90]
Dizziness	5.3– 6.0	[32,41]
Malaise	1–13.1	[29,32,39,45]
Influenza type illness	4.4	[32]
Fatigue	10.5–28.6	[29,32,63,69,90]
Asthenia	3.0–5.3	[39]
Nausea	<1–7.0	[39,41,45]
Vomiting	0.6–1.7	[39]
Gastrointestinal	<1–20.1	[29,45,63,69,90]
Dyspepsia	5.8	[32]
Pain	0	[45]
Back pain	4.9	[32]
Myalgia	1–8.7	[39,45]
Rigors	0	[45]
Rhinitis	5	[41]
Purpura	<1	[45]
Cough	14.1	[32]
(Upper) Respiratory tract infection	<1–18.0	[32,45]
(Naso)phyaryngitis	11.0–16.0	[32,41]
Toothache	5.3	[32]
Hypertension	5.8	[32]
SAE, n	0–58	[28,31–33,40,43,46,52,63,66,67,69,71]
Vaccine-related SAE, n	0–1	[31–33,39,43,63,66,67,69,74,78]
Unsolicited events, n	44	[63]

SAE: Serious adverse event; n: number of reports.

3.13.1. Solicited adverse events

In the adult population vaccinated with GSK HepB, up to 40.9% of subjects reported having any local reaction after vaccination. The occurrence of injection site pain or soreness ranged from 1.5% to 39.8%, redness from 0.0% to 24.4%, and swelling from 0.0% to 12.0%.

Solicited systemic reactions were reported by 0.6–34.4% of adults vaccinated with GSK HepB. One of the most commonly reported systemic events was fatigue (10.5–25.2% of subjects). The occurrence of headache following vaccination was reported by 0.7–22.4% of subjects, fever by 0.0–14.8%, malaise by 1–13.1% and gastrointestinal events by <1.0–10.2% of subjects.

3.13.2. Unsolicited adverse events

One study reported on unsolicited events following GSK HepB. Forty-four unsolicited events were reported after 327 doses of GSK HepB in prehemodialysis and dialysis patients following a four-dose (40 µg) schedule [63]. No other details were available.

3.13.3. Serious adverse events

The number of SAEs following vaccination with GSK HepB ranged from 0 to 58 in 13 studies. None of the SAEs were considered to be related to vaccination except for one SAE (reactive airways disease) reported in a healthy adult [33].

4. Discussion

A previous systematic review of the data published in 2001 found that the overall seroprotection rate among a diverse population of 24,277 subjects (from 134 publications) immunized with GSK HepB was 95.8% [91]. However, that review only provided information using schedules approved in the product information, and only included studies that used accelerated schedules when the recommended booster dose was administered. In our more recent review of the literature, we report the results from a similarly diverse group of subjects, but we have included all of the reported schedules and dosages limited to adults (immunogenicity and safety in children and adolescents are reviewed in a different report). Our approach updates a similar review published in 2003 [92].

Primary three-dose vaccination of healthy individuals is generally associated with seroprotection rates of 90.0% or more, that gradually decreases with increasing age [25,47]. In the studies we identified, seroprotection after immunization of healthy young adult cohorts with three doses of GSK HepB at 0, 1, and 6 months was at least 90.0%, but was lower in cohorts that included adults >40 years of age and was lowest among adults aged 65 years or more. This was confirmed in an integrated analysis showing that seroprotection rates following primary vaccination with GSK HepB decrease with age; remaining at or above 90.0% until age 49 years, at or above 80.0% until 60 years of age, and decreasing thereafter [93]. Studies with data reported according to gender confirmed previous observations that responses to HBV vaccines are lower in men [25,92]. Studies stratified by age and/or gender were mainly conducted in healthy populations. The two studies we identified that reported age stratified seroprotection in an at-risk population (patients undergoing hemodialysis or with diabetes) showed decreased responses in those aged 40 years or more, consistent with data in healthy adults [58,69].

Seroprotection rates following the third dose of an accelerated 0-, 1-, 2-month or 0-, 7-, and 21-day schedule were lower than after the standard 0-, 1-, and 6-month schedule. However, in the two studies in which subjects received the recommended booster dose, seroprotection rates increased to >90.0%, highlighting the importance of the booster dose when an accelerated schedule is used.

GSK HepB has been studied in a range of diverse populations at increased risk for infection, including healthy individuals at increased risk of exposure, such as HCW, sex workers, and family members of chronic carriers, and in groups in whom vaccine immunogenicity is known to be suboptimal due to underlying conditions affecting the integrity of the immune response. The most studied group is patients with CRF and patients undergoing dialysis in whom responses to recombinant HBV vaccines are known to be low [5]. Current recommendations for this group reflect this observation and include the use of more doses, or higher dosage, or the use of an adjuvanted HBV vaccine (approved for use in Europe) [53,54]. Lower anti-HBs seroprotection rates were observed in patient populations with comorbidities including IBD, HIV, liver disease, transplant recipients, patients with cancer, as well as drug uses and individuals with Down syndrome. In a controlled study comparing the immune response to GSK HepB in patients with diabetes with a matched healthy control group, age appeared to be the main factor influencing the magnitude of the immune response [69]. Many studies explored alternative schedules and doses among these patient groups in order to try and improve immunogenicity. In general, alternative schedules/doses achieved higher seroprotection rates than the standard dose and schedule in these populations. A meta-analysis of HBV vaccines in people with HIV confirmed that an increased response was achieved when the vaccine dose was 40μg [94].

We identified no studies that measured the vaccine effectiveness of GSK HepB in adults that met our inclusion criteria. This is not unexpected given that adult HBV vaccination usually occurs on a risk-based individual approach outside of national immunization schedules. In countries of low HBV endemicity, long-term follow-up studies of large cohorts of immunized adults to evaluate effectiveness outcomes are difficult to perform. Population-based seroprevalence studies may be used to indirectly measure the impact of pediatric immunization programs, but are less useful for evaluating adult vaccination.

4.1. Strengths and limitations of the data

This review brings together a cross-section of articles from a range of countries and population groups, including groups at high risk of HBV infection due to increased risk of exposure or underlying immune compromise. The review summarizes three decades experience with GSK HepB.

Interpretation of the studies we identified is limited by diverse study designs that differed in respects such as the timing of antibody testing and use of different assays to measure anti-HBs, although the availability of a generally accepted correlate of protection overcomes some of these limitations.

Older age and male gender are known to be risk factors for a lower immune response to HBV vaccines, and these findings were also reported in the articles in our review that stratified their data by risk factor. As well as older age, the presence of comorbid conditions and male gender, there are numerous factors which are known to impact on the immunogenicity of HBV vaccines, such as underlying obesity and smoking [25]. Many or most of the studies we reviewed did not report these demographic characteristics in their population, which may have influenced the immunogenicity of the vaccine in individual studies.

5. Expert commentary

The use of GSK HepB for adult immunization has contributed to global HBV control for the last 30 years. In this review, we demonstrate the ongoing immunogenicity of GSK HepB and its continued acceptable clinical safety profile. The review highlights how the immune response to HBV vaccination may be negatively impacted by gender, age, and a range of underlying comorbidities. Further investigation is needed into how to optimize seroprotection in these risk groups. Incomplete vaccine uptake by high-risk adults is a long-standing problem and requires continued vigilance by health-care professional to identify those at risk and promote vaccination in these groups [95]. Adults are most likely to respond to HBV vaccines when vaccination is administered early during adulthood (before 40 years of age), particularly in men.

Since they were first licensed, the number of doses of HBV vaccines administered worldwide exceeds 1 billion and these vaccines have a well-documented acceptable safety profile [96]. In the 1990s, several cases of multiple sclerosis were diagnosed in students in France, with apparent onset several weeks after HBV vaccination. Concerns of a causal association led to multiple large epidemiological studies to assess any potential risk. These studies did not show any association between HBV vaccination and the onset or relapse of demyelinating diseases, including multiple sclerosis [96–99].

There are 10 known HBV genotypes (types A–J) whose distribution varies globally. GSKHepB and other recombinant HBV vaccines are of the A2 genotype. Breakthrough infections with non-A2 genotypes among vaccinated individuals have been reported [100]. However, HBV vaccination has proven highly effective in high endemicity countries, such as Asia and Africa, where non-A2 genotypes are prevalent [101]. Available evidence indicates that the current HBV vaccines are effective in preventing infection and clinical disease by all known HBV genotypes [101].

The WHO has adopted a strategic goal of halting viral hepatitis as a major public health threat by 2030 [2]. The goal includes reducing chronic HBV infections from 6–10 million to 0.9 million, and a reduction in annual deaths due to chronic hepatitis B and C from 1.4 million to <0.5 million by 2030. The strategy includes describing and promoting high-impact interventions and hepatitis services to increase vaccination uptake, prevent vertical HBV transmission, improve blood safety and safe injections, and improve access to early diagnosis and treatment of chronic HBV. Achieving sustainable funding for these services and identifying areas where innovation could accelerate HBV control are also strategic goals. Vaccination using currently available recombinant HBV vaccines will continue to play a critical role in achieving these goals.

6. Five-year view

In view of the difficulties in accessing adults and achieving high rates of vaccine uptake, infant HBV immunization will remain the cornerstone of global HBV control. Recombinant vaccines like GSK HepB will continue to be used in the adult populations of healthy and at-risk individuals. The WHO does not recommend postvaccination testing for immunogenicity unless the results are relevant for clinical management of the individual – such as HCW, at-risk infants, patients undergoing dialysis and immunocompromised individuals [1]. The European Consensus Group on Hepatitis B Immunity recommends annual anti-HBs testing in individuals who are immunocompromised, and revaccination if anti-HBs decreases to <10 mIU/ml [102]. Current strategies for improving immunogenicity in poor responders include administering a higher vaccine dose and/or more vaccine doses in an effort to achieve seroprotection. New HBV vaccines developed for use in patients with chronic renal disease could be evaluated in other at-risk groups and in poor responders, in whom recombinant vaccines show reduced immunogenicity.

Systematic and unbiased reviews of published data allow assessment of the benefit versus risk of individual vaccines in specific populations. The currently available data support existing HBV vaccination schedules in healthy and at-risk populations. Nevertheless, there is a need to regularly and systematically review the available data in order to incorporate the findings of new studies, and to continue to monitor the benefit-risk ratio of vaccination in all, but particularly at-risk populations.

Key issues

• GSK HepB was the first recombinant HBV vaccine to be licensed and has contributed to global HBV control for 30 years.

• Regular systematic reviews of the literature are needed for the ongoing assessment of the benefit-risk ratio of vaccination in specific populations. A systematic review of the literature identified 66 articles that reported on the immunogenicity and/or safety of GSK HepB in adults

• At least 90.0% of healthy young adults achieve anti-HBs antibody concentrations ≥10 mIU/ml after a 3-dose course administered at 0, 1 and 6 months. Accelerated immunization schedules require the administration of a booster dose to achieve equivalent seroprotection.

• Seroprotection decreases as age increases, with male gender and the presence of co-morbidities including IBD, HIV, liver disease, transplant recipients, patients with cancer, drug users, and individuals with Down Syndrome.

• GSK HepB has an acceptable clinical safety profile. No safety concerns were raised among healthy, at risk or immunosuppressed populations in the studies we reviewed.

Declaration of interest

E.M Bunge and C.VD Ende and A.V Ahee are employees of Pallas, a commercial entity that has received grants from the GSK Group of Companies and which carried out part of the submitted work as a supplier to GSK Vaccines. C Marano and L. D Moerlooze are employees of the GSK group of companies and hold stock options/restricted shares from the sponsoring company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Trademarks

Engerix-B and Havrix are trademarks of the GSK groups of companies.

Acknowledgments

The authors thank Syedah Maria Bokhari who originally conceived the idea for the manuscript, Joanne Wolter (medical writer on behalf of GSK), and Susana Montenegro Gouveia (from XPE Pharma & Science on behalf of GSK) for coordinating the publication development.

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

This systematic review was sponsored and funded by GlaxoSmithKline Biologicals S.A, Belgium. GlaxoSmithKline Biologicals S.A was involved in all stages of the study conduct and analysis and also took charge of all costs associated with the development and the publishing of the manuscript.

Appendix

Search strategy

PubMed Search

#1. Hepatitis B vaccine

Engerix-B [Supplementary Concept] OR Engerix[tiab] OR ((‘hepatitis B’[ti] OR Hep B[ti] OR HBs[ti]) AND (vaccin*[ti] OR immuni*[ti] OR immune[ti]))

#2. Outcomes

effectiv*[tiab] OR efficac*[tiab] OR immunogen*[tiab] OR safe*[tiab] OR adverse event*[tiab] OR Anti-HBs[tiab] OR adverse reaction*[tiab] OR reactogen*[tiab] OR seroprevalence[tiab]

Cochrane database search

#1. Hepatitis B vaccine

Engerix:ti OR ((hepatitis B:ti OR Hep B:ti OR HBs:ti) AND (vaccin*:ti OR immun*:ti))

#2. Outcomes

effectiv*:ti,ab OR efficac*:ti,ab OR immunogen*:ti,ab OR safe*:ti,ab OR adverse event*:ti,ab OR Anti-HBs:ti,ab OR adverse reaction*:ti,ab OR reactogen*:ti,ab OR seroprevalence:ti,ab