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

Figures & data

Figure 1. PRISMA diagram.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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