PreHevbrio: the first approved 3-antigen hepatitis B vaccine

Figures & data

Table 1. Dose-ranging studies in adults aged 18–45 years (5 µg and 10 µg).

	HB-88002-S Singapore		HB-88002-T Thailand		HBV-003-89 Israel
	5 µg*	10 µg*	5 µg*	10 µg*	5 µg*	10 µg*
	SPR/GMT	SPR/GMT	SPR/GMT	SPR/GMT	SPR/GMT	SPR/GMT
Month	%/mIU/mL	%/mIU/mL	%/mIU/mL	%/mIU/mL	%/mIU/mL	%/mIU/mL
1	15/11	20/10	8/5.9	7/6.5	27/11.5	33/12.3
2	50/23	63/22	56/49.7	63/58.6	80/61.7	75/69.5
6	81/91	96/159	75/62.3	100/102	100/272	100/268
7	92/1473	100/2687	92/3068	100/8329	100/12157	100/13483
12	92/550	100/970	96/661	100/1335	100/3238	100/3273

*Bio-Hep-B/Sci-B-Vac (PreHevbrio) original formulation with AlPO4 adjuvant and thimerosal preservative.

GMT = geometric mean titer.

SPR = seroprotection rate (percentage with anti-HBs ≥10 mIU/mL).

Table 2. Phase 2 and 3 early comparative studies and phase 4 investigator initiated studies.

Study No. (NCT^§) Country Age	Study Design	Study objectives	Study Group (safety set) Vaccine Dose	Seroprotection Rates (%)
HBA 9006-S Singapore 18–45	Phase 2 Comparative Randomized (1:1:1) Open-label	Safety and immunogenicity comparison to two licensed HBV vaccines (Engerix-B and Hepavac II)	Bio-Hep-B × 10 µg^1 (n = 100) Engerix-B 20 µg (n = 100) Hepavac II 10 µg (n = 100)		Month
					6		9		12
				Bio-Hep-B	93		99		99
				Engerix-B	81		94		95
				Hepavac II	83		96		95
38-92-001 Israel 18–45	Phase 2 Comparative Randomized (2:2:1) Single-blind	Safety and immunogenicity Comparison of batch A and B to Engerix-B	Bio-Hep-B* ‘A’ 5 µg^1 (n = 135) Bio-Hep-B* ‘B’ 5 µg^1 (118) Engerix-B 20 µg (n = 51)		Month
					1		6	7		12
				Bio-Hep-B ‘A’	21		92	97		97
				Bio-Hep-B ‘B’	21		88	96		94
				Engerix-B	4		66	90		92
38-96-040 Israel 18–60	Phase 3 Comparative Randomized (1:1) Single-blind	Safety and Immunogenicity comparison to Engerix-B	Bio-Hep-B × 10 µg^2 (n = 260) Engerix-B 20 µg (n = 264)		Month
					1	7		12
				Bio-Hep-B	35	99		98
				Engerix-B	5	92		85
SG-005-05 (NCT04531098) Vietnam 18–45	Phase 3 Comparative Randomized (1:1:1) Single-blind	Safety and Immunogenicity comparison of two production lots (A and B) and comparison to Engerix-B	Sci-B-Vac* ‘A’ 10 µg^3 (n = 134) Sci-B-Vac* ‘B’ 10 µg^3 (n = 131) Engerix-B 20 µg (n = 133)		Month
					6	7		12
				Sci-B-Vac ‘A’	91	97		96
				Sci-B-Vac ‘B’	98	100		99
				Engerix-B	81	98		98
38-13-040 (NCT04209400) Russia 18–45	Phase 3 Comparative Randomized (1:1)	Safety and Immunogenicity comparison to Engerix-B	Sci-B-Vac *10 µg^3 (n = 49) Engerix-B 20 µg (n = 50)		Month
					1	3		6			7
				Sci-B-Vac	61	96		100			100
				Engerix-B	51	87		89			98
HIV-Positive Israel 18–45	Phase 4 Single arm, open-label, prospective cohort	Immunogenicity and safety among HIV-positive	Sci-B-Vac *10 µg^3 (n = 31)		Month
					1	6		7
				Sci-B-Vac	16	65		84
ESRD** in HBV vaccine naïve or nonresponders Israel >18	Phase 4 Comparative Randomized (1:1) Open-label	Safety and Immunogenicity comparison to Engerix-B	Sci-B-Vac *10 or 20 µg^3 x3 doses (n = 43) Engerix-B 40 µg x4 doses (n = 43)		Month
					7
				Sci-B-Vac	73
				Engerix-B	69
ESRD** Israel 30–80	Phase 4 Retrospective Cohort, open-label, comparative to historical cohort, single-center	Immunogenicity in non-responders to four doses of Engerix (40 µg) + a booster dose	Sci-B-Vac *10 µg^3 (n = 29) Historical cohort Engerix-B 40 µg x4 doses (n = 34)		Month
					7
				Sci-B-Vac	86
				Engerix-B	56
IBD^# Israel >18	Phase 4 Prospective, comparative, randomized, single-blind	Safety and Immunogenicity	Sci-B-Vac *10 µg^3 (n = 35) Engerix-B 20 µg (n = 37)		Month
					1		3	7
				Sci-B-Vac	14		47	68
				Engerix-B	21		40	81

*Bio-Hep-B, Sci-B-Vac = PreHevbrio/PreHevbri.

§NCT number = National Clinical Trial number (only available for studies conducted from 2005 onward).

IM = intramuscular; **ESRD= End-Stage-Renal-Disease; # IBD=Inflammatory Bowel Disease.

^bAlPO4 adjuvant with thimerosal preservative.

^cAl(OH)₃ adjuvant with thimerosal preservative.

^dAl(OH)₃ adjuvant.

Figure 1. Seroprotection by month (3A-HBV) in adults 18–45 years of age.

Results are from [45]. Reproduced with permission.

Figure 2. Seroprotection by subgroup (PROTECT).

PROTECT was a phase 3, randomized controlled multinational trial that compared the immunogenicity and safety of 3A-HBV to 1A-HBV in 1607 adults ≥18 years old, including in those with well-controlled chronic conditions. The seroprotection rate (SPR; percentage of subjects with anti-HBs ≥10 mIU/mL) at Day 196 (month 7) in subgroups and differences in SPR between 3A-HBV and 1A-HBV are displayed. Results are from [18]. Reproduced with permission.

*Difference in seroprotection rate (SPR) = SPR 3A-HBV – SPR 1A-HBV.

Figure 3. A. Seroprotection rate over 12 months and by age group. B. Retention of seroprotection after 2–3 years of follow-up (PROTECT).

PROTECT was a phase 3, randomized controlled multinational trial that compared the immunogenicity and safety of 3A-HBV to 1A-HBV in 1607 adults ≥18 years old, including in those with well-controlled chronic conditions. (A) The seroprotection rate (SPR; percentage of subjects with anti-HBs ≥10 mIU/mL) up to 12 months of follow-up. (B) Antibody titers and SPR after 2–3 years of follow in a subpopulation of PROTECT, the 3A-HBV (blue) or 1A-HBV (orange) SPRs are displayed at 10 and at 100 mIU/mL. The results are from [18 and 54]. Reproduced with permission.

Figure 4. Geometric mean concentration anti-HBs by timepoint and type of vaccine and lot administered in the phase 3 CONSTANT study.

CONSTANT was a double-blind, 4-arm, randomized study in healthy adults 18–45 years designed to demonstrate the manufacturing equivalence in terms of immunogenicity of 3 lots (A, B, and C) of 3A-HBV (PreHevbrio, 10 µg) and to compare the immunogenicity and safety to 1A-HBV (Engerix-B, 20 µg). The geometric mean concentration of anti-HBs titers are displayed at day 168 (after two vaccinations), day 196 (1 month after the third vaccination) and at the end of study, day 336. Results are from [46]. Reproduced with permission.

The antibody response, as measured by geometric mean concentration of anti-HBs, at study day 168 (i.e., 20 weeks following the second vaccination and prior to the third vaccination), study day 196 (4 weeks after the third vaccination), and at the end of study, day 336.

Figure 5a. Severity of local reactions by type of vaccine administered in the pivotal phase 3 studies CONSTANT and PROTECT.

Pooled safety data from two double-blind randomized phase 3 trials (PROTECT and CONSTANT) that compared the 3A-HBV (PreHevbrio/PreHevbri, 10 µg) with 1A-HBV (Engerix-B, 20 µg). The severity of local reactions at the injection site on the day of vaccination and during the next 6 days are displayed (Available at ACIP meeting Jan 12, 2022 downloads at https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-01-12/02-HepWG-Diaz-Mitoma-508.pdf).

Figure 5b. Severity of systemic reactions and fever by type of vaccine administered in the pivotal phase 3 studies CONSTANT and PROTECT.

Pooled safety data from two double-blind randomized phase 3 trials (PROTECT and CONSTANT) that compared the 3A-HBV (PreHevbrio/PreHevbri, 10 µg) with 1A-HBV (Engerix-B, 20 µg). The severity of systemic reactions and fever on the day of vaccination and during the next 6 days are displayed (Available at ACIP meeting Jan 12, 2022 downloads at https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-01-12/02-HepWG-Diaz-Mitoma-508.pdf).

Atsmon J, Machluf N, Yayon-Gur V, et al. Rapid and high seroprotection rates achieved with a tri-antigenic hepatitis B vaccine in healthy young adults: results from a phase IV study. Vaccine. 2021;39(8):1328–1332. doi: 10.1016/j.vaccine.2020.12.050

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