VBI Vaccines : Canadian Liver Meeting 2021

Higher seroprotection rates (SPR) and higher anti-HBs concentrations in adults age 18-45 immunized with 3-antigen hepatitis B vaccine (3A-HBV) compared to 1-antigen hepatitis B vaccine (1A-HBV):

Results from the pivotal, double-blind, randomized Phase 3 study (CONSTANT)

Abstract Identifier : 071

Francisco Diaz-Mitoma1, Timo Vesikari2, Adam Finn3, Pierre van Damme4, Isabel Leroux-Roels5, Geert Leroux-Roels5, Nathan Segall6, Azhar Toma7, Naveen Garg8, Gerald Vallieres9, Ronnie Aronson10, Dennis Reich11, Hamilton Sah12, Samir Arora13, Peter J Ruane14, Corey Anderson15, Clancy L. Cone16, Michael Manns17, Catherine Cosgrove18, Saul N. Faust19, Maheshi N. Ramasamy20, Nathalie Machluf1, Johanna N. Spaans1, Bebi Yassin-Rajkumar1, David Anderson1, Vlad Popovic1, for the CONSTANT Study Group

1VBI Vaccines Inc., Cambridge, Massachusetts, United States.2Nordic Research Network Ltd., Tampere, Finland; 3Bristol Royal Hospital for Children, Bristol, UK; 4University of Antwerp-Center for the Evaluation of Vaccination, Universiteitsplein, Wilrijk, Belgium; 5Ghent University, Gent, Belgium; 6Clinical Research Atlanta, Stockbridge, Georgia, USA; 7Manna Research, Toronto, Ontario, Canada; 8Manna Research, Montreal QC, Canada;

9Manna Research, Quebec, Canada; 10LMC Diabetes and Endocrinology, Toronto, Ontario, Canada; 11Medicor Research Inc., Sudbury, Ontario, Canada; 12Care One, North Hollywood, CA, USA; 13Aventiv Research, Columbus OH, USA; 14Ruane Clinical Research Group Inc., Los Angeles, CA, USA; 15Clinical Research Consortium, Tempe, AZ, USA; 16Montana Medical Research Inc., Missoula MT, USA; 17Medizinishe Hochschule, Hannover, Lower Saxony, Germany; 18St. George's University Hospital NHS Foundation Trust, London, UK; 19NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 20Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital and University of Oxford, Oxford, UK

INTRODUCTION

STUDY SUBJECT DISPOSITION

IMMUNOGENICITY RESULTS

• Hepatitis B Virus (HBV) remains a significant public health risk, with an estimated 240-350 million people chronically infected worldwide
• In Canada, an estimated 250,000-460,000 individuals have chronic hepatitis B, with highest rates found in urban centres1
• Though infection rates in Canada have declined, reported acute infection rates are likely an underestimate because of the asymptomatic nature of the disease, and therefore patients do not get tested and remain unidentified2
• Rates of new HBV infections are highest among individuals age 30- 39 years, underscoring the importance of continued adult vaccination against HBV, as well as the need for a highly effective and safe HBV vaccine with a rapid onset of protection
• 3A-HBVis a 3-antigen HBV vaccine that contains all three HBV surface antigens (HBsAg) - S, pre-S1, and pre-S2 - is adjuvanted with alum, and manufactured in mammalian CHO cells
• The pre-S1 antigen induces key neutralizing antibodies that block virus-receptor binding. T cell response to pre-S1 and pre-S2 antigens could further boost responses to the S antigens, resulting in a more immunogenic vaccine3,4

Individuals Screened

• Screened Failure
  Participants Randomized

Clinical Study Arms

Participants Randomized Mean Age

Gender

• Male
• Female
  Mean BMI Race
• White
• Asian
• Black or African American
• Other

Ethnicity

- Hispanic or LatinX

4,452

1,614 (36%)

2,838 at 35 study sites

Lot A	Lot B	Lot C	1A-HBV
3A-HBV	3A-HBV	3A-HBV
711	709	706	712
33.8	32.9	33.9	33.4
303	(43%)	313	(44%)	291	(41%)	291	(41%)
408	(57%)	396	(56%)	415	(59%)	421	(59%)
25.9	25.8	26.0	25.7
650	(91%)	642	(91%)	651	(92%)	654	(92%)
9 (1%)	15	(2%)	13	(2%)	9 (1%)
46	(7%)	43	(6%)	34	(5%)	38	(5%)
6 (1%)	9 (1%)	8 (1%)	11 (2%)
64	(9%)	70 (10%)	61	(9%)	74 (10%)

Figure 1 : Anti-HBs GMCs for 3A-HBV were consistent across lots (A, B, C) and were >7.5x higher after 2 vaccinations (Day 168) and >3x higher after 3 vaccinations (Day 196) compared to 1A-HBV

	10000			5,980				4,855				5,553
(mIU/mL)					2,422				1,794				2,109			1,526
1000																473
GMC	100		124				113			121
-HBs															15
Anti
10
		2				2				2				2
	1	0	168	196	336	0	168	196	336	0	168	196	336	0	168	196	336
	DAYS
			3A-HBV : Lot A			3A-HBV : Lot B			3A-HBV : Lot C			1A-HBV
				N=590				N=591				N=597			N=603

STUDY OBJECTIVES & DESIGN

[NCT03408730]

•	The CONSTANT study was one of two studies in the pivotal Phase 3
	program of 3A-HBV that was conducted from 2017-2020
• CONSTANT was a four-armlot-to-lot consistency study
•	Primary Objective : To demonstrate the manufacturing equivalence,
	in terms of immunogenicity, of 3 independent consecutive lots of 3A-
	HBV at Day 196, four weeks post-3rd vaccination

- Non-Hispanic or LatinX

- Not collected

Country/Region

- United States

- Europe

- Canada

Withdrew

Completed Study

643	(90%)	639	(90%)	644	(91%)	636	(89%)
4 (1%)	0 (0%)	1 (0.1%)	2 (0.3%)
191	(27%)	187	(26%)	186	(26%)	188	(26%)
489	(69%)	493	(70%)	490	(70%)	493	(69%)
31	(4%)	29	(4%)	30	(4%)	31	(4%)
75 (10.5%)	72 (10.2%)	81 (11.5%)	69	(9.7%)
636 (89.5%)	637 (89.8%)	625 (88.5%)	643	(90.3%)

Figure 2 : SPR achieved with 3A-HBV was higher after both the 2nd and 3rd vaccination and was statistically non-inferior at Day 196 compared to the SPR achieved with 1A-HBV

	100%
				99.3%
	90%
(SPR)	90.4%					94.8%
80%
70%
Rate

CONCLUSIONS

• Lot-to-lot manufacturing consistency of 3A-HBV was

demonstrated at Day 196

• SPR of 99.3% after the 3rd vaccination with 3A-HBV was non-

inferior to that achieved with 1A-HBV (94.8%)

• SPR of 90.4% after the 2nd vaccination with 3A-HBV was higher

than that achieved with 1A-HBV (51.6%)

• Secondary and Exploratory Objectives :

• Safety, tolerability, and reactogenicity : Standardized methods for

local and systemic vaccine reactions, repeated vital signs and

physical examinations, 48 weeks follow-up for serious adverse

events (SAEs), medically-significant events (MAAEs) or new onset

of chronic illness (NOCI), and changes in concomitant medication

• Immunogenicity : Seroprotection rates (SPR), GMC of anti-HBs

titers, and kinetics of immunogenicity

N size	2,838
Age Range	18-45 years
3A-HBV	10 µg

SAFETY & TOLERABILITY RESULTS

	Pooled 3A-HBV	1A-HBV
	n=2,124	n=712
	(% of subjects)	(% of subjects)
Vaccine withdrawal due to AE/SAE	0.5	0.3
Study discontinuation due to AE/SAE	0.4	0.1
Local Reactogenicity (most common)
Injection site pain	75.6	53.9
Injections site tenderness	75.1	54.9
Systemic Reactogenicity (most common)
Myalgia	44.4	32.4
Fatigue	40.1	39.9
Headache	38.2	37.6

Seroprotection	60%
50%
					51.5%
40%
30%
20%			Day 168		Day 196		Day 168		Day 196
	10%
	0%			2 Doses		3 Doses		2 Doses		3 Doses
			3A-HBV		1A-HBV
				N = 1,753		N = 592
				(pooled data)

DISCLOSURE

Dr. Francisco Diaz-Mitoma is the Chief Medical Officer of VBI Vaccines Inc.

• 3A-HBV induced robust immune response; anti-HBs GMCs >

7.5x higher after the 2nd dose and > 3x higher after the 3rd dose

vs.1A-HBV

• No new or unexpected safety signals - safety profile remains

consistent with known profile of 3A-HBV

• Most common AEs mild or moderate local reactogenicity

symptoms, which resolved without intervention within 1-2 days

and with no increase of reactogenicity with subsequent dosing

• SAEs uncommon with either vaccines

We thank all clinicians, nurses, and volunteers who contributed to this study. The contribution of scientists and technologists at VBI Vaccines Inc. is greatly appreciated.

Control Vaccine	20 µg 1A-HBV
Random.	1:1:1:1
Dosing	0, 4, 24 weeks

Treatment-emergent AEs (TEAEs)	53.1	52.1
Medically-attended AEs (MAAEs)	21.7	17.6
New Onset of Chronic Illness (NOCI)	1.6	1.1
SAEs	2.0	0.4
Death	1	0

	REFERENCES		CONTACT INFORMATION
1.	Sherman, M. 2013. Canadian Liver Foundation		Dr. Francisco Diaz-Mitoma
2.	Coffin CS et al. 2018. Canadian Liver Journal
3.	Heermann KH et al., J Virol. 1984;52(2):396-402		[e-mail]
4.	Milich DR et al. Science. 1985;228(4704):1195-1199.