STUDY PROTOCOL Official Title: A Phase 3 Double-Blind Randomized Controlled Trial to Compare the Immunogenicity and Safety of a Three-dose Regimen of Sci-B-Vac® to a Three- dose Regimen of Engerix-B® in Adults (PROTECT) Protocol Identifying Number: Sci-B-Vac–001 NCT Number: NCT03393754 Version: 2.0, Amendment 1 Date of Version: July 17, 2017 Study Sponsor: VBI Vaccines Inc. 310 Hunt Club Road East Ottawa, ON K1V 1C1 Canada Telephone: (613) 749-4200 TITLE: A Phase 3 Double-Blind Randomized Controlled Trial to Compare the Immunogenicity and Safety of a Three-dose Regimen of Sci-B-Vac™ to a Three-dose Regimen of Engerix-B® in Adults (PROTECT) Protocol Identifying Number: Sci-B-Vac–001 EudraCT Number: 2017-001819-36 Version: 2.0 Amendment 1 Date of version: July 17, 2017 Study sponsor: VBI Vaccines Inc. 310 Hunt Club Road East Ottawa, ON K1V 1C1 Canada Telephone: (613) 749-4200 Confidentiality Statement The information in this document contains trade secrets and proprietary or commercial information that are privileged or confidential and may not be disclosed to any third party without the prior written authorization of VBI Vaccines Inc. Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) Version 2.0– July 17, 2017, Amendment 1 Sponsor Signature Page Sponsor Signatory: 21/07/2017 Francisco Diaz-Mitoma Date (dd/mm/yyyy) Chief Medical Officer VBI Vaccines Inc. 310 Hunt Club Road East Ottawa, ON K1V 1C1 Canada Telephone: (613) 749-4200 ii | P a g e CONFIDENTIAL Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) Version 2.0– July 17, 2017, Amendment 1 Table of contents SPONSOR SIGNATURE PAGE .................................................................................................................................. II TABLE OF CONTENTS ............................................................................................................................................ III LIST OF FIGURES .................................................................................................................................................. VII LIST OF TABLES .................................................................................................................................................... VII LIST OF ABBREVIATIONS ..................................................................................................................................... VIII STATEMENT OF COMPLIANCE ................................................................................................................................ X PROTOCOL SUMMARY .......................................................................................................................................... XI SCHEMATIC OF STUDY DESIGN .......................................................................................................................... XXII PROTOCOL AMENDMENTS SCI-B-VAC-001 ........................................................................................................ XXIII 1 BACKGROUND AND RATIONALE .................................................................................................................... 1 1.1 EPIDEMIOLOGY .................................................................................................................................................................................................. 1 1.2 IMMUNOGENICITY OF LICENSED VACCINES ....................................................................................................................................................... 1 1.3 SCI-B-VAC™ ................................................................................................................................................................ 2 1.3.1 Description ............................................................................................................................................... 2 1.3.2 Overview of clinical pharmacology .......................................................................................................... 2 1.3.3 Potential risks and benefits ...................................................................................................................... 3 1.4 RATIONALE FOR CONDUCTING THE STUDY ........................................................................................................................................................ 3 2 OBJECTIVES ................................................................................................................................................... 3 2.1 CO-PRIMARY OBJECTIVES .................................................................................................................................................................................. 3 2.2 SECONDARY OBJECTIVES .................................................................................................................................................................................... 4 2.3 EXPLORATORY OBJECTIVES ................................................................................................................................................................................ 4 3 STUDY DESIGN AND ENDPOINTS ................................................................................................................... 5 3.1 STUDY DESIGN.................................................................................................................................................................................................... 5 3.2 PRIMARY ENDPOINT .......................................................................................................................................................................................... 6 3.3 SECONDARY ENDPOINTS .................................................................................................................................................................................... 6 3.4 EXPLORATORY ENDPOINTS ................................................................................................................................................................................ 6 4 STUDY ENROLLMENT AND WITHDRAWAL ..................................................................................................... 7 4.1 SUBJECTS POPULATION ...................................................................................................................................................................................... 7 4.1.1 Inclusion criteria ...................................................................................................................................... 7 4.1.2 Exclusion criteria ...................................................................................................................................... 8 4.2 ENROLLMENT PROCEDURES ........................................................................................................................................................................... 10 4.3 SUBJECT WITHDRAWAL................................................................................................................................................................................... 10 4.3.1 Subject withdrawal from the study ........................................................................................................ 11 4.3.2 Subject withdrawal from investigational product ................................................................................. 11 4.4 TERMINATION OF STUDY OR SUSPENSION OF STUDY .................................................................................................................................... 12 iii5 | PSTUDY a g e AGENTS ............................................................................................................................................CONFIDENTIAL 12 Comparative safety and immunogenicity of Sci-B-Vac and Engerix B in adults (Sci-B-Vac-001) Version 2.0– July 17, 2017, Amendment 1 5.1 SCI-B-VAC™ .............................................................................................................................................................. 12 5.1.1 Acquisition ............................................................................................................................................. 12 5.1.2 Formulation and labelling ...................................................................................................................... 12 5.1.3 Product storage ..................................................................................................................................... 13 5.2 COMPARATOR: ENGERIX B ................................................................................................................................................... 13 5.2.1 Acquisition ............................................................................................................................................. 13 5.2.2 Formulation and labelling ...................................................................................................................... 13 5.2.3 Product storage ..................................................................................................................................... 13 5.3 DOSAGE, PREPARATION ADMINISTRATION OF STUDY VACCINES................................................................................................................... 13