A Phase 1, Double-Blinded, Placebo Controlled, Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of HEV-239 (Hecolin(R)) in a Healthy US Adult Population
Phase: PHASE1
Conditions: Hepatitis E, Immunisation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 15-0108 
Version 2.0 
Phase I Study of HEV-239 
 08 FEB 2019 
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DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
A Phase 1, Double-blinded, Placebo Controlled, Clinical Trial to 
Evaluate the Safety, Reactogenicity, and Immunogenicity of HEV-
239 (Hecolin®) in a Healthy US Adult Population 
DMID Protocol Number: 15-0108 
DMID Funding Mechanism: Vaccine Treatment and Evaluation Units 
 
Pharmaceutical Support: Division of Microbiology and Infectious Diseases 
(DMID), National Institute of Allergy and Infectious Diseases, National Institutes of Health and 
Innovax. 
IND Sponsor: DMID 
Lead Principal Investigator: Evan J. Anderson, MD 
DMID Clinical Project Manager: Vivien Agbakoba 
Draft or Version Number:  2.0 
08 February 2019 
 
 
 

DMID Protocol 15-0108 
Version 2.0 
Phase I Study of HEV-239 
 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subjects research.  Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 
 

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Phase I Study of HEV-239 
 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection 
of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application), 21 CFR 812 (Investigational Device Exemptions) 
• 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use E6(R2) Good Clinical Practice (ICH E6 GCP): Integrated 
Addendum to ICH E6(R1) Guidance for Industry, published in the Federal Register (83 
Federal Register 8882 (2018)), including the latest finalized revision. 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 

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Version 2.0 
Phase I Study of HEV-239 
 08 FEB 2019 
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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Evan J. Anderson, MD 
Associate Professor of Pediatrics and Medicine 
Emory University School of Medicine 
 
 
 
 
 

DMID Protocol 15-0108 
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Phase I Study of HEV-239 
 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................13 
PROTOCOL SUMMARY .............................................................................................................18 
 
KEY ROLES.........................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................22 
 
Background .................................................................................................................22 
 
Scientific Rationale .....................................................................................................25 
2.2.1 Purpose of Study ............................................................................................25 
2.2.2 Study Population ............................................................................................26 
 
Potential Risks and Benefits .......................................................................................26 
2.3.1 Potential Risks ...............................................................................................26 
2.3.2 Potential Benefits ...........................................................................................31 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....32 
 
Study Design Description ...........................................................................................32 
 
Study Objectives .........................................................................................................33 
3.2.1 Primary ...........................................................................................................33 
3.2.2 Secondary .......................................................................................................33 
 
Study Endpoints or Outcome Measures .....................................................................34 
3.3.1 Primary ...........................................................................................................34 
3.3.2 Secondary .......................................................................................................34 
 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT..........................................35 

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Phase I Study of HEV-239 
 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
 
Study Product Description ..........................................................................................35 
4.1.1 Formulation, Packaging, and Labeling ..........................................................35 
4.1.2 Product Storage and Stability .........................................................................37 
 
Acquisition/Distribution .............................................................................................38 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product .........................................................................38 
 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject .....................................................................................................40 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....40 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....42 
 
Eligibility Criteria .......................................................................................................42 
5.1.1 Subject Inclusion Criteria ..............................................................................42 
5.1.2 Subject Exclusion Criteria .............................................................................44 
 
Requirements Prior to Administration of the Second and Third Vaccinations ..........47 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................47 
5.3.1 Withdrawal from the Study or Discontinuation of the Study Product ...........47 
5.3.2 Subject Replacement ......................................................................................48 
5.3.3 Study Termination .........................................................................................49 
 
STUDY PROCEDURES ......................................................................................................50 
 
Screening Visit: Visit 00 (Day -28 to -1, All Groups) ................................................50 
 
Enrollment/Baseline: Visit 01, Day 1, Vaccination Clinic Visit (All Groups) ..........51 
 
Planned Study Visits ...................................................................................................53 
6.3.1 Follow-up .......................................................................................................53 
6.3.1.1 
Visit 02, Day 4 +/- 1 Day; Telephone Call .......................................53 
6.3.1.2 
Visit 03, Day 8 +/- 1 Day; Clinic Visit .............................................53 
6.3.1.3 
Visit 04, Day 15 +/- 2 Days; Clinic Visit .........................................54 
6.3.1.4 
Visit 05, Day 29 +/- 2 Days; Clinic Visit .........................................54 

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Phase I Study of HEV-239 
 08 FEB 2019 
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6.3.1.5 
Visit 06, Day 32 (Day 4 after First Boost; +/- 1 Day); Telephone 
Call ....................................................................................................56 
6.3.1.6 
Visit 07, Day 36 (Day 8 after First Boost; +/- 1 Day); Clinic Visit .56 
6.3.1.7 
Visit 08, Day 43 (Day 15 after First Boost; +/- 2 Days); Clinic Visit
 ..........................................................................................................57 
6.3.1.8 
Visit 09, Day 57 (Day 29 after First Boost; +/- 2 Days); Clinic Visit
 ..........................................................................................................58 
6.3.1.9 
Visit 10, Day 120 (Day 92 after First Boost; +/- 14 Days); Telephone 
Call ....................................................................................................58 
6.3.1.10 Visit 11, Day 180 +/- 14 Days from Prime Vaccination; Clinic Visit
 58 
6.3.1.11 Visit 12, Day 184 (Day 4 after Second Boost; +/- 1 Day); Telephone 
Call ....................................................................................................60 
6.3.1.12 Visit 13, Day 187 (Day 8 after Second Boost; +/- 1 Day); Clinic 
Visit ...................................................................................................60 
6.3.1.13 Visit 14, Day 194 (Day 15 after Second Boost; +/- 2 Days); Clinic 
Visit ...................................................................................................61 
6.3.1.14 Visit 15, Day 208 (Day 29 after Second Boost; +/- 2 Days); Clinic 
Visit ...................................................................................................61 
6.3.1.15 Visit 16, Day 270 (Day 90 after Second Boost; +/- 14 Days); 
Telephone Call ..................................................................................62 
6.3.2 Final Study Visit: Visit 17, Day 360 +/- 28 days (Day 180 after Second 
Boost); Clinic Visit ........................................................................................62 
6.3.3 Early Termination Visit .................................................................................62 
 
Unscheduled Study Visits ...........................................................................................63 
 
Protocol Deviations ....................................................................................................64 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................65 
 
Clinical Evaluations ....................................................................................................65 
7.1.1 Research Procedures: Medical History ..........................................................65 
7.1.2 Research Procedures: Physical Examination .................................................65 
7.1.3 Research Procedures: Vital Signs ..................................................................66 

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Phase I Study of HEV-239 
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7.1.4 Research Procedures: Post Vaccination .........................................................66 
7.1.5 Assessment of Concomitant Medications/Treatments other than Study 
Product ...........................................................................................................67 
7.1.6 Assessment of Subject Compliance with the Study Visit Schedule ..............67 
 
Laboratory Evaluations ...............................................................................................67 
7.2.1 Clinical Laboratory Evaluations ....................................................................67 
7.2.1.1 
Baseline Screening Laboratories ......................................................67 
7.2.1.2 
Subsequent Testing Including Safety Laboratories ..........................68 
7.2.2 Research Assays .............................................................................................68 
7.2.2.1 
Laboratory Specimen Preparation, Handling, and Storage ...............70 
7.2.2.2 
Laboratory Specimen Shipping ........................................................70 
 
ASSESSMENT OF SAFETY ...............................................................................................71 
 
Assessing and Recording Safety Parameters ..............................................................71 
8.1.1 Adverse Events (AEs) ....................................................................................71 
8.1.1.1 
Adverse Events Grading ...................................................................72 
8.1.2 Reactogenicity (Solicited Local and Systemic Events) .................................73 
8.1.3 Unsolicited Adverse Events ...........................................................................76 
8.1.4 Serious Adverse Events (SAEs) .....................................................................76 
 
Specification of Safety Parameters .............................................................................77 
 
Reporting Procedures ..................................................................................................78 
8.3.1 Reporting Serious Adverse Events ................................................................78 
8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................79 
8.3.3 Reporting of Pregnancy .................................................................................80 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................80 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................81 
 
Halting Rules ..............................................................................................................81 
8.6.1 Study Halting Criteria ....................................................................................81 

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Phase I Study of HEV-239 
 08 FEB 2019 
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8.6.2 Individual Halting Criteria .............................................................................82 
 
Safety Oversight (ISM, SMC) ....................................................................................83 
8.7.1 Independent Safety Monitor (ISM) ................................................................83 
8.7.2 Safety Monitoring Committee (SMC) ...........................................................84 
 
HUMAN SUBJECTS PROTECTION .................................................................................85 
 
Institutional Review Board/Independent Ethics Committee ......................................85 
 
Informed Consent Process ..........................................................................................85 
 
Consent for Future Use of Stored Specimens and Data .............................................87 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................88 
 
Subject Confidentiality ...............................................................................................88 
 
Certificate of Confidentiality ......................................................................................88 
 
Costs, Subject Compensation, and Research Related Injuries ...................................89 
 
STATISTICAL CONSIDERATIONS .................................................................................90 
 Study Hypotheses .......................................................................................................90 
 Sample Size Considerations .......................................................................................90 
 Treatment Assignment Procedures .............................................................................91 
10.3.1 Randomization Procedures ............................................................................91 
10.3.2 Masking Procedures .......................................................................................91 
 Planned Interim Analyses ...........................................................................................92 
 Final Analysis Plan .....................................................................................................92 
10.5.1 Analysis Populations ......................................................................................92 
10.5.2 Safety Data .....................................................................................................93 
10.5.3 Immunogenicity Data .....................................................................................93 
10.5.4 Missing Values and Outliers ..........................................................................94 
 
ELECTRONIC CASE REPORT FORMS AND ACCESS TO SOURCE DATA ..............95 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................97 
 
DATA HANDLING AND RECORD KEEPING ................................................................98 
 Data Management Responsibilities ............................................................................98 

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Phase I Study of HEV-239 
 08 FEB 2019 
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 Data Management Responsibilities ............................................................................98 
 Data Capture Methods ................................................................................................98 
 Types of Data ..............................................................................................................99 
 Study Records Retention ............................................................................................99 
 
CLINICAL MONITORING ...............................................................................................100 
 
PUBLICATION POLICY ..................................................................................................101 
 
LITERATURE REFERENCES ..........................................................................................102 
 
APPENDICES ....................................................................................................................104 
 
Schedule of Events..........................................................................104 
 ........................................................................................................................108 
 
 

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LIST OF TABLES 
Table 1: Study Groups ...................................................................................................................32 
Table 2: Composition of Recombinant (E. coli) Hepatitis E Vaccine / HEV-239 ........................36 
Table 3: Local (Injection Site) Reactogenicity Grading ................................................................73 
Table 4: Local (Injection Site) Reactogenicity Measurements ......................................................74 
Table 5: Subjective Systemic Reactogenicity Grading ..................................................................74 
Table 6:Quantitative Systemic Reactogenicity Grading ................................................................75 
Table 7: Probability (%) of Observing at Least One Adverse Event .............................................90 
Table 8: TOXICITY TABLE .......................................................................................................108 
Table 9: VITAL SIGNS REFERNCE RANGES ........................................................................110 
 
 

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LIST OF FIGURES 
Figure 1: 
 Schematic of Study Design ........................................................................................20 
 
 

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Phase I Study of HEV-239 
 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
LIST OF ABBREVIATIONS 
aa 
Amino acids 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCs 
Antibody secreting cells 
β-hCG 
β-human chorionic gonadotropin 
BLA 
Biologics License Applications 
BMI 
Body mass index 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CMS 
Clinical Material Services 
CONSORT 
Consolidated Standards of Reporting Trials 
Cr 
Creatinine 
CRO 
Contract Research Organization 
CSR  
Clinical Study Report 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
DSMB 
Data and Safety Monitoring Board 

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Phase I Study of HEV-239 
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DTaP 
Diptheria, tetanus, acellular pertussis vaccine 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme Linked Immunosorbent Assay 
e-CRFs 
Electronic-Case report forms 
e-Memory 
Electronic memory aid 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GMCs 
Geometric Mean Concentrations 
GT 
Genotype 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HEV 
Hepatitis E virus 
HEV-239 
Hepatitis E virus vaccine containing a 239 amino acid 
subfragment of (Hecolin®) 
HgB 
Hemoglobin 
Hib 
Haemophilus influenzae type B 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPV 
Human Papillomavirus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 

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ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
Ig 
Immunoglobulin 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
kDA 
KiloDaltons 
mITT 
Modified intent-to-treat 
MBCs 
Memory B cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Micrograms 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 

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ORF 
Open reading frames 
OTC 
Over the counter 
P 
Protruding (domain) of hepatitis E virus 
PBMCs 
Peripheral Blood Mononuclear Cells 
PE 
Physical examination 
PFS 
Pre-filled syringe 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per protocol 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red blood cell 
RNA  
Ribonucleic acid 
RCD 
Reverse cumulative distribution 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
US 
United States 
VLP 
Virus Like Particle 
VTEU 
Vaccine Treatment and Evaluation Unit 
WBC 
White blood cell count 
WFI 
Water for Injection 

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Phase I Study of HEV-239 
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WHO 
World Health Organization 
 
 
 
 
 

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Phase I Study of HEV-239 
 08 FEB 2019 
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PROTOCOL SUMMARY 
 
Title: 
A Phase 1, Double-blinded, Placebo Controlled, Clinical Trial to 
Evaluate the Safety, Reactogenicity, and Immunogenicity of 
HEV-239 (Hecolin®) in a Healthy US Adult Population 
Design of the Study: 
 
This is a Phase I double-blind, placebo controlled trial (4:1 ratio 
of vaccine to placebo) of HEV-239 in 25 US males and non-
pregnant females to assess the safety, reactogenicity, and 
immunogenicity of HEV-239. Subjects will receive 3 doses of 
study product on Days 1, 29, and 180, by intramuscular injection 
(IM) 
Study Phase: 
1 
Study Population: 
25 US healthy male or non-pregnant female adults (ages 18 – 45 
years inclusive), who meet all eligibility criteria. 
Number of Sites: 
1 
Description of Study 
Product or Intervention: 
This vaccine is a 239 amino acid sub-fragment of the 660 amino 
acid structural protein of HEV (genotype 1) produced in E. coli. 
The vaccine consists of 30 micrograms of the purified 239 amino 
acid protein adsorbed to 0.8 mg aluminum hydroxide, suspended 
in 0.5 mL buffered saline, and contains thimerosal.  
Study Objectives: 
 
Primary: 
• 
Assess the safety and reactogenicity of HEV-239 following 
delivery of each vaccine dose.  

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• 
Assess the number of subjects with ≥4 fold rise in HEV IgG 
at any time after vaccination.  
 
Secondary: 
• 
Assess the number of subjects with HEV IgM seroconversion 
at any time after vaccination.  
• 
Assess the number of subjects with HEV IgG seroconversion 
at any time after vaccination.  
• 
Assess the HEV IgG geometric mean concentrations (GMCs) 
at any time after vaccination.  
 
Duration of Individual 
Subject Participation: 
Up to 13 months.  
Estimated Time to Last 
Subject/Last Study Day: 
Approximately 15 months. 

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Figure 1: 
 Schematic of Study Design 
Prior to  
Enrollment 
 
 
 
 
 
 
Days 1, 29, 180 
Days 4, 32, 184 
 
Days 8, 36, 187 
 
Days 15, 43, 57,  
194, 208 
Days 120, 270 
 
Day 360 
 
 
 
Total N:  Obtain informed consent. Screen subjects by criteria; obtain history, perform physical 
examination, and screening laboratories. 
Randomize 
Perform pregnancy test; collect blood for immunogenicity and future use. Administer study product. 
Observe for 30 minutes after study product administration.  
20 subjects 
HEV-239  
5 subjects 
placebo 
Telephone call for solicited AEs, unsolicited AEs, serious adverse events (SAE) 
Study visit for SAEs and blood draw for immunogenicity and future use 
Assessment of Final Study Outcome 
Measures 
Study visit for solicited AEs, unsolicited AEs, SAEs, blood draw for safety labs, immunogenicity 
and future use 
Study visit for unsolicited AEs, SAEs, immunogenicity and future use 
Telephone call for SAEs 

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KEY ROLES 
Lead Principal 
Investigator: 
 
                                      
 
DMID Clinical Project 
Manager: 
 
Evan J. Anderson, MD  
Emory University of Medicine 
2015 Uppergate Drive 
Atlanta, GA 30322  
Work: 404-727-1746 
Email: evanderson@emory.edu 
 
Vivien Agbakoba  
Clinical Project Manager (CPM) 
Virology Branch/DMID/NIAID/NIH/DHHS 
5601 Fishers Lane 
Room: 8F36 
Bethesda, MD 20892-9826 
Telephone: (301) 761 7662  
Vivien.agbakoba@nih.gov 
 
 
Statistical and Data 
Coordinating Center: 
 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
Phone: (301) 251-1161   
Email: enterics@emmes.com 
 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide.1 Clinical 
manifestations range from asymptomatic infection to fulminant hepatitis, acute hepatitis, hepatic 
failure, and death. Although typically self-limited, HEV has been reported to cause chronic 
hepatitis with progression to liver cirrhosis and hepatocellular carcinoma in 
immunocompromised hosts.2 HEV has an incubation period of 2 – 8 weeks (mean of 40 days).3  
The symptoms of acute HEV infection are similar to those of hepatitis A and include fever, 
vomiting, myalgias, and malaise, followed by progression in some to jaundice, acholic stools, 
darkened urine, and elevated liver transaminases lasting 1 to 6 weeks.3   Extra-hepatic 
manifestations are uncommon, but may include Guillain-Barre syndrome, neuralgic amyotrophy, 
meningoencephalitis, pancreatitis, and glomerulonephritis.4,5 Adults are more likely to develop 
symptomatic disease than children, and pregnant women are most severely affected with 
mortality rates of 10 – 30% in the third trimester. Mother-to-infant transmission may also occur, 
resulting in fetal loss and increased perinatal morbidity and mortality.6,7 Unfortunately, 
supportive care is the only medical therapy available for hepatitis E. 
Globally it is estimated that HEV causes 20 million infections each year, resulting in 3.3 million 
cases of symptomatic disease and 70,000 deaths.8  Although the virus is globally distributed, it is 
highly endemic in several countries in Asia and Africa, where the seroprevalence of HEV IgG 
approaches 50%.9  HEV is mainly transmitted via the fecal-oral route due to contaminated water 
although vertical and iatrogenic transmission from infected blood products can occur. HEV is 
responsible for sporadic cases and large outbreaks in the developing world and disproportionally 
affects areas with poor hygiene standards and population crowding such as refugee camps.10,11 
Although less common, HEV also causes sporadic cases in industrialized nations, and the disease 
burden may be underestimated.12 
HEV has traditionally been grouped into four different genotypes (GTs 1-4) with a single known 
serotype. GT 1 is endemic in many tropical countries and exclusively infects humans via the 
fecal-oral route. Data about GT 2 is limited,13 but also supports exclusive infection of humans 
via the fecal-oral route.14 GTs 3 and 4 are known zoonoses responsible for sporadic transmission 
via consumption of raw or undercooked meat. Common animal reservoirs for HEV include 
swine, deer, rabbits, cows, sheep, and wild boars.15 GT3 is the most commonly identified 
genotype in Europe,12 while GT4 is most commonly identified in Asian industrialized 

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countries.3,16 The implication is that autochthonous transmission of HEV in the developed world 
is often as a foodborne zoonosis.  
An effective HEV vaccine is needed, particularly for the mitigation of outbreaks and for the 
prevention of maternal, fetal, and infant morbidity and mortality. Infection with HEV results in 
cross-protective neutralizing antibodies against all four genotypes,17 which appear to confer 
long-term protection against symptomatic disease.18 Thus, a vaccine that is effective in one 
country is expected to provide protection against hepatitis E elsewhere.  
HEV is a small (27-34 nm) non-enveloped, single-stranded, positive-sense RNA virus of the 
genus Hepevirus within the family Hepeviridae.  Its genome contains 3 partially overlapping 
open reading frames (ORFs 1-3) flanked by two short non-coding regions. ORF2 encodes the 
major HEV capsid protein, a 660-amino-acid (aa) protein which is responsible for virion 
assembly, target cell attachment, and for viral immunogenicity.1 Structural analysis studies using 
cryoelectron microscopy and crystallography predicted that the predominant HEV neutralizing 
epitope resides in the protruding (P) domain (aa 459-607) of ORF2.19 
 
Vaccine Development: 
Two HEV vaccine candidates have been evaluated in clinical trials to date although HEV-239 
(Hecolin®) is the only vaccine currently commercially available. The first vaccine candidate was 
a 56 kDa recombinant HEV protein expressed in insect cells that was highly efficacious in a 
phase II trial of Nepalese army recruits, but was not further developed by the sponsoring 
commercial entity.20 The second vaccine HEV-239 is a 26kDa protein expressed in Escherichia 
coli as a non-fusion virus-like particle (VLP). It was licensed in 2012 for use in China and is 
produced and marketed by Xiamen Innovax Biotech Co. Ltd. HEV-239 encompasses the 
neutralizing epitope within the (P) domain (aa 368-606; 239 amino acids in length). The purified 
protein is adsorbed to aluminum hydroxide in buffered saline and then packaged into a pre-filled 
syringe for IM use.  
Preclinical testing of HEV-239 was performed in Balb/c mice, Kunming (KM) mice, Sprague 
Dawley rats, and rhesus monkeys, which demonstrated safety and immunogenicity eliciting both 
HEV-specific antibodies and T-cell mediated responses.21,22  HEV-239 provided 100% 
protection against hepatitis E virus challenge (both homologous and heterologous) in naïve 
rhesus monkeys.22 

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An initial Phase I study was conducted in an unpublished study of 44 healthy individuals, 16 – 
55 years of age.21 Immunogenicity data are not available in the IB for this study, safety data are 
outlined in Section 2.3.1 below.21 
In a randomized, placebo-controlled phase II clinical trial in healthy seronegative adults, HEV-
239 was tested in 16 – 55 year old adults in China.23  In this study, several different 
administration schedules and doses were tested against placebo (hepatitis B vaccine).  Group A 
received a 20µg dose in a 0/1/6 month schedule; Group B received a 20µg dose in a 0/6 month 
schedule; Group C received placebo (hepatitis B vaccine) in a 0/1/6 month schedule; and Groups 
E – H received an escalating dose (10 – 40 µg doses) on a 0/1/6 month schedule.  In this study, 
rates of Grade 3 local or systemic reactions were similar (see Section 2.3.1 for additional details) 
between HEV-239 and placebo recipients.  All subjects receiving 3 doses of HEV-239 
seroconverted after the 3rd dose of vaccine. Group A serum HEV IgG Geometric Mean 
Concentrations (GMCs) were 5.95 U/mL one month after the second dose. These were higher 
than the HEV serum IgG GMCs of 0.8 U/mL observed in Group B one month after the first dose 
of the vaccine.  Group A titers also remained higher than Group B at 6 months after enrollment 
(3.12 U/mL versus 0.5 U/mL).23    Both groups boosted to similar levels after the final dose was 
administered at 6 months.  The GMC observed in the lowest dose (10 µg dose) was lower than 
that observed for the other doses (20 – 40 µg doses).  Subjects in Groups A and B were followed 
with serology and an efficacy of 85.2 – 88.7% was observed in prevention of HEV in 
comparison to placebo recipients through 13 months. The 30µg dose was chosen for the 
subsequent Phase III clinical trial of HEV-239.  
This study was followed by a landmark Phase III clinical trial of HEV-239 in healthy Chinese 
adults, which formed the foundation for vaccine approval and licensure in China. The study was 
a randomized, double-blinded, placebo-controlled (1:1 ratio) trial which evaluated the safety, 
immunogenicity, and efficacy of HEV-239 in subjects from 11 townships in the Jiangsu Province 
of China from August 2007 to June 2009.24 Healthy adults ages 16-65 years were randomized to 
receive three doses of either HEV-239 (30 µg of purified recombinant hepatitis E antigen 
adsorbed to 0.8 g aluminum hydroxide suspended in 0.5 mL buffered saline) or placebo (a 
licensed hepatitis B vaccine) administered intramuscularly at 0, 1, and 6 months. The primary 
endpoint was prevention of hepatitis E during 12 months following the 31st day after the third 
vaccine dose. Overall 56,302 were randomized in both the vaccine and placebo groups to achieve 
this primary endpoint.  Smaller groups were followed for immunogenicity (over 5,500 in both 
vaccine and placebo groups) and reactogenicity (over 1,300 in both vaccine and placebo groups). 
Overall, vaccine was well tolerated with similar systemic AEs but slightly higher rates of 
swelling and pain in HEV-239 recipients in comparison to placebo (See Section 2.3.1 for 
additional details). SAEs and deaths were similar between the groups. Overall, 100% protection 

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against pre-specified hepatitis E infection was observed after administration of either 2 or 3 
doses of vaccine.24  In those that received at least one dose of HEV-239, efficacy was 93.8% 
(59.8 – 99.9%).  
A follow-up study was subsequently conducted through 4.5 years for evidence of hepatitis E 
infection.25 In this study, 7 cases of hepatitis E were identified in vaccine recipients versus 53 in 
placebo recipients (vaccine efficacy 86.8%, 95% CI of 71 – 94%).25 In those enrolled in the 
immunogenicity subset, among those that were seronegative prior to vaccination, 87% of those 
who received 3 doses of HEV-239 maintained antibodies against hepatitis E through 4.5 years.    
 
Scientific Rationale 
2.2.1 
Purpose of Study 
A vaccine against HEV that has undergone safety and immunogenicity testing outside of China 
therefore would be very beneficial. Such a vaccine could provide protection for travelers or be 
used in outbreaks to prevent continued transmission of disease. It also would be highly beneficial 
in preventing maternal, fetal, and infant deaths. The vaccine, though licensed in China, is neither 
FDA approved nor WHO prequalified. Although vaccine safety is established in a Chinese 
population, safety in other population cannot be presumed. Data are needed establishing its 
safety and immunogenicity in other populations. Such safety and immunogenicity data from this 
study could enhance efforts to use this important vaccine in other countries around the world.  
This Phase I study will use the dose (30 µg), dosing schedule (0, 1, and 6 months), and route of 
administration (IM) that was used in the Phase 3 study in China.   
 
The purpose of this Phase 1 randomized-controlled double-blind study is to assess the safety, 
reactogenicity, and immunogenicity of HEV-239 in healthy adults. After screening and 
determining their eligibility, 25 subjects will be randomized (4 vaccine: 1 placebo) to receive 
vaccine (n = 20) or placebo (n = 5). Vaccine will be administered intramuscularly (IM) in 0.5 mL 
buffered saline containing 30 μg of purified antigen adsorbed to 0.8 mg aluminum hydroxide.  
The vaccine is provided as single dose units in prefilled syringes (Innovax Biotech); the placebo 
subjects will receive normal saline. Each subject will receive 3 injections, either vaccine or 
placebo at Days 1, 29, and 180. Subjects will be followed through 12 months for safety and 
durability of the immune responses observed.  
 

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2.2.2 
Study Population 
This study will enroll 25 healthy adults in the US population and will include male or non-
pregnant females ages 18-45 (inclusive). They will have no significant medical illness or 
clinically significant physical exam findings including vitals upon enrollment.  They will need to 
meet all eligibility criteria. The subjects will be recruited from the general community 
surrounding Emory University in Atlanta that has substantial experience conducting Phase I 
studies. 
 
 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The potential risks of participating in this trial are those associated with having blood drawn, the 
IM injection and possible reactions to the HEV-239 vaccine with aluminum adjuvant, and breach 
of confidentiality. 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down and elevate his/her legs. Bruising at the blood draw site 
may occur but can be prevented or lessened by applying pressure to the blood draw site for a few 
minutes after the blood is taken. IM injection may also cause transient discomfort and fainting. 
Drawing blood and IM injection may cause infection. The use of aseptic (sterile) technique will 
make infection at the site where blood will be drawn or where the study vaccination will be 
given extremely unlikely. 
There is a small amount of risk to subjects who report that they are in good health but who may 
have an unknown health problem at the time of screening. This trial will screen by physical 
exam, history, and vital signs. The following baseline laboratories will be obtained at screening 
on all subjects to determined eligibility. 
Baseline Laboratories: 
• Hematology  
o Complete blood count with differential (which will include white blood cells, the 
absolute neutrophil count (ANC), the absolute eosinophil count (AEC), 
hemoglobin, and platelets). 
 A WBC evaluation may include any abnormal cells, which will then be 
reported by the laboratory. A hematology evaluation may include 
abnormalities in the red blood cell (RBC) count and/or RBC parameters 

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and/or RBC morphology, which will then be reported by the laboratory. In 
addition, any other abnormal cells in a blood smear will also be reported.  
• Chemistry (fasting or non-fasting) 
o Creatinine 
o Glucose 
o Alanine aminotransferase (ALT) 
• Serology 
o Hepatitis B surface antigen 
o Hepatitis C antibody 
o HIV types 1 and 2 antigen/antibody 
o Hepatitis E virus IgM and IgG antibodies 
• Serum pregnancy test (in women of childbearing potential)  
• Urine 
o A urine drug screen will be obtained  
 
Safety laboratories will be obtained on Day 8 after each vaccine dose and also before the Day 
180 vaccination. To minimize risks, subjects will not receive the subsequent study vaccinations 
if a related Grade 3 laboratory abnormality occurs. The following safety laboratories will be 
obtained on all subjects to determined safety. 
Safety Laboratories:  
• Hematology  
o Complete blood count with differential (which will include white blood cells, ANC, 
AEC, hemoglobin, and platelets).  
 A WBC evaluation may include any abnormal cells, which will then be 
reported by the laboratory. A hematology evaluation may include 
abnormalities in the red blood cell (RBC) count and/or RBC parameters 
and/or RBC morphology, which will then be reported by the laboratory. In 
addition, any other abnormal cells in a blood smear will also be reported. 
Only clinically significant abnormal WBC, abnormal RBC, or any other 
abnormal cells in a blood smear will be reported as AEs.  Relatedness and 
clinical significance for abnormal results will be entered on the Local 
Laboratory Results eCRF. 
• Chemistry (fasting or non-fasting) 
o Creatinine 
o Alanine aminotransferase (ALT) 
 

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Expected risks include pain, soreness, redness, warmth, swelling, firmness and itching at the site 
of injection.  Other reactions may include fever, chills, rash, myalgias, nausea, headache, fatigue, 
malaise and arthralgias.  As with other vaccines, an allergic reaction including anaphylaxis is 
possible.  There may be other side effects from the study vaccinations, even serious ones that are 
not yet known. 
Pre-Clinical and Phase I-III Data: 
Pre-clinical toxicology studies included acute single dose toxicity in mice, repetitive injection 
toxicity and immunogenicity in rats, teratogenic and developmental toxicity studies in mice and 
rats, a local tolerability study in rabbits, and a systemic anaphylaxis study in guinea pigs with 
HEV-239.21   Administration of HEV 239 protein at multiples of clinically relevant doses in a 
relevant clinical formulation was well tolerated in mice, rats, and rabbits. No significant adverse 
effects were identified in single dose and short-term repeat dose studies. In a developmental 
study in the mouse there was a possible dose-related trend towards higher numbers of fetal 
resorptions and abnormal ossification was observed at the highest doses. However, in a second 
study in rats at a higher dose, no adverse effects of treatment were identified.21 No unexpected 
local tolerance issues were identified in any of the preclinical studies. 
Undesirable effects were assessed in a Phase I study in 44 subjects, Phase II (dose-ranging and 
dose scheduling) studies in 505 subjects and a double-blinded, placebo-controlled Phase 3 study 
in which 56,302 subjects were assigned to receive recombinant hepatitis E test vaccine by the 
intramuscular route at 0, 1 and 6 months.  
• 
An initial Phase I study was conducted in an unpublished study of 44 healthy individuals 16 
– 55 years of age.21 Two 20 µg doses (0 and 1 month) were administered IM in an open label 
study in 2005.  No SAEs were observed and local reactions of swelling, itching, and/or pain 
were observed in 3/44 subjects after the first dose and 3/42 subjects after the second dose.  
These symptoms resolved within 48 – 72 hours after inoculation except for one subject who 
had swelling and pain on Day 7. Three subjects had a systemic increase in body temperatures.  
A single subject had a temperature rise to 38.5oC at 72 hours after the second vaccine dose.  
No subjects had clinically significant changes in kidney or liver function 30 days after the 
second dose of vaccine. 
• 
In the randomized placebo-controlled Phase II clinical trial in healthy seronegative adults, 
Grade 3 local reactions were observed only in Group A (20 µg dose x 3 doses) and H (40 µg 
dose x 3 doses) subjects, (rates of 1.6% and 1.7% respectively per dose). Grade 3 systemic 
reactions were observed only in Group H (1.7% per dose).23  The rates of Grade 3 local or 

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systemic reactions were similar in vaccine groups A, B, E – H and those receiving placebo 
(hepatitis B vaccine). The rates of local AEs were similar in vaccine groups, but higher rates 
of itching (6.0% versus 1.6%), swelling (4.3% versus 0.7%), and any local reactions (8.5% 
versus 2.0%) were observed with vaccine group A versus placebo. Pain was also slightly more 
common in all HEV-239 recipients than in placebo (2.4% versus 0.2%). The rates of total 
systemic AEs were also similar between vaccine groups and the placebo group. Rates of AEs 
were the same with different vaccine doses (range 10 – 40 µg). 
• 
Phase III safety data was obtained from 56,302 subjects who received HEV-239 30 µg dose 
at 0, 1, and 6 months and a similar placebo group (hepatitis B vaccine)21,24 who were followed 
up to 4.5 years.25 The population was 16-65 years of age predominantly female (56.5%) and 
Asian. Most of the adverse events were Grade 1 adverse events that generally resolved 
spontaneously without special treatment. Overall, vaccine was well tolerated with similar 
systemic AEs (20.3% versus 19.8%) to placebo. The most common systemic events included 
fever (18.6% vs 18.0%), fatigue and asthenia (2.1% versus 1.5%), and headache (1.1% versus 
0.6%) in vaccine versus placebo. Higher rates of local adverse events were observed with 
vaccine versus placebo (13.5% versus 7.1%) although ≥Grade 3 events were similar. These 
local reactions were primarily increased pain (10.3 versus 5.5%) and swelling (2.3% versus 
0.6%) in comparison to placebo. Unsolicited AEs (12% versus 11.9%), SAEs within 30 days 
of any dose (0.4% versus 0.4%), SAEs after the 30 day window periods (2.5% versus 2.5%), 
and deaths (0.2% versus 0.2%, none were considered related) were similar between vaccine 
and placebo recipients respectively. SAEs that were reported in the Phase 3 study were 
considered unrelated to study vaccine by the Data Safety Monitoring Board (DSMB).  
• 
Retrospective data about women that became pregnant during the Phase III vaccine trial have 
been published.21,26  37 pregnant women in the vaccine group received 53 doses of vaccine 
versus 31 pregnant women in the placebo group receiving 46 doses of placebo. The rates of 
adverse reactions were similar between the two groups and no SAEs reported.  Importantly, 
fetal outcomes (rates of prematurity, body length, and weight) were similar in HEV-239 and 
placebo recipients suggesting the vaccine is safe for both the mother and fetus. 
• 
Data have also been published regarding the safety of HEV-239 vaccination in hepatitis B 
surface antigen carriers.21,27 Local and systemic AEs overall and those ≥Grade 3 were similar 
in vaccine recipients and those that received placebo.  
 
Post-Licensure Data: 
After the vaccine was launched in China in October 2012,28 Innovax implemented a series of 
post-marketing clinical studies but data are limited. A post-marketing surveillance database 
supports the safety of the vaccine based upon an estimated >279,000 administrations of HEV-

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239 to nearly 93,000 people.21 Post-licensure safety data are limited but include a systemic rash 
that occurred 2 days after vaccination in a 28-year-old man.21 This resolved within 3 weeks of 
onset. 
 
Summary Data: 
Clinical trials of HEV-239 were conducted in China and included both hepatitis E immune and 
susceptible individuals.  A vaccine dose of 30 µg absorbed to aluminum hydroxide was selected 
for the Phase III study.  Increased local reactions (primarily pain and swelling) have been 
observed with HEV-239 in comparison to placebo (a hepatitis B vaccine).  Systemic AEs, 
unsolicited AEs, SAEs, and deaths have been similar between HEV-239 and placebo recipients.  
Extensive experience exists with the adjuvant used in this study (aluminum hydroxide). 
Aluminum is currently used in hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTaP, 
Tdap), Haemophilus influenzae type b (Hib), human papillomavirus (HPV) and pneumococcal 
vaccines. Aluminum hydroxide was used as the adjuvant in the Phase I-III studies of HEV-239 
and so the safety profile is anticipated to be incorporated into the overall vaccine safety profile. 
HEV-239 also contains small amounts of thimerosal.  Although concern has been raised about 
thimerosal and risk of autism in children, multiple studies have demonstrated no increase in 
risk.29-31 Thimerosal was also used in the Phase I-III studies of HEV-239, so the safety profile is 
also anticipated to be incorporated into the overall vaccine safety profile.    
Although limited data are available from the Phase III study,26 it is not really known whether this 
vaccine poses risks to an unborn child.  Therefore, women of childbearing potential must agree 
to use an effective method of birth control for at least 28 days prior to first study vaccination and 
for at least 3 months following the third vaccination. 
Subjects will be asked to provide personal health information (PHI). All attempts will be made to 
keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the participating VTEU sites. Electronic files will be 
password-protected. Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this trial will be allowed access to the PHI that is collected. Any publications from 
this trial will not include information that will identify subjects by name. Organizations that may 
inspect and/or copy research records maintained at the participating VTEU sites for quality 
assurance and data analysis include groups such as the local Institutional Review Board (IRB), 
NIAID, and the FDA. 

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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This web site will not include information that can identify subjects.  
There may be other risks, discomforts, or side effects that are unknown at this time. 
 
2.3.2 
Potential Benefits 
It is unknown whether there are direct benefits attributable to the receipt of the HEV-239 
vaccine. Vaccination using the HEV-239 vaccine may or may not provide protection against a 
serious disease with the hepatitis E virus, should the participant be exposed. Exposure is 
uncommon in the US, but occurs particularly with travel outside the US to outbreak or endemic 
areas.  The duration of any such protection against hepatitis E is currently unknown although it is 
thought to be at least 5 years after receipt of the vaccine.25 There may be preparedness benefits to 
society if HEV-239 evaluated in this clinical trial proves to be sufficiently safe and immunogenic 
that it could be employed if an outbreak of hepatitis E virus occurred or as immunoprophylaxis 
for travelers. 
In addition to endemic areas, HEV infection is also a real threat to the displaced populations.  
Outbreaks are common in refugee camps (ref. 
http://www.who.int/mediacentre/factsheets/fs280/en/).  Medical providers, military personnel, 
and peacekeeping force personnel dispatched could also benefit from the protection afforded by 
a HEV vaccine.    
 

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a Phase I double-blind, randomized, placebo controlled trial (1:4 ratio of placebo to 
vaccine) of HEV-239 in 25 US males and non-pregnant females ages 18 – 45 (inclusive) to 
assess the safety, reactogenicity, and immunogenicity of HEV-239. Subjects will receive 3 doses 
of study product on Days 1, 29, and 180 (Table 1: Study Groups). Subjects will remain in the 
study for up to 13 months (including screening). Subjects and study staff will be blinded to a 
subject’s study vaccine assignment. This vaccine is a 239 amino acid sub-fragment of the 660 
amino acid HEV structural protein that is produced in E. coli.  
Table 1: Study Groups 
Study Group 
Number of 
Subjects 
First Dose  
(Day 1, Visit 01) 
Second Dose 
(Day 29, Visit 05) 
Third Dose  
(Day 180, Visit 11) 
HEV-239 
Vaccine 
20 
HEV-239  
HEV-239 
HEV-239 
Placebo 
5 
Placebo 
Placebo 
Placebo 
Total 
25 
 
 
 
• 
The HEV-239 vaccine dose contains 30 micrograms of purified protein adsorbed to 0.8 mg 
aluminum hydroxide suspended in 0.5 mL buffered saline, and thimerosal. 
• 
The placebo will be 0.9% Sodium Chloride Injection, USP (Normal Saline) is a sterile, 
nonpyrogenic, isotonic solution of sodium chloride and Water for Injection (WFI).  A total of 
0.5 mL will be administered which contains sodium chloride 4.5 mg.  It contains no 
bacteriostatic, antimicrobial agent, preservatives, or added buffer and may contain 
hydrochloric acid and/or sodium hydroxide for pH adjustment (pH 5.3 [4.5 to 7.0]). 
Thorough medical history, physical examination (PE), and screening laboratory tests (see 
Sections 7.1 and 7.2) will be obtained at screening after informed consent is obtained.  Each 
subject may be screened beginning 28 days prior to the prime vaccination. At Day 1, the 
inclusion and exclusion criteria will be reviewed prior to randomization.  Subjects who sign an 
informed consent and meet all inclusion criteria and no exclusion criteria will be enrolled in the 
study.   

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Subjects will be observed for 30 minutes after vaccination. The occurrence of solicited injection 
site and systemic reactogenicity events will be measured from the time of study vaccination 
through Day 8 after each vaccination. These will be ascertained through use of an electronic 
Memory (e-Memory) aid, a telephone call on Day 4 after each dose of vaccine, a Day 8 clinic 
visit, and potentially at the Day 15 clinic visit after each dose of vaccine. Unsolicited AEs will be 
collected from vaccination through D29 after each vaccination. SAEs will be collected from the 
time of the first study vaccination through the last study visit (Day 360). 
The study includes multiple phlebotomy time points for immunogenicity and blood collection for 
future use at Visit 1 and Days 8, 15, and 29 after each vaccination. The durability of the immune 
response and future use collection will be assessed at 5 months after the first boost (Day 180) 
and at 6 months after the second boost (Day 360).  
Note: The study day and the day after boost vaccination may not always align due to the 
study windows (See Appendix A) for the appropriate windows of time for each study visit.  
Schematic of Study Design: See Figure 1. 
 
Study Objectives 
3.2.1 
Primary  
• 
Assess the safety and reactogenicity of HEV-239 following delivery of each vaccine dose.  
• 
Assess the number of subjects with ≥4 fold rise in HEV IgG at any time after vaccination.  
 
3.2.2 
Secondary 
• 
Assess the number of subjects with HEV IgM seroconversion at any time after vaccination.  
• 
Assess the number of subjects with HEV IgG seroconversion at any time after vaccination.  
• 
Assess the HEV IgG geometric mean concentrations (GMCs) at any time after vaccination.  
 

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Study Endpoints or Outcome Measures 
3.3.1 
Primary  
• 
Determine the number of solicited local and systemic reactogenicity events from the time of 
study vaccination through D8 after each study vaccination. 
• 
Determine the number of vaccine-related unsolicited adverse events (AE) from the time of 
each study vaccination through D29 after each study vaccination.  
• 
Determine the number of clinical safety laboratory AEs at Day 8 after each study 
vaccination. 
• 
Determine the number of vaccine-related serious adverse event (SAE) from the time of first 
study vaccination through 6 months after the last dose of vaccine. 
• 
Determine the number of subjects showing ≥4 fold rise in serum HEV IgG concentration by 
ELISA from the baseline at Days 8, 15, 29, 36, 43, 57, 180, 187, 194, 208, and 360.  
 
3.3.2 
Secondary  
• 
Determine the number of subjects with HEV IgM seroconversion by ELISA at Days 8, 15, 
29, 36, 43, 57, 180, 187, 194, 208, and 360. 
• 
Determine the number of subjects with HEV IgG seroconversion by ELISA at Days 8, 15, 
29, 36, 43, 57, 180, 187, 194, 208, and 360. 
• 
Determine the HEV IgG GMCs by ELISA in subjects at Days 1, 8, 15, 29, 36, 43, 57, 180, 
187, 194, 208, and 360. 

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STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
HEV-239 (Hecolin®) 
The HEV-239 is a recombinant protein vaccine for the prophylaxis of HEV group 1. The 
Chinese group 1 HEV strain was used to provide the open reading frame 2, which encodes a 239 
amino acid long sub-fragment of the HEV capsid protein. The HEV 239 protein is then 
expressed in E.coli ER2566 using the expression vector pTO-T7 containing the HEV 239 gene.32 
The pTO-T7 prokaryotic vector was derived by inserting the T7 promoter and ribosome binding 
site of pET11a (New England Biolabs) and a plant-derived enhancer upstream of the promoter 
(Xiamen University).33 
The plasmid pGEX-20T-E2 with the HEV ORF2 gene (gift from Hong Kong University) was 
subcloned into the pMD 18-T vector using a TA cloning kit (Takara, Dalian, China) and then 
digested with NdeI and EcoRI.34 The HEV 239 gene fragment was purified by gel electrophoresis 
and a gel extraction kit (Watson Inc., Shanghai, China) and then ligated to the pTO-T7 vector 
previously linearized with NdeI and EcoRI.  
The recombinant plasmids were transfected into E.coli ER2566 and one isolate selected based on 
kanamycin resistance and DNA sequencing for the inserted fragment. The protein assembles into 
virus like particles (VLP). The purified, transformed E. coli (vaccine) is added to an aluminum 
adjuvant and sterilely packaged in a pre-filled syringe (PFS). 
Placebo (Sterile Normal Saline) 
0.9% Sodium Chloride Injection, USP (Normal Saline) is a sterile, nonpyrogenic, isotonic 
solution of sodium chloride and water for injection (WFI).  This product is used as the placebo 
and is packaged in single use containers. Each mL contains sodium chloride 9mg and may 
contain HCl or NaOH for pH adjustment (pH 5.3 [4.5 – 7.0]). It contains no bacteriostatic, 
antimicrobial agent, preservative or added buffer. 
 
4.1.1 
Formulation, Packaging, and Labeling 
HEV-239 (Hecolin®) 

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HEV-239 is a PFS preparation for injection containing the active ingredient, the HEV-239 
protein that assembles into a VLP.  HEV-293 is a truncated HEV capsid protein manufactured by 
fermentation in recombinant E. coli.  The recombinant hepatitis E vaccine (E. coli) finished 
product is manufactured by mixing HEV-239 bulk with aluminum adjuvant.  The formulation 
also includes the excipients sodium chloride, dibasic sodium phosphate, monobasic potassium 
phosphate, potassium chloride, thimerosal and water for injection.  The finished product is a 
white suspension that is sterile filled into PFS for IM injection.  Sedimentation of the HEV-239 
bulk may occur, which can be re-suspended with gentle inversion of the PFS several times.  
Each single-dose PFS contains 30 μg (60 μg/mL) of the recombinant hepatitis E virus antigen in 
a sterile 0.5 mL volume.  See details of the vaccine in Table 2: Composition of Recombinant (E. 
coli) Hepatitis E Vaccine / HEV-239. 
Table 2: Composition of Recombinant (E. coli) Hepatitis E Vaccine / HEV-239 
 
Ingredient 
Quantity (per 1000 doses) 
Active ingredient 
HEV239 protein 
0.030 mg 
Inactive ingredient 
Aluminum hydroxide 
0.800 mg 
Sodium chloride 
4.250 mg 
Thimerosal 
0.025 mg 
Dibasic sodium phosphate 
0.144 mg 
Monobasic potassium 
phosphate 
0.057 mg 
Potassium chloride 
0.010 mg 
Water for injection 
0.5 mL 
  
This study product will be labeled according to manufacturer specifications and include the 
statement “Caution: New Drug – Limited by Federal Law to Investigational Use.” 
 
Further details are included in the package insert for HEV-239 and the Investigator’s Brochure. 

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Placebo (Sterile Normal Saline) 
The placebo consists of physiological saline and is a clear, colorless solution.  It will be provided 
to the pharmacy in vials. The pharmacist will, using sterile technique, fill the syringe with 0.5 
mL volume of normal saline. A label with the statement “Caution: New drug -Limited by Federal 
Law to investigational use” will be placed on the immediate package. 
 
4.1.2 
Product Storage and Stability 
HEV-239 (Hecolin®) 
HEV-239 30µg PFS must be stored between 2ºC to 8ºC (36ºF to 46ºF), protected from light and 
not frozen. In stability studies, the degree of alum adsorption and the antigen content of the 
vaccine at 4°C, 25°C and 37°C remained above 95% for up to 3 months. In addition, in animal 
studies the immunogenicity of the vaccine drug product, when stored at 37°C for 5 weeks, 
showed no significant change from storage at 4oC. HEV-239 is considered stabile for at least 36 
months when maintained under 2oC to 8oC. 
 
Placebo (Sterile Normal Saline) 
Sterile Normal Saline vials are stored at 20ºC to 25ºC (68ºF to 77ºF) [excursions between 15ºC 
and 30ºC (59ºF and 86ºF) are permissible]. 
The temperature of the storage unit must be manually recorded daily (excluding non-business 
days and holidays, as applicable) and continuously monitored and recorded during the course of 
this trial per the participating VTEU site standard operating procedures (SOPs), and 
documentation will be maintained. If the temperature fluctuates outside of the required range, the 
affected study product(s) must be quarantined at the correct storage temperature and labeled as 
‘Do Not Use’ (until further notice). The participating VTEU site’s research pharmacist must alert 
the site principal investigator and study coordinator, if the temperature fluctuates outside of the 
required range. In the event the temperature fluctuates outside of the required range, including 
accidental deep-freezing or disruption of the cold chain, the affected study product(s) must not 
be administered. The site principal investigator or responsible person should immediately contact 
the DMID Product Support Team at DMIDProductSupportTeam@niaid.nih.gov for further 
instructions before any additional study vaccinations are administered. Based on the information 

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collected, DMID and/or the manufacturer will determine whether the affected study product(s) 
can be used. If it cannot be used, the site will receive specific instructions on how to return the 
affected study product(s) to the DMID CMS or destroy it on site. Additional instructions for 
quarantine and DMID contact information are provided in the protocol-specific MOP. 
 
Acquisition/Distribution 
HEV-239 will be supplied by Xiamen Innovax Biotech Co., Ltd.. Upon request by DMID, HEV-
239 will be transferred to the following address: 
DMID Clinical Materials Services (CMS) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone: 240-477-1350 
Fax: 240-477-1360 
Email: DMID.CMS@ThermoFisher.com 
Study products (HEV-239 and the normal saline placebo) for study vaccine preparation will be 
provided through the DMID CMS to the participating VTEU site prior to the start of this trial 
upon request and with prior approval from DMID. Should the site principal investigator require 
additional HEV-239, placebo, or sterile empty syringes or needles during this trial, further 
instructions are provided in the protocol-specific MOP. 
 
Dosage/Regimen, Preparation, Dispensing and Administration of 
Study Intervention/Investigational Product 
Visually inspect the study products upon receipt and prior to use. If the study product(s) 
appear(s) to have been damaged, contaminated or discolored, contain(s) visible particulate 
matter, or if there are any concerns regarding the integrity, do NOT use the affected study 
product(s). The affected study product(s) must be quarantined at 2°C to 8°C (36°F to 46°F) for 
HEV-239 and at 20ºC to 25ºC (68ºF to 77ºF) [excursions between 15ºC and 30ºC (59ºF and 
86ºF) are permissible] for sterile normal saline and labeled as ‘Do Not Use’ (until further notice). 
The site principal investigator or responsible person should immediately contact the DMID 

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Product Support Team at DMIDProductSupportTeam@niaid.nih.gov and DMID Clinical Project 
Manager for further instructions before any additional study vaccinations are administered. 
Based on the information collected, DMID and/or the manufacturer will determine whether the 
affected study product(s) can be used. If the affected study product(s) cannot be used, the site 
will receive specific instructions on how to return the affected study product(s) to the DMID 
CMS or destroy the affected study product(s) on site. If the study product is unusable, study 
personnel will use another syringe or vial from the study supply. Replacement syringe or vial 
may be requested by contacting DMID. Additional instructions for quarantine and DMID contact 
information are provided in the protocol-specific MOP. 
 
HEV-239 (Hecolin®) 
HEV-239 is a pre-filled syringe (PFS) preparation for injection. The finished product is a white 
suspension that is sterile filled into PFS for intramuscular (IM) injection. Sedimentation of the 
HEV bulk may occur, which can be re-suspended with gentle inversion of the PFS several times. 
Each single-dose PFS contains 30 μg (60 μg/mL) of the recombinant hepatitis E virus antigen in 
a sterile 0.5 mL volume.  
 
Placebo (Sterile Normal Saline) 
0.9% Sodium Chloride Injection, USP (Normal Saline) is a sterile, nonpyrogenic, isotonic 
solution of sodium chloride and WFI.  Each mL contains sodium chloride 9 mg.  It contains no 
bacteriostatic, antimicrobial agent, preservatives, or added buffer and may contain hydrochloric 
acid and/or sodium hydroxide for pH adjustment (pH 5.3 [4.5 to 7.0]).  This product will be used 
as the placebo and is supplied as a single-dose vial. The sterile Normal Saline vials are stored at 
20ºC to 25ºC (68°F to 77ºF) [See USP Controlled Room Temperature; excursions between 15°C 
and 30°C (59°F and 86°F) are permitted].  The placebo will be prepared by withdrawing 
sufficient volume to deliver a dose of 0.5 mL of 0.9% Sodium Chloride, USP. 
Administration of Vaccine 
Based on dosing group assignment, subjects will receive study vaccine (HEV-239) or Placebo as 
a 0.5 mL IM injection into the central and thickest portion of the deltoid muscle.  An unblinded 
study vaccine administrator will vaccinate the subject. Study product will be distributed from the 
pharmacy with a sleeve (e.g., tape) over the syringe to prevent unintentional unblinding of blinded 
personnel. The choice of the arm for vaccine administration is at the subject’s discretion.  Aseptic 

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technique will be used for the withdrawal and administration of each dose of study product using 
a sterile needle appropriate in length for each participant.  Detailed information regarding 
administration of study vaccine will be provided in the protocol-specific MOP. 
 
 
Pre-determined Modification of Study Intervention/Investigational 
Product for an Individual Subject 
There will be no dose modifications. If a subject’s second study vaccination is deferred, it should 
be rescheduled to occur within the acceptable protocol-specified window for that visit. No 
exceptions to the protocol-specified window will be made. 
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
After receipt of study products, the site principal investigator is responsible for study product 
distribution and disposition, and has ultimate responsibility for study product accountability.  The 
site principal investigator may delegate to the participating VTEU site’s research pharmacist 
responsibility for study product accountability. The participating VTEU site’s research pharmacist 
will be responsible for maintaining complete records and documentation of study product receipt, 
accountability, dispensation, storage conditions, and final disposition of the study product(s). The 
pre-filled HEV-239 single use syringe and the placebo syringe will be disposed of per site 
processes once the vaccine is administered. 
HEV-239 and placebo normal saline vials will be stored and shipped from the DMID contract 
Clinical Material Services (CMS) to the Clinical Sites. Once received, HEV-239 and placebo 
normal saline vials will be stored in and dispensed by the Investigational Pharmacy.   Unused 
product will be handled in accordance with the MOP. 
The Food and Drug Administration (FDA) requires accounting for the disposition of all 
investigational products. The Investigator is responsible for ensuring that a current record of 
product disposition is maintained and product is dispensed only at an official study site by 
authorized personnel as required by applicable regulations and guidelines. Records of product 
disposition, as required by federal law, consist of the date received, date administered, quantity 
administered, and the subject number to whom the drug was administered.  

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The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the investigational product. The pharmacy records must be available 
for inspection by the DMID monitoring contractors, and is subject to inspection by a regulatory 
agency (e.g., FDA) at any time. An assigned Study Monitor will review the pharmacy records. 
Unused investigational product HEV239 syringes stored at [2oC to 8oC] and sterile normal saline 
at 20ºC to 25ºC (68°F to 77ºF) will be stored in the Investigational Pharmacy until clinical trial 
accountability is completed, monitored and released for disposition when written authorization 
from the study Sponsor (CPM/DMID) received.  At study termination, all unused investigational 
product will be handled in accordance with the MOP following complete drug accountability and 
monitoring. 

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SELECTION OF SUBJECTS AND STUDY 
ENROLLMENT AND WITHDRAWAL 
Subject Inclusion and Exclusion Criteria must be confirmed by a study clinician licensed to make 
medical diagnoses. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
 
Eligibility Criteria 
Screening for eligible subjects must be performed within 28 days before Day 1. The investigator 
should ensure that all study enrollment criteria have been met at the end of the screening period. 
If a subject’s status changes (including laboratory results or the receipt of additional medical 
records) after screening but before the prime vaccination such that the subject no longer meets all 
eligibility criteria, then the subject should be excluded from participation in the study. 
 
Enrollment will be based solely on the eligibility criteria outlined below and will be open to both 
sexes and all races/ethnicities. Sex and minority breakdown cannot be predicted for this study 
but should follow the general population distribution. Pregnant women and women who are 
breastfeeding will not be eligible for inclusion.  
 
5.1.1 
Subject Inclusion Criteria 
Prospective subjects must meet all of the following inclusion criteria to be considered 
eligible for enrollment: 
1. Subject must provide written informed consent  
2. Subject must be able to comprehend and willing to comply with all study visits 
and procedures (up to 13 months from enrollment). 
3. Subject must be a man or a non-pregnant woman1 aged 18-45 years (inclusive). 
1Females of childbearing potential must have a negative serum human 
chorionic gonadotropin (β-HCG) pregnancy test at screening and negative 
urine β-HCG pregnancy test within 24 hours prior to (each) vaccination. 

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4. Subject must be in good general health as determined by medical history, vital 
signs,2 body mass index (BMI),3 physical examination, and clinical judgment of 
the investigator. 
2Oral temp <38.0°C/100.4°F; pulse 51 to 100 bpm; systolic blood pressure 
90 to 140 mm Hg, and diastolic blood pressure 55 to 90 mmHg.  
3BMI ≥18.5 and <35 kg/m2. 
 
5. Subject’s screening laboratory values4,5 must be within site normal limits6 within 
28 days of enrollment. 
4Screening labs will include: 
• White blood cell (WBC) count 
• Hemoglobin (HgB) 
• Platelets 
• Absolute neutrophil count (ANC) 
• Absolute eosinophil count (AEC) 
• Creatinine 
• Glucose (random, must be <140) 
• Alanine Aminotransferase (ALT)  
• HIV 1/2 antibody/antigen test, Hepatitis B surface antigen 
(HBsAg), and Hepatitis C virus (HCV) antibody  
 
5Minor abnormalities are considered acceptable if not clinically significant 
(e.g., MCV). Repeating the screening tests once is permitted for out-of-
range values provided there is an alternative explanation for the out-of-
range value. The alternative explanation for the out-of-range value should 
be documented in the subject’s source documents. 
 
6See Appendix B for site normal values.  Creatinine, glucose, and ALT 
values lower than the normal range may be acceptable if the PI or a 
designated licensed clinician determines that these laboratory findings are 
not clinically significant. The HIV 1/2 antibody/antigen test, Hepatitis B 
surface antigen (HBsAg), and Hepatitis C virus (HCV) antibody must be 
non-reactive.   
 
6. Subject’s HEV-specific IgG and IgM are negative by ELISA at screening.  
7. Subject agrees to not to participate in another clinical trial during the study period.  

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8. Subject agrees not to donate blood from screening through Day 270.  
9. Female subjects must be of non-childbearing potential7 OR must use an 
acceptable method of contraception8 from 28 days before prime vaccination until 
at least 3 months after the last vaccination. 
7Surgically sterile via tubal ligation, bilateral oophorectomy, hysterectomy 
or postmenopausal for ≥1 year. 
 
8Abstinence (defined as refraining from heterosexual intercourse), 
monogamous relationship with vasectomized partner, barrier methods 
such as male or female condoms with spermicide or diaphragms with 
spermicide, intrauterine devices, and licensed hormonal methods (such as 
birth control pills, skin patches, Implanon®, Nexplanon®, DepoProvera®, 
or NuvaRing®). 
 
10. Male subjects must be surgically sterile via vasectomy OR must use an acceptable 
method of contraception9 from prime vaccination until at least 3 months after the 
last boost vaccination. 
9Abstinence (defined as refraining from heterosexual intercourse), or 
condoms with spermicide. 
 
11. Subjects must have consistent access to the internet to perform electronic data 
entry. 
 
5.1.2 
Subject Exclusion Criteria 
Prospective subjects must not meet any of the following exclusion criteria to be considered 
eligible for enrollment: 
1. Has a previous HEV infection or chronic liver disease.  
2. Has received any experimental agent10 within 30 days prior to first vaccination, or 
the expected recipient of any experimental agent during this trial-reporting period.  
10Including vaccines, drugs, biologics, devices, and/or blood products 
3. Female subject is pregnant (or has a positive pregnancy test prior to vaccination) 
or breast feeding, or planning to become pregnant within 3 months after the last 
boost vaccination.  

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4. Fever (≥38.0°C/100.4°F) or other acute illness within 3 days prior to first 
vaccination. 
 
5. Infection requiring systemic antibiotics or antiviral treatment within the 7 days 
prior to first vaccination. 
 
6. Has a positive urine drug screen for amphetamines11, cocaine, opiates, or 
phencyclidine. 
11Prescription amphetamines are not exclusionary. 
7. Chronic, clinically significant medical or psychiatric conditions that,12 in the 
opinion of the investigator, may pose additional risk to the subject if she/he 
participates in the study. 
12Permissible conditions include but are not limited to mild, well-
controlled asthma, well-controlled depression, well-controlled anxiety, 
seasonal allergies, and well-controlled hypertension. 
 
8. Receipt of immunosuppressive drugs13-15 or biologic agents within the 30 days 
prior to enrollment.  
13This includes use of oral or parental prednisone. This also includes 
allergy desensitization injections from 14 days prior to each vaccination 
through 14 days after each vaccination. The use of topical steroids for 
mild uncomplicated dermatitis permissible after therapy is completed. 
Over-the-counter (OTC) corticosteroid nasal sprays for allergic rhinitis are 
permissible. The use of low or moderate dose inhaled steroids is 
permissible. Doses are defined as per age as using inhaled high-dose per 
reference chart in the National Heart, Lung and Blood Institute Guidelines 
for the Diagnosis and Management of Asthma (EPR-3) or other lists 
published in UPTODATE. 
 
14Receipt of systemic, prescription medications for the treatment of 
chronic medical conditions or variations of normal physiologic functions 
may be permissible if, in the opinion of the investigator, they are used for 
conditions that are not clinically significant and would not impact the 
safety of the subject or the safety and immunogenicity outcomes of the 
protocol. 
 
15Use of systemic, over-the-counter medications and PRN systemic, 
prescription medication may be allowed if, in the opinion of the 

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investigator, they pose no additional risk to subject safety or assessment of 
immunogenicity/reactogenicity. 
 
9. Has known neoplastic disease16 anticancer therapy, or radiation therapy within 3 
years prior to first study vaccination.  
16Excluding non-melanoma skin cancer, such as squamous cell skin cancer 
or basal cell skin cancer, cured by surgical excision. 
 
10. Has a history of any hematologic malignancy at any time. 
11. Has a known or suspected congenital or acquired disease that impairs the immune 
system, including functional asplenia or immunosuppression as a result of 
underlying illness or treatment. 
 
12. Has prior organ and/or stem cell transplant. 
13. Has a history of abuse of alcohol or drugs that, in the opinion of the investigator, 
may interfere with the subject’s ability to comply with the protocol. 
 
14. Has behavioral or cognitive impairment or psychiatric conditions that, in the 
opinion of the investigator, may interfere with the subject’s ability to participate 
in the trial. 
 
15. Has received blood products or immunoglobulin within six months prior to 
vaccination.   
 
16. Travel to Asia, the Middle East, Africa, or Central America or to an area with an 
active Hepatitis E outbreak17 within the last 90 days or intention to travel to such 
areas during the study.  
17See study-specific Manual of Operating Procedures (MOP) for a listing 
of outbreaks within the last 3 years.  
 
17. Receipt of any inactivated vaccine from 2 weeks prior to each vaccination through 
2 weeks after each vaccination.  
18. Receipt of any live vaccine from 4 weeks prior to each vaccination through 4 
weeks after each vaccination.   

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19. Known hypersensitivity or allergy to aluminum, any component of the vaccine, or 
other serious adverse reactions to vaccines or vaccine products. 
20. Subject who, in the opinion of the investigator, is unlikely to adhere to the 
requirements of the study. 
21. Any condition that, in the opinion of the investigator, might interfere with 
assessing the study objectives.  
 
 
Requirements Prior to Administration of the Second and Third 
Vaccinations 
The following assessments should be performed prior to the administration of the second and 
third vaccinations to determine if the subject remains eligible: 
Subjects will not receive the subsequent vaccine doses (first or second boost) if any of the pre-
specified individual halting criteria are met (see below and Section 8.6.2). 
• 
For a woman of childbearing potential, an acceptable form of birth control must be verified. 
A urine pregnancy test must be performed and the subject must not be pregnant before 
administering the vaccine.  
• 
Subjects who do not meet inclusion criteria 2 – 4 and 7 – 11, and exclusion criteria 7 – 21 will 
not be given the second or third vaccination.  
• 
Subjects who have a fever (defined as an oral temperature ≥38.0oC) or a moderate or severe 
acute illness at the time of or in the three days prior to boost vaccination administration may 
have the boost vaccination deferred until they recover as long as this remains within the study 
window (see Section 6.3). 
• 
Subjects who do not receive the second dose of vaccine for any reason will not receive the 
third dose of vaccine. 
 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
5.3.1 
Withdrawal from the Study or Discontinuation of the Study Product  
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled.   

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An investigator may also withdraw a subject from receiving the study product for any reason. 
Follow-up safety evaluations and blood draws will be conducted, if the subject agrees.  If a 
subject withdraws or is withdrawn prior to completion of the study, the reason for this decision 
must be recorded in the electronic case report forms (eCRFs).  
The reasons, might include, but are not limited to the following: 
• 
Subject no longer meets eligibility criteria 
• 
Subject meets individual halting criteria (reference to Section 8.6.2) 
• 
Subject becomes noncompliant 
• 
Medical disease or condition, or new clinical finding(s) for which continued participation, in 
the opinion of the investigator might compromise the safety of the subject, interfere with the 
subject's successful completion of this study, or interfere with the evaluation of responses 
• 
Subject lost to follow-up 
• 
Subject becomes pregnant, if applicable 
• 
Determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being (or treatment failure, if applicable) 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product.  If the subject 
consents, every attempt will be made to follow all AEs through resolution.  The procedures that 
collect safety data for the purposes of research must be inclusive in the original informed consent 
or the investigator may seek subsequent informed consent using an IRB/IEC-approved consent 
form with the revised procedures. 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study.  
5.3.2 
Subject Replacement 
Subjects who withdraw, or are withdrawn or terminated from this trial, or are lost to follow-up 
after signing the informed consent form (ICF), randomization and receipt of study vaccine will 
not be replaced. However, if a subject withdraws after signing the ICF, but before randomization 
and/or receipt of study vaccine, they may be replaced. 
 

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5.3.3 
Study Termination  
If the study is prematurely terminated by the sponsor, any regulatory authority, the IRB, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. If the DMID agrees, then other 
study procedures (e.g., safety follow-up, blood sampling for safety and immunogenicity) may be 
continued through the remaining study visits but no further vaccinations will occur. The 
investigator will provide a detailed written explanation of the termination to the IRB/IEC. 

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STUDY PROCEDURES 
 
Screening Visit: Visit 00 (Day -28 to -1, All Groups) 
Up through 28 days before baseline (the day of the subject’s prime vaccination, Day 1), 
screening assessments as indicated in Sections 5.1.1 and 5.1.2 will occur. Screening may be split 
into multiple days or visits. 
The ICF will be signed before any study-specific procedures at the start of the screening period 
(see Section 9.2). For women of childbearing potential, it should be confirmed that adequate 
birth control measures were used from at least 28 days before the prime vaccination with a 
negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test available before Day 1 
and a negative urine β-hCG pregnancy test immediately (within 24 hours) prior to each study 
vaccination. All women, except for those of non-childbearing potential, will be asked to use 
adequate birth control from signing of the ICF onwards until at least 3 months after the last boost 
vaccination.   
The investigator will provide detailed information on the study to the subject and will obtain 
written informed consent prior to each subject’s study participation. The procedures indicated in 
Section 7 will only be performed after the subject’s written informed consent has been obtained.  
The following assessments are performed during the Screening Visit to determine eligibility 
requirements as specified in the inclusion and exclusion criteria (Section 5.1.1 and 5.1.2). The 
written informed consent must be signed prior to conducting any of the assessments listed below:  
• 
Obtain medical history (see Section 7.1.1) 
• 
Review prestudy medications and therapies up to 30 days prior to start of screening and 
record on the eCRF. 
• 
Measure vital signs (HR, BP, and oral body temperature). This will also include height and 
weight for determination of BMI.   
• 
Perform abbreviated physical examination. This will be done by a licensed clinician listed on 
FDA Form 1572.  
• 
Review of birth control history with female subjects. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy   

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• 
Obtain blood and urine for baseline screening laboratories (see Section 2.3.1 for additional 
details). 
• 
Review inclusion and exclusion criteria  
Laboratory values will be determined according to the Appendix B Toxicity Table. 
The overall eligibility of the subject to participate in the study will be assessed once all screening 
values and results of any other required evaluations are available. Retesting of values (e.g., 
baseline screening laboratories) that lead to exclusion is allowed once using an unscheduled visit 
during screening to assess eligibility, provided there is an alternative explanation for the out of 
range value. Study subjects who qualify for inclusion will be contacted and scheduled for 
enrollment and prime vaccination within the window for enrollment. 
 
Enrollment/Baseline: Visit 01, Day 1, Vaccination Clinic Visit (All 
Groups) 
The investigator should ensure that all enrollment criteria have been met during screening. If a 
subject’s status (including any unscheduled laboratory results or the receipt of additional medical 
records) after screening but before the prime vaccination changes such that the subject no longer 
meets all enrollment criteria, then the subject should be excluded from participation in the study.  
If the initial laboratory screening occurred more than 28 days before baseline (Day 1) but the 
subject was unable to be vaccinated within the 28-day window (e.g., due to meeting Exclusion 
Criteria in Section 5.1.2 or for other reasons), the subject must have safety laboratories repeated 
(see protocol-specific MOP for details about laboratories).   
Prior to Vaccination  
• 
Review inclusion and exclusion criteria to ensure the subject remains eligible for enrollment  
• 
Review medical history for any interval changes 
• 
Review prestudy and concomitant medications  
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Subjects who have a diastolic blood pressure value >90 mmHg or a systolic blood pressure 
value >140 mmHg prior to the prime vaccination can receive the vaccination if the elevated 
blood pressure is considered to be not clinically significant and the subject had acceptable 
blood pressure at screening. 

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• 
Perform symptom-directed PE (if needed). 
• 
Perform urine pregnancy test for women of childbearing potential within 24 hours prior to 
immunization. Test result must be known and negative prior to vaccination.  
• 
Review of birth control history with female subjects 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Subjects will be enrolled in Advantage eClinical® and randomly assigned to a Study Group 
(see Section 10.3.1 Randomization Procedures for details). 
• 
Obtain serum for immunogenicity assays. 
• 
Collect PBMCs and plasma for future assays. 
• 
Study vaccine will be prepared on-site by an unblinded site research pharmacist (see Section 
4.3).  
• 
Pre-administration reactogenicity assessments will be performed prior to the first study 
vaccination to establish baseline. A subject with mild pre-administration reactogenicity 
which is transient, resolving, or clinically insignificant may receive vaccination at the 
investigator’s discretion.  
Vaccination  
• 
The unblinded study vaccine administrator will vaccinate the subject according to 
vaccination assignment in the subject’s preferred arm.  
• 
Following receipt of study product, subjects may have the injection site covered with an 
adhesive bandage (e.g. BAND-AID®) as needed.  
 
Following Vaccination  
• 
Observe subjects for a minimum of 30 minutes following immunization. 
• 
Provide subjects with the e-Memory aid instructions, ruler and thermometer and instruct the 
subject on the observance, grading and recording of unsolicited reactions and solicited 
injection site reactions, systemic reactions and daily maximum temperatures through Day 8, 
beginning with the day of vaccination (Day 1). Subjects will be instructed on how to 
complete the e-Memory aid. Reactions that persist beyond Day 8 will continue to be recorded 

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until the subject is symptom-free. As a back-up method in the event of internet connectivity 
issues, subjects will also be provided a paper memory aid. 
• 
Instruct subjects as to when to contact the investigator about unsolicited AEs.  
• 
Review hypersensitivity symptoms with the subject and counsel to contact study personnel or 
seek medical attention immediately. 
• 
Post-administration reactogenicity assessments will be performed, vital signs will be 
obtained, and the vaccination site assessed at a minimum of 30 minutes following 
immunization.  
• 
Evaluate vaccination site. 
• 
Solicited and Unsolicited AEs, and SAEs will be collected and documented on the eCRFs, 
together with the information on any concomitant medications. 
 
Planned Study Visits 
6.3.1 
Follow-up 
6.3.1.1 
Visit 02, Day 4 +/- 1 Day; Telephone Call 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
Review concomitant medications  
 
6.3.1.2 
Visit 03, Day 8 +/- 1 Day; Clinic Visit 
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Perform symptom-directed PE (if needed) 
• 
Evaluate vaccination site  
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 

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 08 FEB 2019 
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• 
If symptoms persist, clinic staff will attempt to follow up with the subject until the symptoms 
resolve. Maximum severity post Day 8 and stop date of the symptoms will be recorded by 
clinic staff on the Solicited Events eCRF.  
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain blood for safety laboratories (Section 2.3.1). 
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.1.3 
Visit 04, Day 15 +/- 2 Days; Clinic Visit 
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Perform symptom-directed PE (if needed) 
• 
Evaluate vaccination site (if needed) 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain blood for safety laboratories (if needed due to abnormalities at prior visit, Section 
2.3.1) 
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.1.4 
Visit 05, Day 29 +/- 2 Days; Clinic Visit 
Prior to Vaccination  
• 
Review medical history for any interval changes 

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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Review concomitant medications  
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Subjects who have a diastolic blood pressure value >90 mmHg or a systolic blood pressure 
value >140 mmHg prior to the prime vaccination can receive the vaccination if the elevated 
blood pressure is considered to be not clinically significant and the subject had acceptable 
blood pressure at screening. 
• 
Perform symptom-directed PE (if needed) 
• 
Perform urine pregnancy test for women of childbearing potential within 24 hours prior to 
immunization. Test result must be known and negative prior to vaccination.  
• 
Review of birth control history with female subjects. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy. 
• 
Obtain serum for immunogenicity assays. 
• 
Collect PBMCs and plasma for future assays. 
• 
Review inclusion and exclusion criteria to ensure the subject remains eligible for boost 
vaccination. 
• 
Study vaccine will be prepared on-site by an unblinded site research pharmacist (see Section 
4.3).  
• 
Pre-administration reactogenicity assessments will be performed prior to vaccination to 
establish baseline. A subject with mild pre-administration reactogenicity which is transient, 
resolving, or clinically insignificant may receive vaccination at the investigator’s discretion.  
Vaccination  
• 
The unblinded study vaccine administrator will vaccinate the subject according to 
vaccination assignment in the subject’s preferred arm.  
• 
Following receipt of study product, subjects may have the injection site covered with an 
adhesive bandage (e.g. BAND-AID®) as needed.  
 
Following Vaccination  

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• 
Observe subjects for a minimum of 30 minutes following immunization. 
• 
Provide subjects with the e-Memory aid instructions, ruler and thermometer and instruct the 
subject on the observance, grading and recording of unsolicited reactions and solicited 
injection site reactions, systemic reactions and daily maximum temperatures through Day 8, 
beginning with the day of vaccination (Day 1). Subjects will be instructed on how to 
complete the e-Memory aid. Reactions that persist beyond Day 8 will continue to be recorded 
until the subject is symptom-free. As a back-up method in the event of internet connectivity 
issues, subjects will also be provided a paper memory aid. 
• 
Instruct subjects as to when to contact the investigator about unsolicited AEs.  
• 
Review hypersensitivity symptoms with the subject and counsel to contact study personnel or 
seek medical attention immediately. 
• 
Post-administration reactogenicity assessments will be performed, vital signs will be 
obtained, and the vaccination site assessed at a minimum of 30 minutes following 
immunization.  
• 
Evaluate vaccination site. 
• 
Solicited and Unsolicited AEs and SAEs will be collected and documented on the eCRFs, 
together with the information on any concomitant medications. 
 
6.3.1.5 
Visit 06, Day 32 (Day 4 after First Boost; +/- 1 Day); Telephone Call 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
Review concomitant medications  
 
6.3.1.6 
Visit 07, Day 36 (Day 8 after First Boost; +/- 1 Day); Clinic Visit 
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Perform symptom-directed PE (if needed) 
• 
Evaluate vaccination site  

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 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
If symptoms persist, clinic staff will attempt to follow up with the subject until the symptoms 
resolve. Maximum severity post boost Day 8 and stop date of the symptoms will be recorded 
by clinic staff on the Solicited Events eCRF.  
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain blood for safety laboratories (Section 2.3.1). 
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.1.7 
Visit 08, Day 43 (Day 15 after First Boost; +/- 2 Days); Clinic Visit 
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Perform symptom-directed PE (if needed) 
• 
Evaluate vaccination site (if needed) 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain blood for safety laboratories (if needed due to abnormalities at prior visit, Section 
2.3.1) 
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 

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Phase I Study of HEV-239 
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6.3.1.8 
Visit 09, Day 57 (Day 29 after First Boost; +/- 2 Days); Clinic Visit 
• 
Perform symptom-directed PE (if needed) 
• 
Review of Unsolicited AEs and SAEs. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.1.9 
Visit 10, Day 120 (Day 92 after First Boost; +/- 14 Days); Telephone Call 
• 
Review of SAEs. 
• 
Review concomitant medications if associated with an SAE. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy 
  
6.3.1.10 
Visit 11, Day 180 +/- 14 Days from Prime Vaccination; Clinic Visit 
Prior to Vaccination  
• 
Review medical history for any interval changes 
• 
Review concomitant medications  
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Subjects who have a diastolic blood pressure value >90 mmHg or a systolic blood pressure 
value >140 mmHg prior to the prime vaccination can receive the vaccination if the elevated 
blood pressure is considered to be not clinically significant and the subject had acceptable 
blood pressure at screening. 
• 
Perform symptom-directed PE (if needed). 
• 
Perform urine pregnancy test for women of childbearing potential within 24 hours prior to 
immunization. Test result must be known and negative prior to vaccination.  
• 
Review of birth control history with female subjects. 

DMID Protocol 15-0108 
Version 2.0 
Phase I Study of HEV-239 
 08 FEB 2019 
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DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy.  
• 
Obtain blood for safety laboratories (Section 2.3.1).  
• 
Obtain serum for immunogenicity assays. 
• 
Collect PBMCs and plasma for future assays 
• 
Review inclusion and exclusion criteria to ensure the subject remains eligible for boost 
vaccination 
• 
Study vaccine will be prepared on-site by an unblinded site research pharmacist (see Section 
4.3).  
• 
Pre-administration reactogenicity assessments will be performed prior to vaccination to 
establish baseline. A subject with mild pre-administration reactogenicity which is transient, 
resolving, or clinically insignificant may receive vaccination at the investigator’s discretion.  
 
Vaccination  
• 
The unblinded study vaccine administrator will vaccinate the subject according to 
vaccination assignment in the subject’s preferred arm.  
• 
Following receipt of study product, subjects may have the injection site covered with an 
adhesive bandage (e.g. BAND-AID®) as needed.  
 
Following Vaccination  
• 
Observe subjects for a minimum of 30 minutes following immunization. 
• 
Provide subjects with the e-Memory aid instructions, ruler and thermometer and instruct the 
subject on the observance, grading and recording of unsolicited reactions and solicited 
injection site reactions, systemic reactions and daily maximum temperatures through Day 8, 
beginning with the day of vaccination (Day 1). Subjects will be instructed on how to 
complete the e-Memory aid. Reactions that persist beyond Day 8 will continue to be recorded 
until the subject is symptom-free. As a back-up method in the event of internet connectivity 
issues, subjects will also be provided a paper memory aid. 
• 
Instruct subjects as to when to contact the investigator about unsolicited AEs.  

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Version 2.0 
Phase I Study of HEV-239 
 08 FEB 2019 
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DMID eCTD Compliant Interventional Protocol Template and Instructions, Version 4.0, Dated May 15, 2018 
• 
Review hypersensitivity symptoms with the subject and counsel to contact study personnel or 
seek medical attention immediately. 
• 
Post-administration reactogenicity assessments will be performed, vital signs will be 
obtained, and the vaccination site assessed at a minimum of 30 minutes following 
immunization.  
• 
Evaluate vaccination site. 
• 
Solicited and Unsolicited AEs and SAEs will be collected and documented on the eCRFs, 
together with the information on any concomitant medications. 
 
6.3.1.11 
Visit 12, Day 184 (Day 4 after Second Boost; +/- 1 Day); Telephone Call 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
Review concomitant medications  
 
6.3.1.12 
Visit 13, Day 187 (Day 8 after Second Boost; +/- 1 Day); Clinic Visit 
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Perform symptom-directed PE (if needed) 
• 
Evaluate vaccination site  
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
If symptoms persist, clinic staff will attempt to follow up with the subject until the symptoms 
resolve. Maximum severity post boost Day 8 and stop date of the symptoms will be recorded 
by clinic staff on the Solicited Events eCRF.  
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  

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 08 FEB 2019 
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• 
Obtain blood for safety laboratories (Section 2.3.1).  
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.1.13 
Visit 14, Day 194 (Day 15 after Second Boost; +/- 2 Days); Clinic Visit 
• 
Obtain vital signs (HR, BP, and oral temperature) 
• 
Perform symptom-directed PE (if needed) 
• 
Evaluate vaccination site (if needed) 
• 
Interview the subject and review the e-Memory aid data. Address any incomplete, missing, or 
inconsistent data.  
• 
Review of Unsolicited AEs and SAEs. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain blood for safety laboratories (if needed due to abnormalities at prior visit, Section 
2.3.1). 
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.1.14 
Visit 15, Day 208 (Day 29 after Second Boost; +/- 2 Days); Clinic Visit 
• 
Perform symptom-directed PE (if needed) 
• 
Review of Unsolicited AEs and SAEs. 
• 
Counsel subjects to use adequate birth control methods to avoid pregnancy  
• 
Review concomitant medications.  
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 

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 08 FEB 2019 
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6.3.1.15 
Visit 16, Day 270 (Day 90 after Second Boost; +/- 14 Days); Telephone Call 
• 
Review of SAEs. 
• 
Review concomitant medications if associated with an SAE. 
6.3.2 
Final Study Visit: Visit 17, Day 360 +/- 28 days (Day 180 after Second Boost); 
Clinic Visit 
• 
Perform symptom-directed PE (if needed) 
• 
Review of SAEs. 
• 
Review concomitant medications if associated with an SAE. 
• 
Obtain serum for immunogenicity assays 
• 
Collect PBMCs and plasma for future assays. 
 
6.3.3 
Early Termination Visit  
The following activities may be performed at the early termination visit for subjects who 
withdraw, or are withdrawn or terminated from this study: 
• Obtain vital signs (BP, HR, and oral temperature) (if needed) 
• Perform symptom-directed PE (if needed) 
• Evaluate vaccination site if within Day 15 after each vaccination 
• 
Review Unsolicited AEs if within Day 29 after each vaccination 
• Review of SAEs.  
• If occurring through Day 8 after any vaccine dose, interview the subject and review the e-
Memory aid data. Address any incomplete, missing, or inconsistent data. If visit occurs 
between Day 8 and Day 29, if needed the subject will be interviewed and ongoing 
solicited AEs will be reviewed.  
• If symptoms persist post Day 8, clinic staff will attempt to follow up with the subject 
daily until the symptoms resolve. Maximum severity post Day 8 and stop date of the 
symptoms will be recorded by clinic staff on the Solicited Events eCRF. 
• Review concomitant medications.  
• Obtain blood for safety laboratories (if needed) 
• Obtain serum for immunogenicity assays (if needed) 

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• Collect PBMCs and plasma for future assays (if needed).  
• Review of birth control history with female subjects. 
• Counsel subjects to use adequate birth control methods to avoid pregnancy if before 3 
months after the last study vaccination 
• A urine pregnancy test for women of childbearing potential may be performed.  
 
 
Unscheduled Study Visits  
Unscheduled visits may occur at any time during this study.  Any of the following activities may 
be performed: 
• Obtain vital signs (BP, HR, and oral temperature) (if needed) 
• Perform symptom-directed PE (if needed) 
• Evaluate vaccination site if within Day 15 after each vaccination 
• 
Review Unsolicited AEs if within Day 29 after each vaccination 
• Review of SAEs.  
• If occurring through Day 8 after any vaccine dose, interview the subject and review the e-
Memory aid data. Address any incomplete, missing, or inconsistent data. If visit occurs 
between Day 8 and Day 29, if needed the subject will be interviewed and ongoing 
solicited AEs will be reviewed.  
• If symptoms persist post Day 8, clinic staff will attempt to follow up with the subject 
daily until the symptoms resolve. Maximum severity post Day 8 and stop date of the 
symptoms will be recorded by clinic staff on the Solicited Events eCRF. 
• Review concomitant medications.  
• Obtain blood for safety laboratories (if needed) 
• Obtain serum for immunogenicity assays (if needed) 
• Collect PBMCs and plasma for future assays (if needed).  
• Review of birth control history with female subjects (if needed). 
• Counsel subjects to use adequate birth control methods to avoid pregnancy if before 3 
months after the last study vaccination. 
• A urine pregnancy test for women of childbearing potential may be performed.  
 

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 08 FEB 2019 
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Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements.  The noncompliance may be either on the part of the subject, the site 
principal investigator, or the site personnel.  As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site principal investigator and personnel to use continuous vigilance 
to identify and report deviations within five working days of identification of the protocol 
deviation, or within five working days of the scheduled protocol-required activity.  All 
deviations must be promptly reported to DMID per the DCC protocol deviation reporting 
procedures. 
All protocol deviations, as defined above, must be addressed in study subject data collection 
forms.  A completed copy of the DMID Protocol Deviation Form must be maintained in the 
Regulatory File, as well as in the subject's chart.  Protocol deviations must be sent to the local 
IRB/IEC per their guidelines.  The site principal investigator and personnel are responsible for 
knowing and adhering to their IRB requirements. 

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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
7.1.1 
Research Procedures: Medical History  
Complete medical history will be obtained by interview of the subjects at the Screening Visit. 
Subjects will be queried regarding a history of significant medical disorders of the head, eyes, 
ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, 
musculoskeletal system, skin, and genital/reproductive tract. A focused vaccination history will 
be obtained. A history of any allergies, cancer, immunodeficiency, psychiatric illness, substance 
abuse, and autoimmune disease will be solicited. History of receipt of medications which modify 
the host immune response (e.g., cancer chemotherapeutic agents, parenteral corticosteroids), any 
experimental therapeutic agent, and blood product or immunoglobulin receipt will be solicited.  
A history of use of contraception will be solicited. Interview of subjects is sufficient for 
obtaining medical history. Solicitation of medical records from the subject’s primary care 
provider is not required. Pre-vaccination reactogenicity symptoms will be solicited and recorded.  
 
7.1.2 
Research Procedures: Physical Examination 
At the screening visit, an abbreviated physical examination will be performed by a study 
clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or 
sub-investigator. An abbreviated PE is distinguished from a complete PE as all assessments are 
not required (e.g., pelvic, rectal). The abbreviated PE will include assessments of the following 
organs and organ systems: skin, HEENT, neck, lungs, heart, liver, spleen, abdomen, extremities, 
lymph nodes (axillary and cervical), and nervous system. On Day 1 and at follow-up visits after 
the first study vaccination a symptom-directed PE may be performed by a study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-
investigator, if indicated based on subject’s interim medical history. This symptom-directed PE 
will be performed as indicated by the investigator based on any clinically relevant issues, 
clinically relevant symptoms and medical history. The symptom-directed PE may be repeated if 
deemed necessary by the investigator. Any abnormal finding that represents an increase in 
toxicity grade post study vaccination must be recorded on the AE page of the eCRF. All events 
should be followed to resolution, or until reaching a clinically stable endpoint. 

DMID Protocol 15-0108 
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Phase I Study of HEV-239 
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7.1.3 
Research Procedures: Vital Signs 
Vital signs (oral temperature, pulse, and BP) will be collected at the Screening Visit, and prior to 
and at a minimum of 30 minutes after each study vaccination (Day 1, Day 29, and Day 180). 
Vital signs assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
Vital signs will also be assessed at Days 8, 15, 36, 43, 187, and 194 in all subjects. Blood 
pressure and heart rate measurements should be preceded by at least 5 minutes of rest in a quiet 
setting without distractions (e.g., television, cell phones). Confirmatory vital sign measurements 
can be repeated once. Subjects must not eat or drink anything hot or cold, or smoke within 10 
minutes prior to taking oral temperature. The repeated measurement may be used to determine 
eligibility per the judgment of the investigator.  Height and weight will be collected at the 
Screening Visit for the calculation of BMI. See the protocol specific MOP for additional details.  
 
7.1.4 
Research Procedures: Post Vaccination 
Subjects will be observed in the clinic for at least 30 minutes after each study vaccination (Days 
1, 29, and 180). Vital signs will be obtained at a minimum of 30 minutes after each study 
vaccination. The study vaccination site will be examined, post-reactogenicity symptoms will be 
recorded, and any AE/SAEs will be assessed and recorded on the appropriate eCRF prior to 
discharge from the clinic. The study vaccination site will also be examined at follow-up visit Day 
8 after each study vaccination. The study vaccination site will be examined at follow-up visit 
Day 15 after each study vaccination as well, if needed. 
All subjects will enter reactogenicity symptoms via an e-Memory aid to the SDCC beginning on 
the evening of the day of vaccination (Day 1, Day 29, and Day 180) through Day 8 after each 
study vaccination. Subject e-Memory aids will be reviewed with the subject for AEs on Days 4 
(by telephone), Day 8, and if needed on Day 15 after each study vaccination. Reactogenicity 
assessments will include an assessment of solicited AEs including an assessment of injection site 
reactions of pruritus (itching), ecchymosis (bruising), erythema (redness), induration 
(hardness)/swelling, pain, and tenderness as well as systemic reactions including fever, 
feverishness (chills/ shivering/ sweating), fatigue (tiredness), malaise (general unwell feeling), 
myalgia (body aches/muscular pain exclusive of the injection site), arthralgia (joint pain 
exclusive of the injection site), headache, nausea, and vomiting. 
 

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7.1.5 
Assessment of Concomitant Medications/Treatments other than Study Product 
Medications history (concomitant medications) will include a review of all current medications 
and medications taken within 30 days prior to signing the informed consent form through Day 
57, or Day 29 for those who only receive one dose of study vaccine, or early termination (if prior 
to Day 29 after any study vaccine dose), whichever occurs first. Concomitant medications will 
also include all current medications and medications taken within 30 days prior to Vaccine Dose 
3 (Day 180) through Day 208. Concomitant therapies outside these times should only be 
recorded if administered in conjunction with SAEs. Prescription and over-the-counter drugs and 
vaccines will be included as well as vitamins, herbals, and supplements. Assessment of eligibility 
will also include a review of all permitted and prohibited medications per the Subject Inclusion 
and Exclusion Criteria (see Section 5.1.1 and 5.1.2). 
Medications that might interfere with the evaluation of the investigational product should not be 
used unless necessary.  Medications in this category include, but are not limited to, 
glucocorticoids (i.e., oral, parenteral and high-dose inhaled steroids), and immunosuppressive or 
cytotoxic drugs.  Analgesics and antipyretics should be avoided for the 24 hours following study 
injection, unless necessary. 
7.1.6 
Assessment of Subject Compliance with the Study Visit Schedule  
Study product will be administered to subjects by an unblinded study vaccine administrator via 
IM injection at all dosing times and as described in Section 4.3. Thus, subject compliance is not 
anticipated to be an issue. Deviations from the dose schedule may only occur as described in 
Section 4.4.  
 
 
Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
7.2.1.1 
Baseline Screening Laboratories  
Serum pregnancy tests will be performed locally by site laboratory at the screening visit and 
urine pregnancy test will be performed prior to each study vaccination on all women of 
childbearing potential. Results must be known and negative prior to randomization on Day 1 to 
be eligible for participation in this trial. Baseline laboratories will be obtained as defined in 
Section 2.3.1. 
 

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7.2.1.2 
Subsequent Testing Including Safety Laboratories 
Urine pregnancy tests will be performed by locally by site laboratory within 24 hours prior to each 
study vaccination (Days 1, 29, and 180) on all women of childbearing potential. Results must be 
known and negative prior to administration of each study vaccination to be eligible for 
participation in the study and receipt of each dose of study vaccine, respectively. Safety 
laboratories will be obtained as defined in Section 2.3.1. Subjects will have follow-up safety 
laboratories obtained on Days 8, 36, 180, and 187 (about 13 mL). 
Laboratory toxicities will be determined according to Appendix B. Laboratory reports must be 
assessed by a study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 
as the site principal investigator or sub-investigator, document this review, and record any 
abnormal laboratory value that represents an increase in toxicity grade post study vaccination on 
the AE page of the eCRF. The laboratory reports must be filed with the source documents. All 
events should be followed to resolution, or until reaching a clinically stable endpoint. 
The volume of venous blood to be collected for clinical safety laboratory evaluations is presented 
in Appendix A. 
 
7.2.2 
Research Assays  
The volume of venous blood to be collected for immunogenicity assays and future research is 
presented in Appendix A. 
Immunogenicity 
Assays to determine serum levels of hepatitis E antibodies (IgG and IgM) will be performed at 
Emory’s VTEU laboratory. Venous blood samples (approximately 10 mL) for antibody assays will 
be collected from each subject at screening and sent directly to Emory’s VTEU laboratory for 
baseline testing. Seronegative samples will be defined as per the Wantai HEV-IgM and IgG ELISA 
package inserts (A/C.O. <0.9).  
Venous blood samples (approximately 10 mL) will be collected immediately prior to each study 
vaccination (Days 1, 29, and 180) and Days 8, 15, after each study vaccination (Days 8, 15, 36, 
43, 187, 194), Day 29 after each boost vaccination (Days 57 and 208), and Day 360. Subjects who 
withdraw early will have hepatitis E antibody assays run on available sera. Samples for 
immunogenicity assessments will be shipped from the DMID CMS to Emory’s VTEU laboratory 
for vaccine immunogenicity assessments beginning with the completion of the Day 360 visit.  
Seroconversion will be defined as a change from a seronegative result to a seropositive result as 
defined by the Wantai HEV-IgM and IgG ELISA package inserts (A/C.O. >1.1). As defined by 

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prior studies,24 the antibody concentration in samples negative for hepatitis E virus IgG was set at 
0.0385 Wu/mL which was half the lower limit of quantification.  A 4-fold seroconversion will be 
defined as a HEV IgG ≥0.154 in a subject that was HEV seronegative at Day 1.  
 
Future Use:  
Residual samples are those that are left over after the study has been completed and are stored for 
possible use in future research studies. Future use samples are extra tube(s) of blood collected and 
stored for possible use in future research studies. Retention of residual and future use samples and 
the potential for use in future research studies will be a condition of study participation. Subjects 
who sign the informed consent form for the study are consenting to allow the collection, storage 
and use of any residual samples (serum or cells derived from venous blood samples) or future use 
samples for possible use in future research studies, such as examining additional immunological 
assessments or testing for antibodies against other viruses or bacteria. Future use research studies 
may include, but are not limited to non-traditional immune assay development, assessing innate 
immune factors, and the ability of HEV vaccine-induced antibodies to cross-react with other 
viruses.  
Residual and future use samples will be encoded with a barcode label and unique tracking number 
to protect subject identity. Samples will be stored indefinitely at a DMID designated central storage 
facility. Residual samples may be shared for purposes other than per protocol analysis with 
investigators at participating VTEU sites and with investigators at other institutions once the 
clinical study report has been finalized. Future use research samples may be requested from DMID 
and shipped from the DMID CMS at any time. 
Residual and future use samples will not be sold or used directly for production of any commercial 
product. Genetic tests may be performed on samples. There are no benefits to subjects in the 
collection, storage and subsequent use of their specimens for future research. Reports about future 
research done with subjects’ samples will NOT be kept in their health records.  
Subjects may withdraw consent for study participation at any time by notifying the study doctors 
or nurses in writing. However, any data from sample(s) collected prior to the withdrawn consent 
will not be removed including genomic data. There will be no further use of residual samples or 
collection and use of future use samples after consent has been withdrawn. 
Venous blood will be collected for PBMCs and plasma (16-64 mL) for future use on Days 1, 8, 
15, 29, 36, 43, 57, 180, 187, 194, 208, and 360.  
 

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7.2.2.1 
Laboratory Specimen Preparation, Handling, and Storage 
Instructions for specimen preparation, handling, and storage are included in the central (clinical) 
laboratory manual and protocol-specific MOP as appropriate. 
 
7.2.2.2 
Laboratory Specimen Shipping 
Specimen shipment will occur at intervals during the course of this trial following all applicable 
International Air Transport Association (IATA) requirements and according to the specifics for 
storage temperature and documentation as detailed in the central (clinical) laboratory manual and 
protocol-specific MOP as appropriate. 
Specimens for safety laboratory evaluation will be shipped from the Emory VTEU to the clinical 
laboratory.  
Screening: Specimens for initial immunogenicity laboratory evaluations at screening will be sent 
to the Emory VTEU laboratory in an unblinded manner. Results will be conveyed back to the 
Emory VTEU clinical team.  
Enrolled Subjects: Specimens for immunogenicity laboratory evaluations beginning Day 1 and 
continuing throughout the study will be shipped from the Emory VTEU to the central repository 
and then provided by the DMID CMS to Emory VTEU laboratory in a blinded manner. 
Further instructions for specimen shipment are included in the central (clinical) laboratory manual 
and protocol-specific MOP, as appropriate. 

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ASSESSMENT OF SAFETY 
Regulatory requirements including the FDA regulations, ICH Guidelines for GCP, and European 
Union (EU) Clinical Trials Directive set forth safety monitoring and reporting responsibilities of 
sponsors and investigators to ensure the safety and protection of human subjects participating in 
clinical trials.  
 
Responsibilities  
Investigators participating in this clinical trial are responsible for and will:  
o 
Evaluate subject safety including assessment of AEs for seriousness, severity, and 
causality;  
o 
Follow up AEs resolution through study follow up period;  
o 
Notify the sponsor (DMID) of SAEs immediately;  
o 
Follow up SAEs until resolution, even if this extends beyond the follow up period  
(resolution of an AE/SAE is defined as the return to baseline or stabilization of the 
condition with the expectation that it will remain chronic) provide detailed written 
reports, including necessary documentation requested by the sponsor or Institutional 
Review Board(IRB)/Independent Ethics Committee (IEC), promptly following 
immediate initial reports, and;  
o 
Inform the IRB/IEC of AEs as required by applicable regulatory requirements.  
 
 
Assessing and Recording Safety Parameters 
8.1.1 
Adverse Events (AEs) 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment.  FDA defines an AE as any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product.  The occurrence of an AE may come to the attention of study personnel during study 

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visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor.  
All AEs, including solicited local (injection site) and systemic (subjective and quantitative) 
reactions, will be captured on the appropriate data collection form and eCRF.  Information to be 
collected for AEs includes event description, date of onset, assessment of severity, relationship to 
study product and alternate etiology (assessed only by those with the training and authority to 
make a diagnosis and listed on the Form FDA 1572 as an investigator), date of resolution, 
seriousness and outcome.  AEs occurring during the trial collection and reporting period will be 
documented appropriately regardless of relationship.  AEs will be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE.  However, if the severity of any pre-existing medical 
condition increases, it should be recorded as an AE. 
 
8.1.1.1 
Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for 
relationship to study product (see definitions). AEs characterized as intermittent require 
documentation of onset and duration of each episode.  The start and stop date of each reported 
AE will be recorded on the appropriate data collection form and eCRF. Changes in the severity 
of an AE will be documented to allow an assessment of the duration of the event at each level of 
intensity. 
Severity of Event:   
AEs will be assessed by the investigator using a protocol-defined grading system (toxicity table 
included as an appendix).  For events not included in the protocol-defined grading system, the 
following guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s usual 
activities of daily living. 
• 
Moderate (Grade 2):  Events that are usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 

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• 
Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  Severe events are usually 
incapacitating. 
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician indicated on the Form FDA 1572 and the assessment 
will be part of the documentation process.  Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this trial.  If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported.   
In a clinical trial, the study product must always be suspect.  The relationship to study product 
will be assessed for AEs using the terms related or not related: 
• 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.1.2 
Reactogenicity (Solicited Local and Systemic Events)  
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine.  The subject will be instructed on noting the presence and severity of 
symptoms through D8 after administration of study vaccine: The following Toxicity Grading 
Scales will be used to grade solicited local (injection site) and systemic (subjective and 
quantitative) reactions: 
Table 3: Local (Injection Site) Reactogenicity Grading 
Local (Injection Site) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous discomfort) 
No pain medication or it 
requires use of a non-
narcotic pain reliever 
≤24hours OR does not 
interfere with activity 
Repeated use of non-
narcotic pain reliever >24 
hours OR interferes with 
activity 
Any use of narcotic pain 
reliever OR prevents daily 
activity 
Tenderness – hurts only 
when injection site is 
Discomfort only to touch 
Discomfort with 
movement 
Significant discomfort at 
rest 

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Local (Injection Site) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
touched or the arm is 
moved 
Pruritus (Itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Ecchymosis (Bruising)* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Induration 
(Hardness)/Swelling* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Will also be measured in mm but size will not be used as halting criteria. 
Erythema (redness), ecchymosis, and induration (hardness)/swelling as analyzed by measurement 
will be graded as follows: 
Table 4: Local (Injection Site) Reactogenicity Measurements 
Local (Injection Site) Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Ecchymosis (Bruising)* 
25mm – 50mm 
51 mm – 100mm 
>100 mm 
Erythema (Redness)* 
25 mm – 50 mm 
51 mm – 100 mm 
>100 mm 
Induration (Hardness)/Swelling* 
25 mm – 50 mm 
51 mm – 100 mm OR 
interferes with activity 
>100 mm OR 
prevents daily 
activity 
*Will not be used as halting criteria. 
Note: Ecchymosis and Induration/Swelling should be evaluated and graded using the symptom scale as well as the 
actual measurement. 
Table 5: Subjective Systemic Reactogenicity Grading 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Feverishness 
(Chills/Shivering/Sweating) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 

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Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fatigue (Tiredness) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise (General Unwell 
Feeling) 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia (Body 
Aches/Muscular Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia (Joint Pain)* 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference 
with daily activity 
Repeated use of non-
narcotic pain reliever 
>24 hours OR some 
interference with 
activity 
Significant; any use of 
narcotic pain reliever OR 
prevents daily activity OR 
requires triptans 
Nausea 
No interference 
with daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Vomiting 
No interference 
with activity or 
1-2 episodes/24 
hours 
Some interference with 
activity or 
>2 episodes/24 hours 
Prevents daily activity or 
requires IV hydration 
* Not at injection site. 
Oral temperature# will be graded as follows: 
Table 6:Quantitative Systemic Reactogenicity Grading 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* - oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# Oral temperature assessed on Day 1 prior to the first study vaccination will be considered as baseline. 
* A fever can be considered not related to the study product if an alternative etiology can be documented. 

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† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
 
Any symptoms still present at the D8 visit after each vaccination will continue to be followed by 
subject until symptom resolution. Subjects will also be asked to call the site if they experience any 
severe symptoms other than what’s listed on the e-Memory aid, if they have any severe symptoms 
that prevents daily activity or any other symptoms and health complaints, even if they are not listed 
on the e-Memory aid. Sites will review the concomitant medications with the subject at subsequent 
clinic visits. The subject’s input into the electronic data capture system will be reviewed with the 
subject at subsequent clinic visits.  
Subjects will be instructed on how to record daily temperature using a thermometer provided for 
home use. Subjects should record the oral temperature in the evening post vaccination, and then 
daily through D8 after each vaccination. Temperature should be measured at approximately the 
same time each day. If more than one measurement is made on any given day, the highest 
temperature will be recorded. This information will be reviewed by study staff during follow-up 
subject contacts.  
The site PI/study staff will also assess the vaccination site and measure edema and erythema at the 
visits post vaccination. Vital sign measurements will be performed at the time points indicated in 
the Section 6. Blood pressure and heart rate measurements should be preceded by at least 
5 minutes of rest and in a quiet setting without distractions (e.g., television, cell phones). 
Confirmatory vital sign measurements can be performed if inconsistent with a prior measurement. 
A symptom-directed examination will be performed as indicated by the investigator based on any 
clinically relevant issues, clinically relevant symptoms and medical history. The symptom-directed 
PE may be repeated if deemed necessary by the investigator. PEs will be performed by a study 
clinician licensed to make medical diagnoses and listed on the FDA Form 1572 as the site principal 
investigator or sub-investigator. 
 
8.1.3 
Unsolicited Adverse Events 
8.1.4 
Serious Adverse Events (SAEs) 
An AE or suspected adverse reaction is considered a serious adverse event (SAE) if, in the view 
of either the site principal investigator or sponsor, it results in any of the following outcomes:  
o 
Death, 
o 
a life-threatening adverse event1,  
o 
inpatient hospitalization or prolongation of existing hospitalization,  

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o 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
o 
a congenital anomaly/birth defect.   
o 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
1Life-threatening adverse event. An AE is considered “life-threatening” if, in the view of either 
the site principal investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death.  It does not include an AE that, had it occurred in a more severe form, might have 
caused death. 
SAEs will be: 
o 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 
or by the Institution as the site Principal Investigator or Sub-Investigator. 
o 
Recorded on the appropriate SAE data collection form and eCRF. 
o 
Followed through resolution by a licensed study physician (for IND studies, a 
physician listed on the Form FDA 1572 as the site Principal Investigator or Sub-
Investigator). 
o 
Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM), the SMC 
(periodic review unless related), and the IRB/IEC. 
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of:  
1. Serious adverse events (see Section 8.1.4) occurring from the time of the first study 
vaccination through the last study visit (Day 360).  
 
2. Solicited Adverse Events (see Section 8.1.2) – reactogenicity events occurring on the 
day of each study vaccination through Day 8 after each study vaccination: 

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a) Injection site reactions including pruritus (itching), ecchymosis (bruising), 
erythema (redness), induration (hardness)/swelling, pain, and tenderness. 
b) Systemic reactions including fever, feverishness (chills/shivering/sweating), 
fatigue (tiredness), malaise (general unwell feeling), myalgia (body aches/muscular 
pain exclusive of the injection site), arthralgia (joint pain exclusive of the injection 
site), headache, nausea, and vomiting. 
3. Clinical safety laboratory AEs (see Appendix B) at Day 8 after each study 
vaccination. Parameters to be evaluated include WBC, ANC, AEC, Hgb, PLT, Cr, 
and ALT (Section 2.3.1). 
4. Unsolicited Adverse Events (see Section 8.1.3) – non-serious adverse events occurring 
from the time of the first study vaccination until Day 57 then from Day 180 through 
Day 208.  Unsolicited AEs will be collected at all visits from the time of the first study 
vaccination until D57, then from Day 180 through 208.  Any safety-related changes 
that occur post-vaccination during these timeframes and that represent an increase in 
grade must be recorded on the eCRF. Thereafter, recording will be limited to SAEs. 
 
All Grade 1, 2, and 3 changes except for Grade 1 and 2 solicited adverse events must 
be assessed for relatedness to the study vaccination. The assessment of causality must 
be determined by a study clinician licensed to make medical diagnoses and listed on 
the FDA Form 1572 as the site principal investigator or sub-investigator. 
 
Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented and reported from 
the time of each study vaccination through D8 after each study vaccination. 
Unsolicited non-serious AEs will be documented and reported at all visits from signing of the ICF 
onwards until D57, then from Day 180 through Day 208.   
SAEs will be collected from the time of the first study vaccination through the last study visit (Day 
360). 
8.3.1 
Reporting Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  

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Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address:  
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into the DCC system. 
Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The site will send a copy of the SAE report(s) to the ISM when they are provided to the DMID 
Pharmacovigilance Group.  The DMID Medical Monitor and DMID Clinical Project Manager 
will be notified of the SAE by the DMID Pharmacovigilance Group.  The DMID Medical 
Monitor will review and assess the SAE for regulatory reporting and potential impact on study 
subject safety and protocol conduct. 
At any time after completion of the study, if the site principal investigator or appropriate sub-
investigator becomes aware of an SAE that is suspected to be related to study product, the site 
principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
 
8.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site Principal Investigator or appropriate sub-investigator, 
DMID, as the IND sponsor, will report any suspected unexpected serious adverse reaction 
(SUSAR).  DMID will report an AE as a suspected unexpected adverse event only if there is 
evidence to suggest a causal relationship between the study intervention and the AE.  DMID will 
submit an IND safety report to the FDA and will notify all participating site Principal 

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Investigators (i.e., all Principal Investigators to whom the sponsor is providing drug under its 
IND(s) or under any Principal Investigator’s IND(s)of potential serious risks from clinical 
studies or any other source, as soon as possible.  DMID will report to the FDA any unexpected 
fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the sponsor’s initial receipt of the information.  If the event is not fatal or life-
threatening the IND safety report will be submitted within 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32.  
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available.  Upon request from FDA, DMID will submit to the FDA any additional 
data or information that the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request.   
All SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format.  
 
 
8.3.3 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported via Advantage eClinical® on the 
Pregnancy Report eCRF. No further study vaccinations will be administered to pregnant subjects, 
but with the subject’s permission all study mandated blood samples will be obtained and the 
subject will continue in follow-up for safety events. Efforts will be made to follow all pregnancies 
reported during the course of the study to pregnancy outcome pending the subject’s permission. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
Solicited AEs are reactogenicity events occurring on the day of each study vaccination through 
Day 8 after each study vaccination. Unsolicited AEs are non-serious adverse events occurring 
from the time of the first study vaccination until Day 57, then from Day 180 through Day 208. 
AEs will be assessed, and followed from initial recognition of the AE through end of the 
protocol defined follow-up period. AEs will be followed to adequate resolution. Resolution of an 
AE/SAE is defined as the return to pretreatment status or stabilization of the condition with the 
expectation that it will remain chronic. 

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SAEs will be collected from the time of the first study vaccination through the last study visit (Day 
360). SAEs will be followed to adequate resolution or stabilization even if this extends beyond the 
study-reporting period.  
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate eCRF. 
 
 
Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
Samples will be collected for hematology, serum chemistry and urinalysis. The study clinician 
licensed to make medical diagnoses and listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator must review the laboratory results, document this review, and 
record attribution to study product and clinical significance for all abnormal laboratory values on 
the Local Laboratory eCRF. Abnormal laboratory results meeting the protocol-defined toxicity 
grading scale are considered adverse events; however, they ARE NOT reported as unsolicited AEs 
on the Adverse Event eCRF. The laboratory reports must be filed with the source documents. 
 
Halting Rules 
8.6.1 
Study Halting Criteria 
Further enrollment and study vaccinations will be halted for SMC review/recommendation if any 
of the following are reported: 
• 
Any subject experiences ulceration, abscess, or necrosis at the injection site related to study 
vaccination. 
• 
Two or more subjects who have received at least one dose of study vaccine to date experience 
the same (at MedDRA PT level) severe (grade 3) study vaccine-related unsolicited adverse 
event.  
• 
Two or more subjects who have received at least one dose of study vaccine to date experience 
a severe (grade 3) study vaccine-related laboratory adverse event in the same laboratory 
parameter. 
• 
Two or more subjects who have received at least one dose of study vaccine to date experience 
the same severe (grade 3) solicited injection site adverse event that persists for 3 or more days 

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and does not resolve or decrease to a lower grade (The size [measured in mm] of ecchymosis, 
erythema and induration/swelling will not be used as a halting criterion). 
• 
Two or more subjects who have received at least one dose of study vaccine to date experience 
the same severe (grade 3) study vaccine-related solicited systemic adverse event that persists 
for 3 or more days and does not resolve or decrease to a lower grade (Subjective systemic 
reaction corroborated by study personnel). 
• 
Any subject experiences a study vaccine-related laryngospasm, bronchospasm, or anaphylaxis 
within 1 day of study vaccination. 
• 
Any subject experiences a study vaccine-related allergic reaction (e.g., generalized urticaria) 
within 3 days of study vaccination. 
• 
Any subject experiences a study vaccine-related SAE from the time of the first study 
vaccination through the subject’s last study visit. 
Grading scales for solicited local (injection site) and systemic (subjective and quantitative) 
reactions are included in Section 8.1.2. 
If any of the halting rules above are met following any subject receipt of any vaccination, the study 
will not continue with the remaining enrollments or study vaccinations without a review by and 
recommendation from the SMC to proceed. DMID retains the authority to suspend additional 
enrollment and study interventions/ administration of study product during the entire study, as 
applicable. 
 
8.6.2 
Individual Halting Criteria 
Individual subjects will not be administered boost vaccination doses (2nd or 3rd vaccination) if he 
or she experiences ANY of the following:  
• 
Anaphylaxis within 1 day after administration of a study vaccine. 
• 
Allergic reaction (e.g., generalized urticaria) within 3 days after administration of a study 
vaccine. 
• 
A serious adverse event (SAE) that is considered to be study vaccine-related. 
• 
A severe (grade 3) laboratory adverse event that is considered to be study vaccine-related and 
persists for 3 or more days. 
• 
A severe (grade 3) unsolicited adverse event that is considered to be study vaccine-related and 
does not resolve or decrease to a lower grade. 

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• 
A severe (grade 3) solicited systemic adverse event that is considered to be study vaccine-
related and persists for 3 or more days and does not resolve or decrease to a lower grade 
(Subjective systemic reaction corroborated by study personnel). 
• 
A severe (grade 3) solicited injection site adverse event that persists for 3 or more days and 
does not resolve or decrease to a lower grade.  (The size [measured in mm] of ecchymosis, 
erythema, and induration/swelling will not be used as a halting criterion). 
Vaccinations for an individual subject may be suspended for safety concerns other than those 
described above, at the discretion of the investigator if he/she feels the subject’s safety may be 
threatened. The investigator may ask for an ad hoc SMC meeting to be held for any single event 
or combination of multiple events which, in his/her professional opinion, could jeopardize the 
safety of the subjects or the reliability of the data. 
 
Safety Oversight (ISM, SMC) 
8.7.1 
Independent Safety Monitor (ISM) 
For certain clinical trials, DMID will require an Independent Safety Monitor (ISM) to be 
assigned for each study site and the requirement for an ISM will be specified in the protocol. An 
ISM is a physician with relevant expertise whose primary responsibility is to provide to DMID 
an independent safety assessment in a timely fashion. The ISM will review SAEs in real time 
and other AEs as needed and provide an independent assessment to DMID.   
For this clinical trial an ISM is required. Participation is for the duration of the DMID study and 
is a voluntary position that does not receive payment. The ISM must meet the requirements of 
the NIAID conflict of interest policy.  The ISM: 
• Is in close proximity to the study site and has the authority and ability to readily access 
study participant records in real time. 
• May be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution. 
• Should not be in a direct supervisory relationship with the investigator. 
• Should have no direct involvement in the conduct of the study. 
 
The ISM will: 
• Sign a COI certification at the time they are asked to participate and provide updates to 
this information as needed. 

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• Receive reports of Serious Adverse Events (SAEs) from the site investigator and will be 
notified by email when DMID is notified of the SAE. 
• Evaluate the SAE and report their clinical assessment to DMID, through DMID-CROMS 
SOCS in a timely manner using the attached report form and email the report to DMID-
CROMS SOCS.   
• Communicate with the investigator at the participating site as needed. 
• Review additional safety related events at the request of DMID. 
• Provide additional information to DMID and/or the SMC by teleconference as requested. 
 
8.7.2 
Safety Monitoring Committee (SMC) 
This clinical study will utilize a SMC, which is an independent group of experts that advises the 
DMID. The primary responsibility of the SMC is to monitor subject safety. The SMC is external 
to the DMID and comprises at least 3 voting members. The SMC will consist of members with 
appropriate phase 1 study expertise to contribute to the interpretation of the data from this trial. 
Its activities will be delineated in a SMC charter that will describe the membership, 
responsibilities, and the scope and frequency of data reviews. The SMC will operate on a 
conflict-free basis independently of the study team. The DMID or the SMC may convene ad hoc 
meetings of the SMC according to protocol criteria or if there are concerns that arise during the 
study. 
As defined in the charter, the SMC will review data at specified times during the course of the 
study for subject and overall study progress, and will conduct ad hoc reviews as appropriate 
when a halting rule is met or for immediate concerns regarding observations during this study. 
The SMC will review study progress and subject clinical, safety, and reactogenicity data at the 
following time points: 
• The SMC will be provided with top line safety data through Day 57 for all participants.  
• Final review meeting: 6 to 8 months after clinical database lock to review the cumulative 
unblinded safety and efficacy data for this trial.  The data will be provided in a standard 
summary format.  The SMC may be asked to provide recommendations in response to 
questions posed by DMID. 
• Ad hoc when a halting rule is met, for immediate concerns regarding observations during 
this trial, or as needed. 

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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
Each site principal investigator will obtain IRB approval for this protocol to be conducted at 
his/her research site(s), and send supporting documentation to the DMID before initiating 
recruitment of subjects.  The investigator will submit applicable information to the IRB/IEC on 
which it relies for the review, to conduct the review in accordance with 45 CFR 46, ICH E6 
GCP, and as applicable, 21 CFR 56 (Institutional Review Boards) and 21 CFR 50 (Protection of 
Human Subjects), other federal, state, and local regulations. The IRB/IEC must be registered 
with OHRP as applicable to the research.  DMID must receive the documentation that verifies 
IRB/IEC-approval for this protocol, associated informed consent documents, and upon request 
any recruitment material and handouts or surveys intended for the subjects, prior to the 
recruitment and enrollment of subjects.     
Any amendments to the protocol or consent materials will be approved by the IRB/IEC before 
they are implemented.  IRB/IEC review and approval will occur at least annually throughout the 
enrollment and follow-up of subjects, and may cease if annual review is no longer required by 
applicable regulations and the IRB/IEC.  The investigator will notify the IRB/IEC of deviations 
from the protocol and reportable SAEs, as applicable to the IRB/IEC policy. 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation.  Before any study procedures 
are performed, informed consent will be obtained and documented.  Subjects will receive a 
concise and focused presentation of key information about the clinical trial, verbally and with a 
written consent form. The explanation will be organized, and presented in lay terminology and 
language that facilitates understanding why one might or might not want to participate. 
An investigator or designee will describe the protocol to potential subjects face-to-face. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 
risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject.   

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Subjects will also receive an explanation that the trial involves research, and a detailed summary 
of the proposed study procedures and study interventions/products.  This will include aspects of 
the trial that are experimental, the probability for random assignment to treatment groups, any 
expected benefits, all possible risks (including a statement that the particular treatment or 
procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may 
become pregnant, that are currently unforeseeable), the expected duration of the subject’s 
participation in the trial, alternative procedures that may be available and the important potential 
benefits and risks of these available alternative procedures.  
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project.  
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled.   
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written informed consent form, the subject is 
authorizing such access.  
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
and/or specimens will be used for additional research, even if identifiers are removed.   

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Subjects will be allowed sufficient time to consider participation in this research trial, and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 
Informed consent forms will be IRB-approved and subjects will be asked to read and review the 
consent form. Subjects must sign the informed consent form prior to starting any study 
procedures being done specifically for this trial. 
Once signed, a copy of the informed consent form will be given to the subject(s) for their 
records.  The subject(s) may withdraw consent at any time throughout the course of the trial.  
The rights and welfare of the subject(s) will be protected by emphasizing to them that the quality 
of their medical care will not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a patient-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent.  In cases where there is not a patient-specific 
screening consent on record, site Clinical staff may pre-screen via chart review and refer 
potential subjects to the Research staff.  Research staff would obtain written consent per the 
standard informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements.  The informed consent document 
will be updated and subjects will be re-consented per IRB requirements, if necessary.  Subjects 
will be given a copy of all informed consent forms that they sign. 
 
Consent for Future Use of Stored Specimens and Data 
Residual samples are those that are left over after the study has been completed and are stored 
for possible use in future research studies. Future use samples are extra tube(s) of blood collected 
and stored for possible use in future research studies. Retention of residual and future use 
samples and the potential for use in future research studies will be a condition of study 
participation. Subjects who sign the informed consent form for the study are consenting to allow 
the collection, storage and use of any residual samples (serum or cells derived from venous blood 
samples) or future use samples for possible use in future research studies. Subjects may 
withdraw consent for study participation at any time by notifying the study doctors or nurses in 
writing. Data from sample(s) collected prior to the withdrawing consent will not be removed. 
There will be no further use of residual samples or collection and use of future use samples after 
consent has been withdrawn. 

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Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will be inclusive of all healthy adults who meet the Subject Inclusion/Exclusion Criteria, 
regardless of religion, sex, or ethnic background.  Should the outcome of this trial be deemed 
acceptable, additional trials may be initiated in other populations. 
Children will be excluded from this Phase I trial since safety and immunogenicity data for HEV 
239 in US healthy adult populations are currently lacking.  
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. This confidentiality extends to research and future use test results, in addition to the 
clinical information relating to participating subjects. No information concerning the study or the 
data generated from the study will be released to any third party without prior written approval of 
the DMID. Subject confidentiality will be maintained when study results are published or 
discussed in conferences.  The study monitor or other authorized representatives of the sponsor 
or governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
Certificate of Confidentiality 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the 
researchers cannot be forced to release information that may identify the research subject, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The researchers will use the Certificate to resist any demands for information 
that would identify the subject, except as explained below. 
The Certificate cannot be used to resist a demand for information from personnel of the United 

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States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the Federal 
Food and Drug Administration (FDA). 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research.  If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information.   
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others.   
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, and for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research.  
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial.  Subjects may be compensated for their participation in this trial.  Compensation will 
be in accordance with the local IRB’s policies and procedures, and subject to IRB approval. 
If it is determined by the site principal investigator that an injury occurred to a subject as a direct 
result of the tests or treatments that are done for this trial, then referrals to appropriate health care 
facilities will be provided to the subject.  Study personnel will try to reduce, control, and treat 
any complications from this trial.  Immediate medical treatment may be provided by the 
participating site.  No financial compensation will be provided to the subject by the NIAID, NIH 
to the subject, or by the participating site for any injury suffered due to participation in this trial. 
 

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STATISTICAL CONSIDERATIONS 
 
Study Hypotheses 
The primary goal of this study is to assess the safety and immunogenicity of HEV 239 
administered in three successive intramuscular injections. This study will also collect blood for 
future use. This study, like other Phase I studies, is exploratory rather than confirmatory, and 
thus is not designed to formally test any hypotheses.   
 
Sample Size Considerations 
A total of 25 subjects, aged 18 to 45 years (inclusive), will be enrolled and randomized to HEV 
239 vaccine (20 subjects) versus placebo (5 subjects) in a blinded manner.  Each subject will 
receive three study injections (0, 1, and 6 months).  The sample size for this study was selected 
to obtain preliminary estimates of HEV 239 vaccine safety and immunogenicity in a time 
sensitive manner.  
Given an N of 20 vaccinees, there is an ~88% probability of detecting an adverse event occurring 
in 10% of the population and a ~99% probability of detecting an adverse event occurring in 20%. 
Placebo subjects are included in order to reduce observer bias and are not intended to be a 
comparison group. Probabilities of observing at least one adverse event for a given true event 
rate are presented in the table below. 
Table 7: Probability (%) of Observing at Least One Adverse Event 
Adverse Event 
Frequency 
N = 20 
0.01% 
Rare 
0.20 
0.1% 
Uncommon 
1.98 
1% 
Common 
18.21 
10% 
Very Common 
87.84 
20% 
Very Common 
98.85 
 

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Treatment Assignment Procedures 
10.3.1 
Randomization Procedures 
Per International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice 
(GCP), screening records will be kept at each participating VTEU site to document the reason why 
an individual was screened, but failed trial entry criteria. The reasons why individuals failed 
screening will be recorded in the SDCC Advantage eClinical® (Electronic Data Capture System). 
Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled. Subjects will be assigned randomly to receive three IM doses of either 
placebo or HEV 239 vaccine. The randomization scheme for this study is listed below and also 
presented in Figure 1.  
• HEV 239 vaccine group (N=20) will receive a three-dose regimen of HEV 239 
administered IM on Days 1, 29, and 180.  
• Placebo group (N=5) will receive three-doses of administered placebo IM on Days 1, 29, 
and 180. 
 
Enrollment of subjects will be done online using the enrollment module of Advantage eClinical®. 
The randomization code will be prepared by statisticians at the SDCC and included in the 
enrollment module for this trial. Advantage eClinical® will assign each subject to a group after the 
demographic and eligibility data have been entered into the system. A designated individual at 
each site will be provided with a code list for emergency unblinding purposes, which will be kept 
in a secure place. Instructions for use of the enrollment module are included in the Advantage 
eClinical® User’s Guide. Manual back-up procedures and instructions are provided for use in the 
event that the site temporarily loses access to the Internet or the online enrollment system is 
unavailable. 
 
10.3.2 
Masking Procedures 
This is a double-blind study. Subjects, investigators, study personnel performing any study-related 
assessments following study vaccine administration, and laboratory personnel performing 
antibody assays will be blinded to whether the subject received placebo or HEV 239.  
The randomization scheme will be generated by the SDCC and provided to unblinded study 
personnel including pharmacists performing study vaccination preparations and unblinded study 
vaccine administrator. 

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The unblinded study vaccine administrator is a study personnel member credentialed to administer 
vaccines and may also participate in dose preparation, but will not be involved in study-related 
assessments or have subject contact for data collection following study vaccine administration. He 
or she will only be involved with vaccine administration. 
 
Planned Interim Analyses 
No formal interim analysis is planned.  
 
Final Analysis Plan 
A formal SAP will be developed and finalized prior to any analysis, or database lock.   
10.5.1 
Analysis Populations 
The Safety Analysis population includes all subjects who received at least one study vaccination. 
The modified intent-to-treat (mITT) population includes all subjects who received at least one 
study vaccination and contributed both pre- and at least one post-study vaccination blood samples 
for immunogenicity testing for which valid results were reported. Subjects will be analyzed 
according to the study arm to which they were randomized.  
The per protocol (PP) population includes all subjects in the mITT subset with the following 
exclusions: 
• Data from all available visits for subjects found to be ineligible at baseline. 
• Data from all visits subsequent to major protocol deviations, such as: 
• Second or third study vaccination not received, 
• Receipt of non-study licensed live vaccine within 30 days prior to or after each study 
vaccination, 
• Receipt of non-study licensed inactivated vaccine within 14 days prior to or after each 
study vaccination, 
• Receipt of immunosuppressive therapy (e.g., corticosteroids) within 30 days prior to or 
after each study vaccination. 
• Data from any visit that occurs substantially out of window. 
• In the case of miss-randomization, subjects will be analyzed according to the study product 
actually received. 

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10.5.2 
Safety Data  
Safety data will be summarized for the Safety Analysis Population. Subjects receiving a 
vaccination according to a study arm other than the study arm to which they were randomized, will 
be analyzed according to the vaccination they actually received. Solicited AEs will be summarized 
by severity for each day after each study vaccination for Days 1-8 after each study vaccination. 
The number, percentage (observed rate), and exact two-sided 95% CI for subjects reporting each 
solicited AE within 8 days following vaccination will be summarized. In addition, maximum 
severity for each solicited AE will be determined for each subject and reported by study arm and 
the resulting number and percentage of subjects will be summarized by severity grade (none, mild, 
moderate, severe). Summaries of solicited AEs will be presented separately by study arm for each 
study vaccination as well as overall study vaccinations.  
All AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA®) for preferred 
term and system organ class (SOC). The final clinical study report will include a summary of all 
SAEs as well as a summary of all SAEs by relatedness to study product. The number of SAEs 
considered related to study vaccination are likely to be small in this trial and will be reported by 
detailed listings showing the event description, MedDRA® preferred term and SOC, relevant dates 
(study vaccinations and AEs), severity, relatedness, and outcome for each event. Non-serious 
unsolicited vaccine-related AEs will be summarized as number and percentage of subjects 
reporting at least one event in each MedDRA® preferred term and SOC, cross tabulated by severity 
and relationship to study product. Additionally, the proportion of subjects and exact 95% 
confidence intervals of AEs by study arm for each study vaccination as well as overall study 
vaccinations and by MedDRA® categories will be calculated. 
The number and percentage (observed rate) of subjects that withdrew or discontinued their 
vaccination series will be tabulated for each study arm. 
10.5.3 
Immunogenicity Data 
Immunogenicity data summaries and analysis will be presented for the mITT and PP populations.  
Immune responses for antibodies against HEV-specific IgM and IgG will be summarized at each 
time point by study arm. GMCs and corresponding 95% confidence intervals will be reported. The 
number and percentage of subjects with seroconversion (defined as crossing the threshold from 
negative to positive) and 4-fold rise from baseline will be reported for each post-vaccination time 
point. 
Graphical presentations of immune response may include reverse cumulative distribution (RCD) 
curves, and longitudinal presentation of GMCs.  

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10.5.4 
Missing Values and Outliers 
All attempts will be made to collect all data per protocol. As missing data are expected to be 
minimal, no imputation will be performed for missing values. Any data point that appears to be 
erroneous or inexplicable based on clinical judgment will be investigated as a possible outlier. If 
data points are identified as outliers, sensitivity analyses will be performed to examine the impact 
of including or excluding the outliers. Any substantive differences in these analyses will be 
reported.   

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ELECTRONIC CASE REPORT FORMS AND ACCESS 
TO SOURCE DATA 
The participating VTEU site will maintain appropriate medical and research records in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects. Each site will permit authorized representatives of the 
DMID, its designees, and appropriate regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress. These representatives will be permitted access to 
all source data and source documents (paper and electronic), which include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. Source data are all information, 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial. 
The study uses direct data entry for the participating clinic site and a web-based e-Memory aid 
for subjects. All eCRFs serve as the source documents. Subjects will be trained to use a database 
to complete a web based “e-Memory aid” and are expected to enter information in the e-Memory 
aid each day.  Subjects using the e-Memory aid will also be provided a paper memory aid for 
their use in the event they are unable to access the web-based system.  The subjects will be asked 
to enter the information from the paper memory aid into the e-Memory aid once they are able to 
access the web-based system. 
Subjects will record temperature, local and systemic symptoms and any new medications used 
following vaccination or changes to previously reported medications daily for 8 days after any 
vaccination.  
Subjects will be instructed to contact the clinic staff immediately if they experience severe 
symptoms at any time during the study, for prompt follow-up in real time.  The study clinic will 
be alerted in real time of any potential solicited events of Grade 3 severity entered in the e-
Memory Aid.  An email alert will be sent to the clinic site and the Emmes study team. Within 
one business day of site awareness, the site must attempt to follow up with the subject on the 
severe solicited event and send an email to Emmes confirming attempted follow up with the 
subject.  Instructions for completing the e-Memory aid are provided in the MOP and in a 

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separate e-Memory aid instructions document that will be provided to the subjects at each 
vaccination. The site staff must review the e-Memory aid information and interview the subject 
at the next scheduled visit. The subject-entered data will be available for review by the clinician 
during the clinical interview. 
The site staff will be the data originators for the clinically reviewed data in Advantage eClinical® 
that will be used for the study endpoints.  A list of all authorized site staff data originators will be 
included on the Study Personnel/Signature Responsibility List. 
 

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QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating site is 
responsible for conducting routine quality assurance (QA) and quality control (QC) activities to 
internally monitor study progress and protocol compliance.  The site PI will provide direct access 
to source data/data collection forms, and reports for the purpose of monitoring and auditing by 
the sponsor, and inspection by local and regulatory authorities.  The site PI will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database.  Any missing data or data 
anomalies will be communicated to the participating site for clarification and resolution. 
 

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DATA HANDLING AND RECORD KEEPING 
 
Data Management Responsibilities 
The site principal investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Electronic case report forms will be created by the SDCC to record and maintain data for each 
subject enrolled in this study.   
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the eCRF. 
 
Data Management Responsibilities 
All electronic case report forms and laboratory reports must be reviewed by the clinical team and 
data entry personnel, who will ensure that they are accurate and complete.  Adverse events must 
be recorded on the appropriate electronic case report form, assessed for severity and relationship, 
and reviewed by the site principal investigator or appropriate sub-investigator. 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator.  During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values), reactogenicity and immunogenicity data 
will be entered into eCRFs via a 21 CFR Part 11-compliant internet data entry system provided 
by the SDCC.  The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate.  
Clinical data will be entered directly into electronic case report forms by the study personnel. 

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Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values, reactogenicity, and immunogenicity data). 
 
Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and study drug disposition records will be retained for 2 years after a 
marketing application is approved for the study product for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the study 
product, until 2 years after the investigation is discontinued and the FDA has been notified. 
These documents will be retained for a longer period, however, if required by local regulations. 
ICFs for future use will be maintained as long as the sample/specimen exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site principal investigator when these documents no longer need to be 
retained. The participating VTEU sites must contact DMID for authorization prior to the 
destruction of any study records. 
 

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CLINICAL MONITORING 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures.  DMID, the sponsoring agency, or its designee will conduct site-
monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, informed consent forms, medical and laboratory 
reports, and protocol and GCP compliance.  Site monitors will have access to each participating 
site, study personnel, and all study documentation according to the DMID-approved site 
monitoring plan.  Study monitors will meet with site principal investigators to discuss any 
problems and actions to be taken, and will document site visit findings and discussions. 
 

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PUBLICATION POLICY 
Following completion of the study, the lead Principal Investigator is expected to publish the 
results of this research in a scientific journal.  All investigators funded by the NIH must submit 
or have submitted for them to the National Library of Medicine’s PubMed Central 
(http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication.  The NIH Public Access Policy ensures the public 
has access to the published results of NIH funded research.  It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the results posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClincialTrials.gov. 
For this trial the responsible party is DMID, which will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 

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LITERATURE REFERENCES 
1. 
Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. Lancet 2012;379:2477-88. 
2. 
Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and chronic hepatitis in organ-
transplant recipients. N Engl J Med 2008;358:811-7. 
3. 
Wedemeyer H, Pischke S, Manns MP. Pathogenesis and treatment of hepatitis e virus 
infection. Gastroenterology 2012;142:1388-97 e1. 
4. 
Pischke S, Hartl J, Pas SD, Lohse AW, Jacobs BC, Van der Eijk AA. Hepatitis E virus: 
Infection beyond the liver? Journal of hepatology 2017;66:1082-95. 
5. 
Kamar N, Bendall RP, Peron JM, et al. Hepatitis E virus and neurologic disorders. Emerg 
Infect Dis 2011;17:173-9. 
6. 
Krain LJ, Atwell JE, Nelson KE, Labrique AB. Fetal and neonatal health consequences 
of vertically transmitted hepatitis E virus infection. Am J Trop Med Hyg 2014;90:365-70. 
7. 
Khuroo MS, Teli MR, Skidmore S, Sofi MA, Khuroo MI. Incidence and severity of viral 
hepatitis in pregnancy. Am J Med 1981;70:252-5. 
8. 
Rein DB, Stevens GA, Theaker J, Wittenborn JS, Wiersma ST. The global burden of 
hepatitis E virus genotypes 1 and 2 in 2005. Hepatology 2012;55:988-97. 
9. 
Taniguchi M, Kim SR, Mishiro S, et al. Epidemiology of hepatitis E in Northeastern 
China, South Korea and Japan. J Infect 2009;58:232-7. 
10. 
Boccia D, Guthmann JP, Klovstad H, et al. High mortality associated with an outbreak of 
hepatitis E among displaced persons in Darfur, Sudan. Clin Infect Dis 2006;42:1679-84. 
11. 
Ahmed JA, Moturi E, Spiegel P, et al. Hepatitis E outbreak, Dadaab refugee camp, 
Kenya, 2012. Emerging infectious diseases 2013;19:1010-2. 
12. 
Adlhoch C, Avellon A, Baylis SA, et al. Hepatitis E virus: Assessment of the 
epidemiological situation in humans in Europe, 2014/15. J Clin Virol 2016;82:9-16. 
13. 
Nicand E, Armstrong GL, Enouf V, et al. Genetic heterogeneity of hepatitis E virus in 
Darfur, Sudan, and neighboring Chad. Journal of medical virology 2005;77:519-21. 
14. 
Geng Y, Wang Y. Epidemiology of Hepatitis E. Adv Exp Med Biol 2016;948:39-59. 
15. 
von Wulffen M, Westholter D, Lutgehetmann M, Pischke S. Hepatitis E: Still Waters 
Run Deep. J Clin Transl Hepatol 2018;6:40-7. 
16. 
Chang Y, Wang L, Geng J, et al. Zoonotic risk of hepatitis E virus (HEV): A study of 
HEV infection in animals and humans in suburbs of Beijing. Hepatol Res 2009;39:1153-8. 
17. 
Zhou YH, Purcell RH, Emerson SU. A truncated ORF2 protein contains the most 
immunogenic site on ORF2: antibody responses to non-vaccine sequences following challenge 
of vaccinated and non-vaccinated macaques with hepatitis E virus. Vaccine 2005;23:3157-65. 
18. 
Zhang J, Zhang XF, Zhou C, et al. Protection against hepatitis E virus infection by 
naturally acquired and vaccine-induced immunity. Clin Microbiol Infect 2014;20:O397-405. 
19. 
Xing L, Wang JC, Li TC, et al. Spatial configuration of hepatitis E virus antigenic 
domain. J Virol 2011;85:1117-24. 

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20. 
Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E 
vaccine. N Engl J Med 2007;356:895-903. 
21. 
Investigator's Brochure Recombinant Hepatitis E Vaccine (E. coli) - Hecolin® May 
2018. Report No.: Version 3.1. 
22. 
Li SW, Zhang J, Li YM, et al. A bacterially expressed particulate hepatitis E vaccine: 
antigenicity, immunogenicity and protectivity on primates. Vaccine 2005;23:2893-901. 
23. 
Zhang J, Liu CB, Li RC, et al. Randomized-controlled phase II clinical trial of a 
bacterially expressed recombinant hepatitis E vaccine. Vaccine 2009;27:1869-74. 
24. 
Zhu FC, Zhang J, Zhang XF, et al. Efficacy and safety of a recombinant hepatitis E 
vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 
trial. Lancet 2010;376:895-902. 
25. 
Zhang J, Zhang XF, Huang SJ, et al. Long-term efficacy of a hepatitis E vaccine. N Engl 
J Med 2015;372:914-22. 
26. 
Wu T, Zhu FC, Huang SJ, et al. Safety of the hepatitis E vaccine for pregnant women: a 
preliminary analysis. Hepatology 2012;55:2038. 
27. 
Wu T, Huang SJ, Zhu FC, et al. Immunogenicity and safety of hepatitis E vaccine in 
healthy hepatitis B surface antigen positive adults. Human vaccines & immunotherapeutics 
2013;9:2474-9. 
28. 
Global Advisory Committee on Vaccine Safety, 11-12 June 2014. Releve 
epidemiologique hebdomadaire / Section d'hygiene du Secretariat de la Societe des Nations = 
Weekly epidemiological record / Health Section of the Secretariat of the League of Nations 
2014;89:325-35. 
29. 
In: Stratton K, Gable A, McCormick MC, eds. Immunization Safety Review: Thimerosal-
Containing Vaccines and Neurodevelopmental Disorders. Washington (DC)2001. 
30. 
Price CS, Thompson WW, Goodson B, et al. Prenatal and infant exposure to thimerosal 
from vaccines and immunoglobulins and risk of autism. Pediatrics 2010;126:656-64. 
31. 
Thompson WW, Price C, Goodson B, et al. Early thimerosal exposure and 
neuropsychological outcomes at 7 to 10 years. N Engl J Med 2007;357:1281-92. 
32. 
Brown A, Halliday JS, Swadling L, et al. Characterization of the Specificity, 
Functionality, and Durability of Host T-Cell Responses Against the Full-Length Hepatitis E 
Virus. Hepatology 2016;64:1934-50. 
 

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APPENDICES 
  Schedule of Events  
Study Visit 
Screening 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
17 
 
Study day from 1st  vaccine 
Screening 
(≤28 
days)a,b 
Day 
1c 
Day 
4**
+/-1 
Day 
8  
+/-1 
Day 
15   
+/-2 
Day 
29 
+/-2 
Day 
32** 
Day 
36 
Day 
43 
Day 
57 
Day 
120** 
Day 
180 
+/- 14 
Day 
184 
** 
Day 
187 
Day 
194 
Day 
208 
Day 
270** 
Day 
360 
+/-28 
Early 
Termination/ 
Unscheduled 
Study day from 2nd vaccine 
 
 
 
 
 
Day 
1 
Day 
4**
+/-1 
Day 
8 +/-
1 
Day 
15  
+/-2 
Day 
29 
+/-2 
Day 
92**  
+/- 14 
 
 
 
 
 
 
 
 
Study day from 3rd vaccine 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
Day 
4** 
+/-1 
Day 
8 +/-
1 
Day 
15  
+/-2 
Day 
29  
+/-2 
Day 
90** 
+/-14 
Day 
180 
+/- 14  
 
Obtain Informed Consent 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History* 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum pregnancy teste  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy teste 
 
Xh
 
 
 
Xh
 
 
 
 
 
Xh 
 
 
 
 
 
 
{X} 
Review of birth control history 
with female subjects 
X 
Xe 
 
 
 
Xe 
 
 
 
 
 
Xe 
 
 
 
 
 
 
X 
Counsel on pregnancy 
avoidancee 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
{X} 
Physical examination i 
X 
{X}h
 
 
{X} 
{X} 
{X}h
 
 
{X} 
{X} 
{X} 
 
{X}h 
 
{X} 
{X} 
{X} 
 
{X} 
{X} 
Vital signsj 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
 
 
{X} 
Review of Eligibility Criteria 
X 
Xc,h 
 
 
 
X
h 
 
 
 
 
 
X
h 
 
 
 
 
 
 
 

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Study Visit 
Screening 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
17 
 
Study day from 1st  vaccine 
Screening 
(≤28 
days)a,b 
Day 
1c 
Day 
4**
+/-1 
Day 
8  
+/-1 
Day 
15   
+/-2 
Day 
29 
+/-2 
Day 
32** 
Day 
36 
Day 
43 
Day 
57 
Day 
120** 
Day 
180 
+/- 14 
Day 
184 
** 
Day 
187 
Day 
194 
Day 
208 
Day 
270** 
Day 
360 
+/-28 
Early 
Termination/ 
Unscheduled 
Study day from 2nd vaccine 
 
 
 
 
 
Day 
1 
Day 
4**
+/-1 
Day 
8 +/-
1 
Day 
15  
+/-2 
Day 
29 
+/-2 
Day 
92**  
+/- 14 
 
 
 
 
 
 
 
 
Study day from 3rd vaccine 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
Day 
4** 
+/-1 
Day 
8 +/-
1 
Day 
15  
+/-2 
Day 
29  
+/-2 
Day 
90** 
+/-14 
Day 
180 
+/- 14  
 
Pre-Administration 
Reactogenicity Assessments 
 
Xh 
 
 
 
Xh 
 
 
 
 
 
Xh 
 
 
 
 
 
 
 
Randomization 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study vaccine administration 
 
▲ 
 
 
 
▼ 
 
 
 
 
 
▼ 
 
 
 
 
 
 
 
Distribution of memory aid 
 
Xk 
 
 
 
Xk 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
Review of subject diary/solicited 
events by staff 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
 
 
{X} 
AE/SAE Assessmentm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
{X} 
Evaluate vaccination site 
 
X 
 
X 
{X} 
X 
 
X 
{X} 
 
 
X 
 
X 
{X} 
 
 
 
{X} 
Post-Administration 
Reactogenicity Assessments 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
X
X
X
X
X
Xl 
Xl 
Xl 
Hematology, chemistryf (mL) 
13n 
 
 
13 
{13} 
 
 
13 
{13} 
 
 
13
 h
 
 
13 
{13} 
 
 
 
{13} 
Hepatitis B surface antigen, 
hepatitis C antibody, HIV types 1 
and 2 antigen/antibody 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis E IgM and IgG 
antibodies 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum: Immunogenicity (mL) 
 
10h 
 
10 
10 
10 h 
 
10 
10 
10 
 
10 h 
 
10 
10 
10 
 
10
{10} 

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Study Visit 
Screening 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
17 
 
Study day from 1st  vaccine 
Screening 
(≤28 
days)a,b 
Day 
1c 
Day 
4**
+/-1 
Day 
8  
+/-1 
Day 
15   
+/-2 
Day 
29 
+/-2 
Day 
32** 
Day 
36 
Day 
43 
Day 
57 
Day 
120** 
Day 
180 
+/- 14 
Day 
184 
** 
Day 
187 
Day 
194 
Day 
208 
Day 
270** 
Day 
360 
+/-28 
Early 
Termination/ 
Unscheduled 
Study day from 2nd vaccine 
 
 
 
 
 
Day 
1 
Day 
4**
+/-1 
Day 
8 +/-
1 
Day 
15  
+/-2 
Day 
29 
+/-2 
Day 
92**  
+/- 14 
 
 
 
 
 
 
 
 
Study day from 3rd vaccine 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
Day 
4** 
+/-1 
Day 
8 +/-
1 
Day 
15  
+/-2 
Day 
29  
+/-2 
Day 
90** 
+/-14 
Day 
180 
+/- 14  
 
PBMC and Plasma Collection 
for Future Use 
 
48h 
 
16 
36 
48h 
 
16 
36 
32 
 
48h 
 
16 
36 
32 
 
32 
{≤48} 
Total Blood Volume per visit 
(mL)n 
33 
58 
 
39 
{59} 
58 
 
39 
{59} 
42 
 
71 
 
39 
{59} 
42 
 
42 
{71} 
Cumulative Blood Volume n 
33 
91 
 
130 
{189
} 
247 
 
286 
{345
} 
387 
 
458 
 
497 
{556
} 
598 
 
640 
 
▲Prime dose: HEV 239 or Placebo; ▼Boost dose: HEV 239 or Placebo;  
NOTE 1: In case of early withdrawal due to an adverse event, the investigator will collect all information relevant to the AE and safety of the subject, and will 
follow the subject to resolution, or until reaching a clinically stable endpoint. If feasible, blood will be drawn for immunologic assays. Subjects who wish to 
withdraw consent will be offered an optional visit for safety follow-up (before the formal withdrawal of consent). The subject has the right to refuse. 
a)  Screening may be split into multiple days or visits. This will include collection of baseline demographics and subject contact information.  
b)  Signing of the informed consent form (ICF) needs to be done before the first study-related activity. 
c)  The investigators should ensure that all study enrollment criteria have been met at the end of the screening period. If a subject’s status changes 
(including laboratory results or the receipt of additional medical records) after screening but before Day 1 such that the subject no longer meets all 
eligibility criteria, then the subject should be excluded from participation in the study. 
d)  Pre-study medications and therapies will be reviewed and recorded for the 30 days prior to the start of screening. 
e)  Subjects will be counselled to use adequate birth control methods to avoid pregnancy. 
f)  Baseline laboratories include complete blood count with differential (which will include white blood cells, absolute neutrophil count (ANC), absolute 
eosinophil count (AEC), hemoglobin, and platelets), creatinine, glucose, Alanine aminotransferase (ALT), hepatitis B surface antigen, hepatitis C antibody, HIV 

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types 1 and 2 antigen/antibody, hepatitis E IgM and IgG antibodies, and urine drug screen (Section 2.3.1). Retesting of values that lead to exclusion is allowed 
once using an unscheduled visit during the screening period, provided there is an alternative explanation for the out of range value. If the initial laboratory 
screening occurred more than 28 days before baseline (Day 1) but the subject was unable to be vaccinated within the 28-day window (e.g., due to meeting 
Exclusion Criteria 5.1.2), the subject must have safety laboratories repeated (see protocol-specific MOP for details).  Safety laboratories will be obtained on Days 
8, 36, 180, and 187 will include complete blood count with differential (which will include white blood cells, ANC, AEC, hemoglobin, and platelets), Cr, and 
ALT (Section 2.3.1). 
h)  Prior to study vaccine administration. 
i)  An abbreviated physical examination will be carried out at screening. At other visits, symptom-directed examination will be performed as indicated 
by the investigator. 
j)  Includes heart rate, blood pressure and oral body temperature after at least 5 minutes rest. To be assessed prior to study vaccine administration and at a 
minimum of 30 minutes after study vaccine administration. At screening this will also include height and body weight for determination of body mass 
index (BMI).  
k)   When the memory aid is distributed to subjects, they will also be instructed as to when to contact the investigator about unsolicited AEs.  
Hypersensitivity symptoms will also be reviewed with the subject and they will be counselled that if any of these were occur they must contact study 
personnel or seek medical attention immediately. 
l)  Concomitant therapies between D57 and D150 and from D208 – D360 should only be recorded if administered in conjunction with SAEs.  
m) Solicited AEs: Inclusive of solicited injection site reactions and systemic reactogenicity events performed on the day of each study vaccination through at 
least D8 after each study vaccination (see Sections 8.1.2). Unsolicited AEs: Collection of unsolicited AEs from time of first vaccination through D57; then 
from Day 180 – 208. SAEs: SAEs will be collected from the time of the first study vaccination through the last study visit (Day 360)..  
n) Volumes are the maximum volumes expected to be drawn. Samples may be fasted or non-fasted.  The total volume at an unscheduled or early termination 
visit will not exceed the individual time point volume. 
 { } If indicated based upon timing and/or symptoms. 
* See Section 7.1.1 regarding details of medical history to be collected. 
** Telephone Visit

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Table 8: TOXICITY TABLE 
Laboratory Adverse Events 
Blood, Serum, or Plasma 
Normal Range 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Creatinine – mg/dL (Female) 
0.5 – 1.10  
≥1.11 – 1.79 
≥1.80-2.09 
≥2.10 
Creatinine – mg/dL (Male) 
0.6 – 1.35 
≥1.36 – 1.79 
≥1.80-2.09 
≥2.10 
ALT U/L (Female) 
6 – 29  
30 – 105 
106-175 
>175 
ALT U/L (Male) 
9 – 46 
47 – 105 
106-175 
>175 
Hemoglobin (Female) - g/dL 
11.7 – 15.5  
11.0-11.6 
9.5-10.9 
<9.5 
Hemoglobin (Male) - g/dL 
13.2 – 17.1  
12.0 – 13.1 
10.0 – 11.9 
<10.0 
WBC Increase (Thousand/uL) 
3.8 – 10.8  
10.9 – 15.0 
15.1 – 20.0 
> 20.0 
WBC Decrease (Thousand/uL) 
3.8 – 10.8  
2.5-3.7 
1.5-2.4 
<1.5 
Absolute Neutrophil Count Decrease 
(cells/uL) 
1500 – 7800 
1490 – 1499 
1000-1489 
<1000 
Absolute Eosinophil Count Increase 
(cells/uL) 
15 – 500  
501-749 
750-1500 
>1500 
Platelets Decreased (Thousand/uL) 
140 – 400  
120-139 
100-119 
<100 
 
 

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Clinical Adverse Events 
Category 
Mild (Grade 1) 
Moderate (Grade 2) Severe (Grade 3) 
Allergic reaction 
Pruritus without rash* 
Localized urticarial OR 
requires oral therapy 
Generalized urticaria; 
angioedema OR 
anaphylaxis OR 
requires epinephrine 
Illness or clinical adverse event 
Events that are usually 
transient and may 
require only minimal or 
no treatment or 
therapeutic intervention 
and generally do not 
interfere with the 
subject’s usual 
activities of daily 
living. 
 
Events that are usually 
alleviated with additional 
specific therapeutic 
intervention.  The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant  
Events interrupt usual 
activities of daily 
living, or significantly 
affects clinical status, 
or may require 
intensive therapeutic 
intervention.  Severe 
events are usually 
incapacitating. 
 
* Not at injection site. 

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Table 9: VITAL SIGNS REFERNCE RANGES 
VITAL SIGNS 
 Mild   (Grade 1) 
 Moderate (Grade 2) 
 Severe (Grade 3)  
Fever (°C) * 
38.0 – 38.4 
38.5 – 38.9 
≥39.0 
Tachycardia - beats per 
minute 
101 – 115 
116 – 130 
>130 or ventricular 
dysrhythmias 
Bradycardia - beats per 
minute 
45 - 50 bpm 
40 – 44 bpm  
<40 bpm  
Hypertension (systolic)- mm 
Hg** 
141-150 
151-160 
>160 
Hypertension (diastolic) - 
mm Hg** 
91-95 
96-100 
>100 
Hypotension (systolic) - mm 
Hg** 
85-89 
80-84 
< 80 
Hypotension (diastolic) – 
mm Hg** 
50 – 54 
45 – 49  
<45 
* Oral temperature; no recent hot or cold beverages or smoking. 
** Assuming subject is awake, and resting for AEs; 3 measurements on the same arm with concordant results.