A Randomized, Placebo-controlled, Double-blind Study to Assess the Efficacy and Safety of a Maintenance Dose of GEN-003 in Subjects With Genital Herpes Infection
Phase: PHASE2
Conditions: Genital Herpes, HSV-2 Infection
Sponsor: Genocea Biosciences, Inc.

 
 
CLINICAL TRIAL PROTOCOL 
 
Study Title: 
A Randomized, Placebo-controlled, Double-blind Study to Assess the 
Efficacy and Safety of a Maintenance Dose of GEN-003 in Subjects with 
Genital Herpes Infection 
Study Number: 
GEN-003-005 
Study Phase: 
2 
Test Product: 
GEN-003 
IND Number: 
14910 
Indication: 
Treatment of chronic genital herpes simplex infection 
Sponsor: 
Genocea Biosciences, Inc.  
Cambridge Discovery Park 
100 Acorn Park Drive, 5th Floor 
Cambridge, MA  02140 
Medical Monitor: 
Thomas Heineman, M.D., Ph.D. 
Genocea Biosciences, Inc. 
Phone: 617-715-6670  
 
 
Version 
Date 
1.0 
06 March 2017 
1.1 
15 September 2017 
2.0 
13 October 2017 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without 
written authorization from Genocea Biosciences, Inc., except to the extent necessary to obtain 
informed consent from persons receiving the investigational product or their legal guardians, 
or for discussions with local Regulatory Authorities, Institutional Review Boards, Ethics 
Committees, or persons participating in the conduct of the study.  
 

Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..................................................................................................6 
INVESTIGATOR SIGNATURE PAGE......................................................................................7 
SYNOPSIS ......................................................................................................................................8 
LIST OF ABBREVIATIONS .....................................................................................................11 
1 
INTRODUCTION............................................................................................................13 
1.1 
HSV-2 Infection .................................................................................................................13 
1.2 
Current Treatment of Recurrent HSV-2 and Transmission ...............................................13 
1.3 
GEN-003 ............................................................................................................................14 
1.4 
Nonclinical Pharmacology and Toxicology Studies of GEN-003 Antigens and MM2.....14 
1.4.1 
Nonclinical Models of Immunogenicity and Efficacy .................................................14 
1.4.2 
Nonclinical Toxicology Studies ...................................................................................15 
1.5 
Clinical Trials of GEN-003 ................................................................................................15 
1.5.1 
GEN-003-001: A Phase I/IIa, Randomized, Double-Blind, Dose-Ranging, Placebo-
Controlled Study of the Safety and Immunogenicity of a HSV-2 Vaccine Containing 
Matrix M-2 Adjuvant in Individuals with Documented HSV-2 Genital Infection ......15 
1.5.2 
GEN-003-002: A Randomized, Double-Blind, Factorial Study to Compare the Safety 
and Efficacy of Varying Combinations of GEN-003 and Matrix-M2 in Subjects with 
Genital HSV-2 Infection ..............................................................................................16 
1.5.3 
GEN-003-002a: Rollover Trial for Placebo Subjects Previously Enrolled into GEN-
003-002 - A Randomized, Double-Blind, Factorial Study to Compare the Safety and 
Efficacy of Varying Combinations of GEN-003 and Matrix-M2 in Subjects with 
Genital HSV-2 Infection ..............................................................................................17 
1.5.4 
GEN-003-002b: A Long-term Follow-up Study of Efficacy and Immunogenicity of 
GEN-003 in Subjects with Genital Herpes Simplex Virus Type 2 (HSV-2) 
Infection .......................................................................................................................18 
1.5.5 
GEN-003-003:  A Randomized, Double-blind Study to Evaluate a New Formulation 
of GEN-003 in Subjects with Genital HSV-2 Infection ..............................................18 
1.6 
Study Rationale ..................................................................................................................20 
2 
OBJECTIVES AND ENDPOINTS ................................................................................21 
2.1 
Objectives ..........................................................................................................................21 
2.1.1 
Primary Efficacy Objective ..........................................................................................21 
2.1.2 
Secondary Efficacy Objectives ....................................................................................21 
2.1.3 
Safety Objective ...........................................................................................................21 
2.2 
Endpoints ...........................................................................................................................21 
2.2.1 
Primary Efficacy Endpoint ..........................................................................................21 
2.2.2 
Secondary Efficacy Endpoints .....................................................................................21 
2.2.3 
Safety Endpoints ..........................................................................................................22 
3 
STUDY DESIGN ..............................................................................................................23 
3.1 
Overall Study Design .........................................................................................................23 
3.2 
Rationale for Study Design ................................................................................................24 
3.2.1 
GEN-003 Dose .............................................................................................................24 
3.2.2 
Efficacy Endpoints .......................................................................................................24 
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3.3 
Study Duration ...................................................................................................................25 
4 
SUBJECT POPULATION ..............................................................................................26 
4.1 
Inclusion Criteria ...............................................................................................................26 
4.2 
Exclusion Criteria ..............................................................................................................26 
4.3 
Criteria for Temporary Delay of Dosing ...........................................................................27 
5 
INVESTIGATIONAL PRODUCTS ..............................................................................28 
5.1 
GEN-003/Placebo ..............................................................................................................28 
5.1.1 
Formulation ..................................................................................................................28 
5.1.2 
Packaging and Labeling ...............................................................................................28 
5.1.3 
Storage .........................................................................................................................28 
5.1.4 
Preparation and Administration ...................................................................................29 
5.2 
Randomization ...................................................................................................................29 
5.3 
Blinding and Unblinding....................................................................................................29 
5.4 
Investigational Product Accountability, Dispensing, and Destruction ..............................29 
5.5 
Concomitant Medications ..................................................................................................30 
5.6 
Prohibited Medications ......................................................................................................30 
5.6.1 
Antiviral Medication Use for Suppression or Recurrence of Genital Herpes .............30 
5.6.2 
Medications and Supplements with Anti-HSV Activity ..............................................30 
5.6.3 
Immunosuppressive Medications.................................................................................30 
5.6.4 
Vaccines .......................................................................................................................30 
5.7 
Other Study Restrictions ....................................................................................................31 
5.7.1 
Fluid and Food Intake ..................................................................................................31 
5.7.2 
Birth Control and Prevention of HSV-2 Transmission ................................................31 
5.8 
Treatment Compliance .......................................................................................................31 
6 
STUDY PROCEDURES .................................................................................................32 
6.1 
Definitions and Descriptions of Assessments and Procedures ..........................................32 
6.2 
GEN-003/Placebo Dosing Period ......................................................................................33 
6.2.1 
Maintenance Dose (Day 1) – Clinic Visit ....................................................................33 
6.2.2 
Day 8 (± 3 Days) – Clinic Visit ...................................................................................34 
6.2.3 
Day 29/Month 1 (± 3 Days) – Clinic Visit ..................................................................34 
6.3 
Follow-up Period ...............................................................................................................34 
6.3.1 
Follow-up Telephone Calls ..........................................................................................34 
6.3.2 
Month 3 (Day 85 ± 7 days)  and Month 6 (Day Day 169 ± 14 days) – Clinic Visits ..35 
6.3.3 
Month 9 (Day 253 ± 14 days) and Month 12 (Day 337 ± 14 days) – Clinic Visits .....35 
7 
ADVERSE EVENTS .......................................................................................................36 
7.1 
Reporting Responsibilities .................................................................................................36 
7.2 
Definitions..........................................................................................................................36 
7.2.1 
Adverse Event ..............................................................................................................36 
7.2.2 
Medically Attended Adverse Events ...........................................................................36 
7.2.3 
Adverse Event of Special Interest ................................................................................36 
7.2.4 
Serious Adverse Event .................................................................................................36 
7.2.5 
Relatedness (Causality) ................................................................................................37 
7.2.6 
Severity ........................................................................................................................37 
7.3 
Clinical Laboratory Abnormalities ....................................................................................38 
7.4 
Physical Exam Abnormalities ............................................................................................38 
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7.5 
Pregnancy ...........................................................................................................................38 
7.6 
Reporting of Serious Adverse Events and Adverse Events of Special Interest .................38 
7.7 
Follow-Up of Adverse Events ...........................................................................................39 
8 
SUBJECT AND STUDY DISCONTINUATION ..........................................................40 
8.1 
Screening Failures ..............................................................................................................40 
8.2 
Premature Discontinuation from Study .............................................................................40 
8.3 
Procedures for Premature Discontinuation from Study .....................................................40 
8.4 
Study or Site Termination ..................................................................................................40 
9 
DATA MONITORING COMMITTEE .........................................................................42 
10 
STATISTICAL CONSIDERATIONS ...........................................................................43 
10.1 
Sample Size ........................................................................................................................43 
10.2 
Analysis Conventions ........................................................................................................43 
10.3 
Analysis Populations ..........................................................................................................43 
10.4 
Subject Disposition ............................................................................................................43 
10.5 
Demographic Data and Baseline Characteristics ...............................................................43 
10.6 
Concomitant Medications ..................................................................................................44 
10.7 
Primary Efficacy Endpoint – Genital Herpes Lesion Rate ................................................44 
10.8 
Secondary Efficacy Endpoints ...........................................................................................44 
10.8.1 
Frequency of Genital Herpes Recurrences ..................................................................44 
10.8.2 
Proportion of Subjects Recurrence-Free ......................................................................44 
10.8.3 
Time to First Genital Herpes Recurrence ....................................................................44 
10.8.4 
Duration of Genital Herpes Recurrences .....................................................................44 
10.8.5 
Antiviral Medication Use .............................................................................................44 
10.9 
Safety Analysis ..................................................................................................................45 
10.9.1 
Reactogenicity..............................................................................................................45 
10.9.2 
Adverse Events ............................................................................................................45 
10.10 Interim Analysis .................................................................................................................45 
11 
ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES ....................................46 
11.1 
Ethical Conduct of the Study .............................................................................................46 
11.2 
Institutional Review Board/Ethics Committee Approval ..................................................46 
11.3 
Informed Consent...............................................................................................................46 
11.4 
Confidentiality ...................................................................................................................46 
11.5 
Biological Samples ............................................................................................................46 
11.6 
Protocol Amendments ........................................................................................................47 
11.7 
Protocol Deviations ............................................................................................................47 
11.8 
Case Report Forms .............................................................................................................47 
11.9 
Source Document Maintenance .........................................................................................47 
11.10 Retention of Records..........................................................................................................47 
11.11 Study Monitoring ...............................................................................................................48 
11.12 Financial Disclosure...........................................................................................................48 
11.13 Publication and Disclosure Policy .....................................................................................48 
12 
REFERENCES .................................................................................................................50 
Appendix 1 
Schedule of Events .................................................................................................52 
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Appendix 2 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials ........................................................................54 
Appendix 3 
Sample Diary Card .................................................................................................59 
Appendix 4 
Adverse Events of Special Interest ........................................................................60 
Appendix 5 
Genital Herpes Signs and Symptoms Diary...........................................................62 
Appendix 6 
Protocol Amendments and Summary of Changes .................................................64 
 
 
 
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
INVESTIGATOR SIGNATURE PAGE 
 
GEN-003-005:  A Randomized, Placebo-controlled, Double-blind Study to Assess the 
Efficacy and Safety of a Maintenance Dose of GEN-003 in Subjects with Genital Herpes 
Infection 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  
 
Signed: 
 
 
  
Date:   
 
 
 
Print Name: 
 
 
 
 
 
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
SYNOPSIS 
Sponsor:  Genocea Biosciences, Inc. 
Study Title:  A Randomized, Placebo-controlled, Double-blind Study to Assess the Efficacy 
and Safety of a Maintenance Dose of GEN-003 in Subjects with Genital Herpes Infection 
Test Product:  GEN-003 
Name of Active Ingredients:  GB208, GB217, Matrix-M2 adjuvant (MM2) 
Study Number:  GEN-003-005 
Study Phase:  2 
Study Centers:  Up to 9 centers in the United States 
Primary Efficacy Objective:  
• To evaluate the efficacy of GEN-003 versus placebo administered as a maintenance dose in 
reduction of genital herpes lesion rate 
Secondary Efficacy Objectives: 
• To evaluate the efficacy of GEN-003 versus placebo administered as a maintenance dose on 
genital herpes recurrence through 6 months:   
- Reduction of genital herpes recurrence frequency   
- Increase of proportion of subjects who are genital herpes recurrence-free  
- Increase of time to first genital herpes recurrence  
- Reduction of genital herpes recurrence duration 
Safety Objective: 
• To evaluate the safety and tolerability of a maintenance dose of GEN-003 versus placebo 
Study Design:  This study is a randomized, double-blind, placebo-controlled clinical trial of 
GEN‑003 in subjects who have received previous doses of GEN-003. Subjects who completed 
Study GEN-003-003 and received all 3 doses of GEN‑003, reported data in daily electronic 
reporting period on at least 80% of days, and had no important protocol deviation in that trial 
will be offered enrollment in this study. Subjects who meet all inclusion and no exclusion 
criteria and provide written informed consent for this study will be randomized within 11 to 18 
months after the last active GEN-003 dose in a 1:1 ratio to receive 1 intramuscular (IM) dose 
(the maintenance dose) of GEN-003 or placebo. Randomization will be stratified on the basis of 
the GEN-003 dose received by the subject in Study GEN-003-003.  
Subjects will use a daily electronic tool for reporting the presence or absence of genital herpes 
lesions and the severity of genital herpes symptoms from Day 1 until the Month 6 Visit.  
Subjects will complete the EuroQol – 5 Domains – 5 Levels (EQ-5D-5L) questionnaire on each 
day of the first recurrence after the maintenance dose through Month 6. 
A serum sample will be collected from each subject for future research purposes before the 
maintenance dose (Day 1), 7 and 28 days after the maintenance dose (Day 8 and Day 29/Month 
1) 
At selected investigational sites, a whole blood sample will be collected and processed to 
isolate peripheral blood mononuclear cells (PBMCs) for future research purposes before the 
maintenance dose (Day 1), 7 and 28 days after the maintenance dose (Day 8 and Day 
29/Month 1). 
Local reactions and systemic events will be recorded for the first 7 days after the maintenance 
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
dose on a paper Diary Card; if any event is ongoing after Day 8, it will be followed until 
resolution. All adverse events (AEs) and concomitant medications will be recorded from Day 1 
to Day 29/Month 1. After Day 29/Month 1 to the end of the study, only serious AEs (SAEs), 
AEs of special interest (AESIs), medically attended AEs (MAAEs), antiviral medications, and 
vaccines will be recorded. All AEs will be graded in accordance with the Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials from Grade 1 (mild) to Grade 4 (life-threatening).  
From Month 2 to Month 12, the investigational site will contact each subject by telephone or 
site visit for review of daily electronic reporting tool data and assessment of SAEs, AESIs, and 
antiviral medication (through Month 6). 
A Data Monitoring Committee (DMC) will review safety data at intervals of a minimum of 
3 months until all subjects have completed the GEN-003/placebo dosing period. Any additional 
meetings and the specific safety monitoring plan will be detailed in the DMC charter. 
Efficacy Endpoints:  
Primary: 
• Genital herpes lesion rate (proportion of days with lesions present) in the 6-month period 
after the maintenance dose: Based on subject report of genital lesions via a daily electronic 
reporting tool 
Secondary: 
• Frequency of genital herpes recurrences in the 6-month period after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
• Proportion of subjects genital herpes recurrence-free at 6 months after the maintenance 
dose: Based on subject report of genital lesions via a daily electronic reporting tool 
• Time to first genital herpes recurrence in the 6-month period after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
• Duration of genital herpes recurrences in the 6-month period after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
Safety Endpoints: 
• Reactogenicity  
- Local reactions: Pain, tenderness, swelling, redness 
- Systemic events: Fever, headache, chills, fatigue, nausea, vomiting, diarrhea, muscle 
aches 
• AE, SAEs, AESIs, MAAEs 
Number of Subjects Planned: Up to 90 subjects 
Diagnosis and Main Criteria for Inclusion: Subjects who completed Study GEN-003-003 
(completed all study visits including the Month 12 visit) and received all 3 doses of active 
GEN-003 (any dose combination), received the last dose of GEN-003 within 11 to 18 months, 
and reported data in daily electronic reporting period on at least 80% of days, and had no 
important protocol deviation. 
Duration of Treatment:  1 dose  
Test Product; Dose; and Mode of Administration:  GEN-003 (60 µg of each antigen, GB208 
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and GB217, 50 µg of MM2, and normal saline), administered as a 0.5 mL IM injection 
Control Product; Dose; and Mode of Administration:  Normal saline, administered as a 
0.5 mL IM injection 
Statistical Methods:  
Sample Size: No formal sample size calculations were performed for this study.  
Analyses: 
Efficacy: 
Genital herpes lesion rates (the proportion of days with genital lesions present) in the 6-month 
period after the maintenance dose will be compared between treatment groups using the 
Wilcoxon rank sum text. The median frequencies of recurrences in the 6-month period will be 
compared between treatment groups using the Wilcoxon rank sum test. The proportion of 
subjects in each treatment group who are genital herpes recurrence-free at 6 months after the 
maintenance dose will be tabulated and compared using a chi-square test for homogeneity of 
proportions. Time to first recurrence in the 6-month period after the maintenance dose will be 
tabulated and graphed using the Kaplan-Meier method. The log-rank test will be used to 
compare the time to first recurrence survival curves between the GEN-003 and placebo groups. 
Median of individual mean duration of genital herpes recurrences during the 6-month period 
will be compared using the Wilcoxon rank sum test.  
Safety: 
Safety data will be summarized by the number and proportion of subjects with: 
• Reactogenicity:  local reactions and systemic events 
• AEs, SAEs, AESIs, MAAEs 
 
 
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IND #: 14910 
Version 2.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
CFR 
Code of Federal Regulations 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
EC 
Ethics Committee 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EQ-5D-5L 
EuroQol – 5 Domains – 5 Levels  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
gD 
glycoprotein D 
GH-SSD 
Genital Herpes Signs and Symptoms Diary 
GLP 
Good Laboratory Practice 
GMT 
geometric mean titer 
GrB 
granzyme B 
HIV 
human immunodeficiency virus 
HSV 
herpes simplex virus 
HSV-1 
herpes simplex virus type-1 
HSV-2 
herpes simplex virus type-2 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IFN-γ 
interferon-gamma 
IgG 
immunoglobulin G 
IM 
intramuscular 
IP 
investigational product 
IRB 
Institutional Review Board 
IUD 
intrauterine device  
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM2 
Matrix-M2 adjuvant 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PhRMA 
Pharmaceutical Research and Manufacturers of America 
RGHQoL 
Recurrent Genital Herpes Quality of Life Questionnaire 
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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SFC 
spot-forming cell 
TSS 
total severity score 
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1 INTRODUCTION 
1.1 
HSV-2 Infection 
Herpes simplex viruses (HSVs) are the main cause of genital ulcers worldwide (Looker 2008). 
More than 400 million people worldwide are infected with HSV type 2 (HSV-2), which is 
primarily sexually transmitted, and an estimated 140 million people have genital HSV type 1 
(HSV-1) infection (World Health Organization 2016). Evidence of infection, by serologic 
studies, is present in 1 out of every 6 people aged 14 to 49 in the United States 
(http://www.niaid.nih.gov/topics/genitalherpes/Pages/default.aspx; Centers for Disease Control 
and Prevention 2015). Women are more commonly infected than men, with 1 out of every 5 
women in the US having evidence of infection. Certain groups, such as people with human 
immunodeficiency virus (HIV) and commercial sex workers, have high rates of infection ranging 
from 60 to 95%, (Kimberlin, Rouse 2004; Gupta et al 2007). HSV-2 infection is associated with 
a 3-fold increase in risk of acquiring HIV infection and is considered to be a substantial 
contributor to the worldwide AIDS epidemic (Corey 2007). Most HSV-2 seropositive people are 
unaware of their infection status, probably because of mild and atypical symptoms and signs, and 
this lack of awareness contributes to the continued spread of HSV-2 infection among susceptible 
populations.   
In people with recognized genital herpes, the disease is characterized by the development of 
vesicles at the site of infection, usually the anogenital region (defined as the area covered by 
boxer shorts). Vesicles persist for days and evolve to ulcers that eventually crust and heal. The 
initial clinical manifestations occur approximately 4 days after acquisition of infection and are 
referred to as the primary outbreak or infection (or nonprimary initial, for the first episode of 
HSV-2 in a patient who is HSV-1 seropositive). In the absence of antiviral therapy, lesions 
resolve over the course of 1 to 3 weeks. The virus migrates in a retrograde process to become 
latent in the sensory nerve ganglia. At varying intervals, recurrences (secondary outbreaks or 
infections) develop when the virus travels anterograde to the skin or mucosal surfaces. During 
the first year after primary infection, the median recurrence rate in the absence of therapy is 4 per 
year, and 20% of patients experience more than 10 recurrences (Benedetti et al 1994).  
HSV-2 infection is transmitted by contact with the mucosal membranes of an infected person 
who is shedding the virus. During clinically active recurrences (presence of genital ulcers), 
HSV-2 can frequently be detected in ulcers and the surrounding skin and mucosa. However, 
during asymptomatic periods, shedding of HSV-2 from the anogenital regions of an infected 
person can be detected on approximately 10% to 13% of days (subclinical shedding) by 
polymerase chain reaction (PCR) (Fife et al 2006; Martens et al 2009). Most transmission occurs 
during such periods of subclinical shedding. Transmission may also occur from pregnant mother 
to infant at birth, resulting in a severe form of disseminated infection leading to permanent 
neurologic damage or death of the infant (Whitley 2004). 
1.2 
Current Treatment of Recurrent HSV-2 and Transmission 
There are no known curative treatments or therapeutic vaccines for HSV-2 infection. Current 
therapy is directed at reducing the duration of primary disease or reducing the duration or 
frequency of secondary outbreaks. For these indications, acyclovir, valacyclovir, or famciclovir 
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can be effective. Both clinical and subclinical shedding of HSV-2 are reduced during periods of 
therapy (Wald et al 1996; Gupta et al 2004; Fife et al 2006; Martens et al 2009; Johnston et al 
2012). However, in a clinical trial valacyclovir reduced transmission of HSV-2 from infected 
persons to uninfected partners by only 48% (Corey et al 2004). The limitations of antiviral 
therapy include the requirement for daily treatment, potentially incomplete compliance leading to 
breakthrough of viral shedding or clinical disease, inability to completely suppress clinical 
recurrences, and limited prevention of transmission of infection. Consequently, there have been a 
number of attempts to develop effective vaccines either for prevention or treatment of infection 
with HSV-2 (Stanberry et al 2002; de Bruyn et al 2006; Awasthi & Friedman 2014), but none is 
currently available.   
1.3 
GEN-003  
GEN-003 is an HSV-2 protein subunit vaccine consisting of 2 recombinant T-cell antigens 
(GB208 and GB217) and Matrix-M2 adjuvant (MM2): 
• GB208:  a T-cell antigen and internal fragment of the immediate early protein ICP4. ICP4 
was identified as one of the most frequent proteins recognized by the T-cells of immune 
seronegative subjects studied by AnTigen Lead Acquisition System (ATLASTM), suggesting 
its potential role in control of viral replication and utility as a vaccine candidate.  
• GB217:  a B-cell antigen (also known as glycoprotein D, or gD) that was identified through 
screening at Genocea to also invoke a T-cell response. This surface glycoprotein is a target of 
both HSV-2 neutralizing antibodies and of T-cell responses. 
• MM2:  immune stimulating complexes derived from fractionated Quillaja saponins, 
phosphatidylcholine, and cholesterol 
1.4 
Nonclinical Pharmacology and Toxicology Studies of GEN-003 Antigens 
and MM2 
Non-GLP (Good Laboratory Practice) and GLP studies of immunogenicity and toxicity in mice, 
GLP studies of immunogenicity and toxicity in monkeys, non-GLP and GLP studies of efficacy 
in guinea pigs, and a GLP local tolerance study in rabbits were conducted. Summaries of these 
nonclinical studies are provided below. Additional details of the studies can be found in the 
current Investigator Brochure. 
1.4.1 
Nonclinical Models of Immunogenicity and Efficacy 
Immune responses to components of GEN-003 were evaluated in mice and monkeys. The study 
results indicated that GB208 and GB217 prime potent and functional T-cell and B-cell responses, 
including HSV-2 neutralizing antibodies, when administered with MM2.  
The GLP immunogenicity study results indicated that GB208 and GB217 prime potent and 
functional T-cell and B-cell responses, including HSV-2 neutralizing antibodies, when 
administered with MM2. In a guinea pig model of vaginal HSV-2 infection, GEN-003 induced 
increases in GB208- and GB217-specific IgG titer and HSV-2 neutralizing antibodies (Skoberne 
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2013). Both the number of days with genital HSV-2 lesions and HSV-2 shedding were reduced 
in animals that received active vaccine compared to those in the placebo group.   
1.4.2 
Nonclinical Toxicology Studies 
GLP repeat-dose toxicology studies of GEN-003 antigens and MM2 in mice and monkeys and 
local tolerance study in rabbits showed no safety signals believed to be relevant to potential risks 
to humans receiving GEN-003.   
1.5 
Clinical Trials of GEN-003  
Three clinical trials of GEN-003 have been completed, and 2 trials are ongoing. Summaries are 
provided below. Additional details of the studies can be found in the current Investigator 
Brochure. 
1.5.1 
GEN-003-001: A Phase I/IIa, Randomized, Double-Blind, Dose-Ranging, 
Placebo-Controlled Study of the Safety and Immunogenicity of a HSV-2 
Vaccine Containing Matrix M-2 Adjuvant in Individuals with Documented 
HSV-2 Genital Infection 
Subjects aged 18 to 50 years with documented diagnosis of genital HSV-2 infection for > 1 year 
but who were otherwise healthy were enrolled sequentially into 1 of 3 dose cohorts defined by 
the antigen dose (10, 30, or 100 µg for each of the 2 protein antigens) and randomized within 
each cohort in a ratio of 3:1:1 to receive 3 intramuscular (IM) doses of GEN-003 antigens with 
MM2, GEN-003 antigens without MM2, or placebo at intervals of 21 days. Thus, the treatment 
groups were as follows: 
• 10 µg each GEN-003 antigen + 50 µg MM2 (31 subjects) 
• 30 µg each GEN-003 antigen + 50 µg MM2 (29 subjects) 
• 100 µg each GEN-003 antigen + 50 µg MM2 (27 subjects) 
• 10 µg each GEN-003 antigen (9 subjects) 
• 30 µg each GEN-003 antigen (10 subjects) 
• 100 µg each GEN-003 antigen (9 subjects) 
• Placebo (28 subjects) 
The study is complete; 143 subjects were enrolled. GEN-003 antigens when combined with 
MM2 generated a reduction in HSV-2 shedding rates that was maintained for at least 6 months 
after treatment, and the greatest reduction was achieved in the adjuvanted 30 µg dose group. No 
reduction in HSV-2 shedding occurred in the absence of MM2. 30 µg GEN-003 antigens 
combined with MM2 reduced lesion rates (proportion of days with lesions divided by the 28-day 
duration of the swab collection period) for at least 6 months post-treatment. 100 µg GEN-003 
antigens with MM2 also reduced HSV-2 shedding and lesion rates but less durably. 
GEN-003 antigens elicited strong and durable antibody and T-cell immune responses to both 
vaccine-specific antigens and production of HSV-2 neutralizing antibodies at all doses. The 
addition of MM2 augmented these responses.   
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
GEN-003 antigens with or without MM2 exhibited an acceptable safety and tolerability profile 
for use as a therapeutic vaccine. Five serious adverse events (SAEs) in 5 subjects (femur 
fracture, suicide attempt, complicated migraine, myocardial infraction, abortion spontaneous) 
were reported during the course of the study, and none was considered associated with treatment. 
No adverse events of special interest (AESIs) were reported.   
Three subjects had an adverse event (AE) leading to discontinuation of dosing, and 1 subject 
discontinued the study because of an AE of attempted suicide 21 days after Dose 3 that was 
assessed by the Investigator as not likely related to the investigational product (IP). For AEs, 
incidences were generally higher in the adjuvanted groups than in the unadjuvanted group and 
higher in the unadjuvanted group than in the placebo group. The severity of AEs tended to be 
higher in adjuvanted vaccine groups, and were more often related to the IP, than in the 
unadjuvanted and placebo groups.  
The most common solicited local reactions were pain, tenderness, and induration at the 
administration site, and the most common solicited systemic symptoms were myalgia and 
fatigue. Three subjects discontinued dosing because of reactogenicity.  
1.5.2 
GEN-003-002: A Randomized, Double-Blind, Factorial Study to Compare 
the Safety and Efficacy of Varying Combinations of GEN-003 and Matrix-
M2 in Subjects with Genital HSV-2 Infection 
Subjects aged 18 to 50 years with documented diagnosis of genital HSV-2 infection for > 1 year 
were randomized in equal proportions to receive 3 IM doses of 1 of the following doses at 
intervals of 21 days: 
• 30 µg each GEN-003 antigen + 25 µg MM2 (44 subjects) 
• 30 µg each GEN-003 antigen + 50 µg MM2 (45 subjects) 
• 30 µg each GEN-003 antigen + 75 µg MM2 (44 subjects) 
• 60 µg each GEN-003 antigen + 25 µg MM2 (44 subjects) 
• 60 µg each GEN-003 antigen + 50 µg MM2 (44 subjects) 
• 60 µg each GEN-003 antigen + 75 µg MM2 (44 subjects) 
• Placebo (45 subjects) 
The study is complete; 310 subjects were enrolled.   
Reduction in anogenital HSV-2 shedding was observed in all active treatment groups 
immediately after the last dose and persisted to 12 months after the last dose. The most effective 
dose combinations (60 µg each GEN-003 antigen with 50 µg MM2 and 60 µg each GEN-003 
antigen with 75 µg MM2) also reduced HSV-2 lesion rates. Rate ratios (95% confidence 
intervals) for lesion rate at 12 months compared to baseline were 0.35 (0.18, 0.71; P = 0.0033) 
and 0.53 (0.31, 0.89; P = 0.0165), respectively. These 2 doses are currently being further 
evaluated in Study GEN-003-003. 
GEN-003 elicited strong and durable humoral and cellular immune responses to the vaccine 
antigens (GB208 and GB217) including the production of HSV-2 neutralizing antibodies in all 
active dose groups.  
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
GEN-003 exhibited an acceptable safety and tolerability profile for use as a therapeutic vaccine 
in all dose combinations. Ten SAEs in 8 subjects (femur facture, myocardial infarction, viral 
syndrome, post lumbar puncture syndrome, pyelonephritis, diverticulitis, bipolar disorder 
[exacerbation of existing condition, 2 episodes], cholecystitis, and overdose) were reported 
during the course of the study, and none was considered associated with treatment. No AESIs 
were reported. 
Five subjects had an AE resulting in discontinuation of dosing. AEs occurred at similar rates and 
with similar severity in all the treatment groups, including the placebo group except for chills, 
which occurred about 2.5 times more frequently in the placebo group.  
Three subjects discontinued dosing because of reactogenicity. The frequency of Grade 3 local 
reactions or systemic events within 7 days of any dose was 4.4% for subjects who received 
placebo and ranged from 20.0% to 43.2% among active dose groups; no Grade 4 local reactions 
or systemic events occurred.   
The most common local reactions were pain and tenderness at the injection site, which occurred 
within 7 days following 1 or more vaccinations in most subjects who received active vaccine. 
Swelling occurred in about half of subjects who received active vaccine, and redness in about a 
quarter. The most common systemic events were fatigue and muscle aches, which occurred 
within 7 days following 1 or more vaccinations in most subjects who received active vaccine, 
and nausea, which occurred in 41.1% of subjects who received active vaccine.  
1.5.3 
GEN-003-002a: Rollover Trial for Placebo Subjects Previously Enrolled 
into GEN-003-002 - A Randomized, Double-Blind, Factorial Study to 
Compare the Safety and Efficacy of Varying Combinations of GEN-003 
and Matrix-M2 in Subjects with Genital HSV-2 Infection 
Subjects who received placebo in Study GEN-003-002 were offered enrollment in this study of 
the same active dose combinations given in that study.  
The study is complete; 37 subjects were enrolled. The low number of subjects per group 
precluded a meaningful inference about the effect of antigen or adjuvant dose on the clinical 
efficacy of the different dose combinations. 
 
No AEs leading to discontinuation of dosing, SAEs, AESIs, or deaths occurred during the study. 
The most common local reactions during the 7 days after vaccination were pain and tenderness at 
the injection site, which occurred in most subjects.  The most common systemic events were 
fatigue and muscle aches, which also occurred in most subjects. The incidence and severity of 
overall AEs and treatment-related AEs were similar across all dose groups.  
 
Within the limitations of the small sample size, the safety profile of GEN-003 in this study was 
similar to previous studies.   
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
1.5.4 
GEN-003-002b: A Long-term Follow-up Study of Efficacy and 
Immunogenicity of GEN-003 in Subjects with Genital Herpes Simplex 
Virus Type 2 (HSV-2) Infection 
Subjects who received at least 1 dose of GEN-003 (any dose combination) and had no important 
protocol deviations in Study GEN-003-002 were offered enrollment in this follow-up study to 
evaluate long-term efficacy and immunogenicity up to 48 months postdose.  A total of 140 
subjects have been enrolled, and the study is ongoing.   
1.5.5 
GEN-003-003:  A Randomized, Double-blind Study to Evaluate a New 
Formulation of GEN-003 in Subjects with Genital HSV-2 Infection 
Subjects aged 18 to 50 with documented diagnosis of genital HSV-2 infection for > 1 year were 
randomized in a 1:1:1 ratio to receive 3 IM doses of 1 of the following doses of a new GEN-003 
formulation at intervals of 21 days: 
• GEN-003: 60 µg each antigen + 50 µg MM2 (43 subjects) 
• GEN-003: 60 µg each antigen + 75 µg MM2 (44 subjects) 
• Placebo: (44 subjects) 
A total of 131 subjects were enrolled, and an interim analysis of data through 6 months postdose 
was conducted in December 2016 and January 2017. In this analysis, the 60 μg each GEN-003 
antigen/50 μg MM2 dose reduced the rate of genital HSV-2 lesions during the 6 months after 
dosing compared to placebo (4.5% of days vs. 7.9%, respectively; 41% reduction vs. placebo, 
P < 0.05). GEN-003 also consistently demonstrated significant benefits compared to placebo for 
the secondary clinical endpoints (Table 1). 
Table 1: 
Study GEN-003-003: Secondary Clinical Endpoints – Interim Analysis 
at 6 Months Postdose 
Endpoint 
Dose 
Placebo 
N = 44 
60 µg each GEN-003 
antigen/50 μg MM2 
N = 43 
60 µg each GEN-003 
antigen /75 μg MM2 
N = 44 
Mean duration of recurrences (days) 
P-value versus placeboa 
4.8 
NA 
3.3 
0.01 
4.3 
0.64 
Mean number of recurrences over 6 months  
P-value versus placeboa 
2.7 
NA 
2.1 
0.08 
1.9 
0.02 
Proportion of subjects recurrence-free 6 
months after first dose (Kaplan-Meier 
estimate) 
P-value versus placebob 
10% 
 
 
NA 
29% 
 
0.03 
31% 
 
0.02 
Proportion of subjects recurrence-free 6 
months after last dose (Kaplan-Meier 
estimate) 
P-value versus placebob 
13% 
 
 
NA 
22% 
 
0.17 
36% 
 
0.02 
Abbreviations: NA = not applicable. 
a by Wilcoxon rank sum test 
b by log-rank test 
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Genocea Biosciences, Inc. 
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IND #: 14910 
Version 2.0 
Overall shedding rates decreased from baseline in both vaccine dose groups.  For the 60 µg 
GEN-003 antigens/50 µg MM2 group, both the decrease from baseline (P = 0.03) and the 
difference from the placebo group (P = 0.05) were statistically significant.  These differences did 
not reach statistical significance for the 60 µg GEN-003 antigens/75 µg MM2 group.  
IgG geometric mean titers (GMTs) to GB208 and GB217 and HSV-2 neutralizing antibodies 
increased after dosing in both active vaccine groups, peaking after Dose 1 for GB208 and Dose 3 
for GB217 and HSV-2 neutralizing antibody. All post-treatment GMTs in both active vaccine 
groups were statistically higher than those in the same group at baseline (Day 1) and those in the 
placebo group at each corresponding time point.   
The IFN-γ spot-forming cells (SFCs) peaked after Dose 3 for GB208 and after Dose 1 for GB217 
in the 60 µg GEN-003 antigens/50 µg MM2 dose group. The IFN-γ SFCs peaked after Dose 1 
for both GB208 and GB217 in the 60 µg GEN-003 antigens/75 µg MM2 dose group and 
declined by Day 50 (7 Days after Dose 3).  The GrB SFCs peaked after Dose 1 for both GB208 
and GB217 in both active vaccine groups.  However, the GrB response remained steady at Day 
50 for the 60 µg GEN-003 antigens/50 µg MM2 dose group but had declined in the 60 µg GEN-
003 antigens/75 µg MM2 dose group.  All post-treatment IFN-γ and GrB SFCs for both antigens 
in the both active vaccine groups were statistically higher than those in the same group at 
baseline and those in the placebo group at each corresponding time point. The observed decrease 
in the T-cell response in the 60 µg GEN-003 antigens/75 µg MM2 dose group at Day 50 
corresponds with the decreased reduction in shedding and lesion rates seen with this dose group, 
implying that the T-cell response may be exhausted due to overstimulation. 
No AESIs occurred during the study. Six SAEs, including 1 death, were reported in 4 subjects:  
• Intraductal proliferative breast lesion 
• Neck pain and pyrexia (2 SAEs) reported on the same day in a subject hospitalized and 
treated for culture-negative meningitis 
• Post laminectomy syndrome requiring hospitalization; 2 months later, toxicity to various 
agents resulting in death 
• Worsening mitral valve regurgitation requiring hospitalization for mitral valve 
replacement 
None of these SAEs were considered related to vaccination by the Investigator.  
Five subjects discontinued dosing for safety reasons (2 in each active group and 1 in the placebo 
group). Two subjects discontinued dosing due to solicited systemic events. 
The frequency of Grade 3 local reactions or systemic events within 7 days of any dose was 
13.6% for subjects who received placebo and ranged from 51.2% in the 60 µg GEN-003 
antigens/50 µg MM2 group and 68.2% in the 60 µg GEN-003 antigens/75 µg MM2 group; no 
Grade 4 local reactions or systemic events occurred.   
The most common local reactions were pain and tenderness at the injection site, which occurred 
within 7 days following 1 or more vaccinations in most subjects who received active vaccine. 
Swelling occurred in 64.4% of subjects who received active vaccine, and redness in 37.9%. The 
most common systemic events were headache, fatigue, and muscle aches, which each occurred 
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
within 7 days following 1 or more vaccinations in about 80% subjects who received active 
vaccine.  
1.6 
Study Rationale 
Data to date from clinical trials of GEN-003 administered as a 3-dose regimen have 
demonstrated an acceptable safety and tolerability profile, strong and durable antibody and T-cell 
immune responses to both vaccine-specific antigens, production of HSV-2 neutralizing 
antibodies, reduction in HSV-2 shedding, and clinical benefit. This study will evaluate the effect 
of an additional dose of GEN-003 administered at approximately 11 to 18 months after the last 
dose in the primary series. 
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Genocea Biosciences, Inc. 
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IND #: 14910 
Version 2.0 
2 OBJECTIVES AND ENDPOINTS 
2.1 
Objectives  
2.1.1 
Primary Efficacy Objective 
• To evaluate the efficacy of GEN-003 versus placebo administered as a maintenance dose in 
reduction of genital herpes lesion rate 
2.1.2 
Secondary Efficacy Objectives 
• To evaluate the efficacy of GEN-003 versus placebo administered as a maintenance dose on 
genital herpes recurrence through 6 months:   
- Reduction of genital herpes recurrence frequency  
- Increase of proportion of subjects who are genital herpes recurrence-free  
- Increase of time to first genital herpes recurrence  
- Reduction of genital herpes recurrence duration 
2.1.3 
Safety Objective 
• To evaluate the safety and tolerability of a maintenance dose of GEN-003 versus placebo 
2.2 
Endpoints 
2.2.1 
Primary Efficacy Endpoint 
• Genital herpes lesion rate (proportion of days with lesions present) in the 6-month period 
after the maintenance dose: Based on subject report of genital lesions via a daily electronic 
reporting tool 
2.2.2 
Secondary Efficacy Endpoints 
• Frequency of genital herpes recurrences in the 6-month period after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
• Proportion of subjects genital herpes recurrence-free at 6 months after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
• Time to first genital herpes recurrence in the 6-month period after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
• Duration of genital herpes recurrences in the 6-month period after the maintenance dose: 
Based on subject report of genital lesions via a daily electronic reporting tool 
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Genocea Biosciences, Inc. 
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2.2.3 
Safety Endpoints 
• Reactogenicity  
- Local reactions: Pain, tenderness, swelling, redness 
- Systemic events: Fever, headache, chills, fatigue, nausea, vomiting, diarrhea, muscle 
aches 
• AE, SAEs, AESIs, Medically attended AEs (MAAEs) 
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Genocea Biosciences, Inc. 
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IND #: 14910 
Version 2.0 
3 STUDY DESIGN 
3.1 
Overall Study Design 
This study is a randomized, double-blind, placebo-controlled clinical trial of GEN‑ 003 in 
subjects who have received previous doses of GEN-003. Subjects who completed Study 
GEN-003-003 and received all 3 doses of GEN‑ 003, reported data in daily electronic reporting 
period on at least 80% of days, and had no important protocol deviation in that trial will be 
offered enrollment in this study. Subjects who meet all inclusion and no exclusion criteria and 
provide written informed consent for this study will be randomized within 11 to 18 months after 
the last active GEN-003 dose in a 1:1 ratio to receive 1 IM dose (the maintenance dose) of GEN-
003 or placebo. Randomization will be stratified on the basis of the GEN-003 dose received by 
the subject in Study GEN-003-003.  
Subjects will use a daily electronic tool for reporting the presence or absence of genital herpes 
lesions and the severity of genital herpes symptoms from Day 1 until the Month 6 Visit.  
Subjects will complete the EuroQol – 5 Domains – 5 Levels (EQ-5D-5L) questionnaire on each 
day of the first recurrence after the maintenance dose through Month 6. 
A serum sample will be collected from each subject for future research purposes before the 
maintenance dose (Day 1), 7 and 28 days after the maintenance dose (Day 8 and Day 29/Month 
1).  
At selected investigational sites, a whole blood sample will be collected and processed to isolate 
peripheral blood mononuclear cells (PBMCs) for future research purposes before the 
maintenance dose (Day 1), 7 and 28 days after the maintenance dose (Day 8 and Day 
29/Month 1). 
Local reactions and systemic events will be recorded for the first 7 days after the maintenance 
dose on the paper Diary Card; if any event is ongoing after Day 8, it will be followed until 
resolution. All AEs and concomitant medications will be recorded from Day 1 to Day 29/Month 
1. After Day 29/Month 1 to the end of the study, only SAEs, AESIs, MAAEs, antiviral 
medications, and vaccines will be recorded. All AEs will be graded in accordance with the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials from Grade 1 (mild) to Grade 4 (life-threatening) (Appendix 2).  
From Month 2 to Month 12, the investigational site will contact each subject by telephone or site 
visit for review of daily electronic reporting tool data and assessment of SAEs, AESIs, and 
antiviral use (through Month 6). 
A Data Monitoring Committee (DMC) will review safety data at intervals of a minimum of 
3 months until all subjects have completed the GEN-003/placebo dosing period. Any additional 
meetings and the specific safety monitoring plan will be detailed in the DMC charter.  
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Genocea Biosciences, Inc. 
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3.2 
Rationale for Study Design  
3.2.1 
GEN-003 Dose 
The selection of the 60 µg GEN-003 antigens/50 µg MM2 dose was based on a benefit/risk 
analysis of data from prior GEN-003 clinical trials in which various GEN-003 antigen and 
adjuvant doses were evaluated. In all GEN-003 clinical trials, the primary biomarker for 
assessing vaccine effect was anogenital HSV-2 shedding.   
In Study GEN-003-001, the 30 µg antigens dose with MM2 yielded the greatest reduction in 
HSV-2 shedding. No safety concerns arose during this study, and increasing antigen dose did not 
correlate with an increased incidence or severity of AEs. 
In Study GEN-003-002, the 60 µg GEN-003 antigens groups generally outperformed the 30 µg 
antigen dose groups, regardless of adjuvant dose, in reducing the rate of HSV-2 shedding.  
Within the 60 µg antigens dose groups, 50 and 75 µg doses of MM2 yielded the greater and 
more durable reductions in HSV-2 shedding rates than 25 µg MM2. GEN-003 exhibited an 
acceptable safety and reactogenicity profile in all dose combinations. The rate of Grade 3 
solicited symptoms (local reactions and systemic events) appeared to be related to dose and was 
highest in the 60 µg GEN-003 antigens/75 µg MM2 dose; however, discontinuations due to AEs 
were rare and did not appear to be related to dose.  
In Study GEN-003-003, the 60 µg GEN-003 antigens/50 µg MM2 dose demonstrated a greater 
reduction in HSV-2 shedding rate than the 60 µg GEN-003 antigens/75 µg MM2 dose. Also, 
6-month data demonstrated that both active groups had similar clinical efficacy against recurrent 
genital herpes. The vaccine containing the higher MM2 dose was associated with a modestly 
higher frequency of Grade 3 solicited symptoms than the 60 µg GEN-003 antigens/50 µg MM2 
dose. 
In an open session of a DMC meeting during the conduct of Study GEN-003-003, Genocea 
requested an opinion as to whether a dose group containing the lower dose of adjuvant (25 µg) 
should be added. In their written response, they stated: “DSMB is not convinced of a dose 
response effect on AEs, therefore an additional arm at a lower dose (as proposed by the Sponsor) 
may not reduce AEs.”  
On the basis of these results, the 60 µg GEN-003 antigens/50 µg MM2 was selected as the final 
dose for this and other future GEN-003 studies.  This decision was supported by review of the 
shedding analyses and the modified intent-to-treat efficacy analyses of lesion rate, frequency, 
and duration of recurrence, which combined with the superior immunology and shedding 
responses of the 60 µg GEN-003 antigens/50 µg MM2 dose, supported the dose selection 
decision. Modified intent-to-treat analyses were used for the efficacy data to best represent real-
world usage. The per-protocol analyses produced similar results. 
3.2.2 
Efficacy Endpoints 
Genital herpes lesion rate in the 6-month period after the maintenance dose was selected as the 
primary endpoint because lesion rate is the most comprehensive measure of genital herpes 
disease burden. It is defined as the proportion of days with genital herpes lesions present.  
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Version 2.0 
Therefore, unlike other measures of vaccine efficacy, lesion rate accounts for both the frequency 
and duration of genital herpes disease. Use of this measure has been facilitated by technological 
advances in data collection methodology, namely, the development of electronic patient-reported 
outcomes tools that facilitate real-time daily data collection and encourages compliance through 
automatic reminders. In addition, assessment of lesion rate mitigates the impact of potential 
inconsistencies in the dataset. Endpoints related to recurrence frequency may be affected by 
patterns of lesion reporting that do not accurately reflect disease activity. For example, a subject 
may report on consecutive days: lesion – no lesion – lesion. This biologically improbable pattern 
may be counted as 2 recurrences, thereby increasing the estimate of disease frequency in a way 
that overstates true disease burden. However, this pattern of reporting would have minimal 
impact on lesion rate because 1 additional lesion day over the year-long follow-up period is 
unlikely to substantially affect the overall lesion rate.   
The secondary efficacy endpoints evaluate other clinically important measures of vaccine effect, 
such as the frequency and duration of genital herpes recurrences.  
3.3 
Study Duration  
The total duration of enrollment is estimated to be 2 months; the actual duration of enrollment 
may be longer. The duration of each subject’s participation is up to 12 months. Thus, the study is 
expected to last approximately 14 months. 
 
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Genocea Biosciences, Inc. 
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IND #: 14910 
Version 2.0 
4 SUBJECT POPULATION 
4.1 
Inclusion Criteria 
1. Completed Study GEN-003-003 (completed all study visits including the Month 12 visit) 
2. Received all 3 GEN-003 doses (any dose combination) in Study GEN-003-003 
3. Received last dose of GEN-003 within 11 to 18 months before the maintenance dose  
4. Reported data in the daily electronic reporting period on at least 80% of days in Study 
GEN‑003-003 
5. Collected at least 45 swabs (of 56 total expected swabs) during the Month 11 to 12 swab 
collection period in Study GEN-003-003 
6. Willing and able to provide written informed consent 
7. Willing to perform and comply with all study procedures, including attending clinic visits 
as scheduled and completion of a daily electronic reporting tool 
8. Postmenopausal (≥12 months with no menses without an alternative medical cause) or 
willing to practice a highly effective method of contraception that may include, but is not 
limited to, abstinence, sex only with persons of the same sex, monogamous relationship 
with a postmenopausal partner, monogamous relationship with vasectomized partner, 
vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal methods, 
intrauterine device (IUD), or use of a spermicide combined with a barrier method (e.g., 
condom, diaphragm) for 28 days before and 90 days after receiving the IP  
4.2 
Exclusion Criteria 
1. Did not meet all eligibility criteria in Study GEN-003-003, or received incorrect 
treatment (treatment different from that to which they were randomized) in Study GEN-
003-003 
2. Use of suppressive antiviral medication within 14 days before the maintenance dose  
3. Use of topical steroids or antiviral medication in the anogenital region from 14 days 
before the maintenance dose 
4. Use of tenofovir, lysine, or other medication or supplement known or purported to affect 
HSV recurrence frequency or intensity from 14 days before the maintenance dose 
5. History of any form of ocular HSV infection, HSV-related erythema multiforme, or 
herpes meningitis or encephalitis  
6. Immunocompromised individuals, including those receiving any type of systemic 
immunosuppressive medication within 30 days prior to the maintenance dose  
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Genocea Biosciences, Inc. 
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IND #: 14910 
Version 2.0 
7. Diagnosis or suspicion of an AESI (refer to Appendix 4 for list). 
 
8. Diagnosis or suspicion of any other autoimmune disease not listed in Appendix 4 
9. Vaccine-related SAE in GEN-003-003 
10. Known current infection with HIV or hepatitis B or C virus 
11. History of hypersensitivity to any component of the vaccine 
12. Prior receipt of another vaccine containing HSV-2 antigens other than GEN-003 
13. Receipt of any IP within 30 days prior to the maintenance dose of GEN-003/placebo 
14. Receipt of any blood product within 90 days prior to the maintenance dose 
15. Receipt of a live vaccine within 28 days prior to or any other vaccine within 14 days prior 
to maintenance dose 
16. Planned use of any vaccine from the maintenance dose to 28 days after the maintenance 
dose  
17. Pregnant or nursing women 
18. History of drug or alcohol abuse that, in the opinion of the Investigator, would interfere 
with the subject's ability to comply with the requirements of the study 
19. Other active, uncontrolled comorbidities that, in the opinion of the Investigator, would 
make the subject unsuitable for the study or unable to comply with the study 
requirements 
20. Changes to medication used to manage an underlying comorbidity within 60 days prior to 
the maintenance dose  
4.3 
Criteria for Temporary Delay of Dosing 
1. Febrile illness (temperature ≥38.0°C) or other acute illness within the past 48 hours  
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Genocea Biosciences, Inc. 
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IND #: 14910 
Version 2.0 
5 INVESTIGATIONAL PRODUCTS 
5.1 
GEN-003/Placebo 
5.1.1 
Formulation 
GEN-003 consists of 2 recombinant antigens corresponding to 2 distinct HSV-2 proteins (GB208 
and GB217) in combination with MM2 and diluent. Placebo is normal saline (diluent). These 
components are detailed in Table 2.  
Table 2: 
Composition of GEN-003 
Ingredient 
Description 
Dose 
GB208 
Corresponds to a ~39 kDa internal fragment of the ICP4 protein    
60 µg 
GB217 
A recombinant version of the glycoprotein gD modified by a deletion of 
the transmembrane region 
60 µg 
Matrix-M2 
Adjuvant 
An immune stimulating complex-based adjuvant containing saponin 
fractions purified from Quillaja saponaria (soapbark tree) bark, 
phosphatidylcholine, and cholesterol  
50 µg 
Diluent 
0.9% normal saline 
Not applicable 
5.1.2 
Packaging and Labeling 
GEN-003/placebo is prepared from the following 3 components before injection:   
• GB208 and GB217 antigens in a lyophilized form are supplied in a 3 mL glass vial 
containing 125 µg, at a concentration of 0.25 mg/mL when reconstituted to a volume of 0.5 
mL. 
• MM2 is supplied in a second 3 mL glass vial containing 0.75 mL of MM2 at a concentration 
of 1 mg/mL. 
• Normal saline (0.9% sodium chloride in water) from commercially available supply is 
supplied in a third vial for dilution of MM2 and reconstitution of antigens to the desired 
concentration and for use as placebo.  
The vaccine components are packaged and labeled as IPs in accordance with applicable legal and 
regulatory requirements.   
5.1.3 
Storage  
The antigens and MM2 are stored at 2°C to 8°C. The site must report excursions above 8°C to 
the Sponsor for an assessment of product quality. 
Normal saline is stored at room temperature. 
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Version 2.0 
5.1.4 
Preparation and Administration 
Preparation of GEN-003/placebo must be performed by a designated unblinded site pharmacist 
(or otherwise qualified personnel) in accordance with the Pharmacy Manual provided by the 
Sponsor. It is important to note that preparation requires approximately 30 minutes. 
GEN-003/placebo will be administered by trained study personnel. Each injection will consist of 
a total volume of 0.5 mL administered IM to the deltoid muscle of either arm. Both 1.0-inch and 
1.5-inch needles will be provided. For obese subjects, a 1.5-inch needle is recommended.  
Administration of GEN-003/placebo will be temporarily delayed if the subject has had a febrile 
illness (temperature ≥38.0°C) or other acute illness within the past 48 hours. 
5.2 
Randomization  
Eligible subjects will be randomized in a 1:1 ratio to receive 1 IM dose of GEN-003 (60 µg each 
antigen and 50 µg MM2) or placebo. 
Randomization will be stratified on the basis of the GEN-003 dose received by the subject in 
Study GEN-003-003.  
Randomization will be achieved using the randomization component of the electronic case report 
form (eCRF). After subject eligibility is confirmed on this form, the system will send an e-mail 
to the unblinded pharmacist (or otherwise qualified personnel) with instructions for accessing the 
treatment assignment.   
5.3 
Blinding and Unblinding 
Subjects, Investigators, and all study staff with direct subject contact will be blinded to treatment 
assignment (GEN-003 vs placebo). A designated unblinded pharmacist (or otherwise qualified 
personnel) at each site will prepare each dose. That individual should have no contact with the 
subjects and minimize contact with other site study personnel. 
Unblinding of treatment assignment is discouraged. In the event of a medical emergency, for 
which the identity of the treatment assignment is critical to the care of a subject, the Investigator 
should call the Medical Monitor to discuss. In the event that unblinding is deemed necessary, an 
unblinded statistician will provide the treatment assignment to the Medical Monitor who will 
provide the information to the Investigator. A decision to discontinue a subject from further IP 
administration is not a rationale for unblinding the treatment assignment. 
An unblinded statistician will be available to the DMC and Medical Monitor and will review 
interim analysis. 
5.4 
Investigational Product Accountability, Dispensing, and Destruction 
The Investigator (or designee) will maintain an accurate record of the receipt of the GEN-003 
components as shipped by the Sponsor (or designee), including the date received and lot or batch 
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numbers. In addition, an accurate disposition record will be kept, specifying the date and lot or 
batch numbers administered of each GEN-003 component or placebo to each subject. 
At the completion of the study, all unused IP supplies will be returned to the Sponsor (or 
designee) or disposed of by the site in accordance with the Sponsor’s (or designee’s) written 
instructions.  
5.5 
 Concomitant Medications 
All concomitant medications, including over-the-counter medications and supplements, will be 
recorded in the eCRF from Day 1 to Day 29/Month 1. Use of antiviral medications will be 
recorded from Day 1 through Month 6. 
5.6 
Prohibited Medications 
5.6.1 
Antiviral Medication Use for Suppression or Recurrence of Genital 
Herpes 
5.6.1.1 
Suppressive Therapy 
Subjects are forbidden from taking suppressive antiviral therapy through the Month 6 Visit.   
5.6.1.2 
Treatment of Recurrences 
Up to 3 days of antiviral treatment is permitted for recurrences.  
5.6.2 
Medications and Supplements with Anti-HSV Activity 
Use of acyclovir, valacyclovir, famciclovir, tenofovir (except for postexposure prophylaxis for 
HIV-1), lysine, or other medication or supplement known or purported to affect HSV recurrence 
frequency or intensity is prohibited from 14 days before the maintenance dose through the Month 
6 Visit (except as noted in Section 5.6.1.2 for the acute treatment of genital herpes recurrences). 
5.6.3 
Immunosuppressive Medications 
Systemic immunosuppressive medications are prohibited from 30 days before the maintenance 
dose to the end of the study. 
5.6.4 
Vaccines 
Subjects may not receive a live vaccine within 28 days prior to the maintenance dose or any 
other vaccine within 14 days prior to the maintenance dose. In addition, subjects may not receive 
any vaccine from maintenance dose to 28 days after the maintenance dose. It is particularly 
important to reinforce this information if the subject will be receiving GEN-003/placebo during 
the influenza season.  
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5.7 
Other Study Restrictions 
5.7.1 
Fluid and Food Intake  
There are no restrictions on fluid or food intake during the study. However, because of the large 
volume of blood drawn on days when PBMCs are obtained, subjects should be well-hydrated.  
5.7.2 
Birth Control and Prevention of HSV-2 Transmission 
Male and female subjects who are not postmenopausal (≥12 months with no menses without an 
alternative medical cause) must be willing to practice a highly effective method of contraception 
that may include, but is not limited to, abstinence, sex only with persons of the same sex, 
monogamous relationship with a postmenopausal partner, monogamous relationship with 
vasectomized partner, vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal 
methods, IUD, or use of spermicide combined with barrier method (e.g., condom, diaphragm) for 
28 days before the maintenance dose through 90 days after the maintenance dose. 
Subjects should be advised that GEN-003 has not been proven to reduce the likelihood of 
transmission of HSV-2 infection to an uninfected sexual partner.  
5.8 
Treatment Compliance 
To ensure compliance with the dosing regimen, the dose of GEN-003/placebo will be 
administered by trained study personnel in the clinic who have been delegated that responsibility 
by the Investigator.    
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6 STUDY PROCEDURES 
Refer to Appendix 1 for the Schedule of Events. 
6.1 
Definitions and Descriptions of Assessments and Procedures 
Serum/urine pregnancy tests – For all women  
Daily electronic reporting tool – Each day subjects will report the presence or absence of 
genital herpes lesions and genital herpes symptoms. In addition, if genital herpes symptoms are 
present, subjects will also rate the severity of the symptoms using the questions from the Genital 
Herpes Signs and Symptoms Diary (Appendix 5). Data must be entered daily through Month 6 
Visit. Each subject will receive a daily reminder if data have not been entered for that day. The 
investigational site will receive a weekly e-mail notification if a subject has missed any data, and 
the site should make contact with the subject to promote compliance. Site staff will also review 
the data in the tool each week and at each visit.  
Genital herpes lesions – Papules, pustules, vesicles, or ulcers, including those that have crusted. 
Symptoms of prodrome, redness, itchiness, or post-inflammatory hyperpigmentation of re-
epithelialized ulcers do not constitute the presence of lesions. 
EQ-5D-5L – The subject will complete this questionnaire on each day of the genital herpes first 
recurrence after the maintenance dose through Month 6. A pad of paper copies of the 
questionnaire will be provided to each subject after the maintenance dose is administered. 
Reactogenicity – Subjects will be interviewed and examined at 1 hour after the maintenance 
dose and the following items will be entered in the eCRF: 
• Local reactions:  Pain, tenderness, swelling, redness  
• Systemic events:  Headache, chills, fatigue, nausea, vomiting, diarrhea, muscle aches 
• Oral temperature  
The subjects will also record these items on a paper Diary Card for the first 7 days after the 
maintenance dose, and the information will be entered in the eCRF. 
Diary Card – Subjects will be provided a Diary Card to record local reactions, systemic events, 
and oral temperature for the 7 days after the maintenance dose. If there are any events ongoing 
after Day 8, these events will be followed until resolution and the stop date recorded. The 
Investigator (or Subinvestigator) will review Diary Cards with the subject. Any changes or 
comments to the subject’s Diary Card must be made on the Diary Card and initialed and dated by 
the Investigator (or Subinvestigator). The Diary Card AND the Investigator’s (or 
Subinvestigator’s) assessment will serve as the source document. A sample of the Diary Card is 
provided in Appendix 3. 
An event recorded on the Diary Card should not be recorded on the AE eCRF unless it meets the 
criteria of an SAE. 
AEs (including SAEs, AESIs, and MAAEs) – refer to Section 7. 
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AESIs – refer to Appendix 4 for list. 
6.2 
GEN-003/Placebo Dosing Period 
6.2.1 
Maintenance Dose (Day 1) – Clinic Visit 
The visit will take approximately 2.5 hours, including observation for 1 hour after vaccination.  
Dosing must be delayed if the following criterion is met: 
• Febrile illness (temperature ≥38.0°C) or other acute illness within the past 48 hours  
The subject may be dosed once the criterion has been resolved and the criterion is no longer met. 
The following procedures will be performed for screening: 
• Written informed consent 
• Medical history, including medication and vaccine history 
• Weight 
• Urine pregnancy test for all women 
Eligibility for study enrollment will be checked. If a subject is excluded because of exclusion 
criteria 1 (important protocol deviation in Study GEN-003-003), 6 (immunocompromise), 7 
(AESI), or 8 (autoimmune disease), then the details of the excluding deviation, diagnosis, or 
medication will be entered in the eCRF. 
Upon determination that a subject meets all eligibility criteria, the following blood samples will 
be collected: 
• Serum for future research 
• At selected investigational sites: whole blood for PBMC isolation for future research  
The subject will then be randomized to treatment assignment (as described in Section 5.2) and 
GEN-003/placebo administered.   
The subject will remain at the investigational site for observation for at least 1 hour, and the 
following procedures will be performed 1 hour after GEN-003/placebo administration: 
• Assessment of local reactions, systemic events, and AEs 
Before discharge from the clinic, the subject will be given a Diary Card and instructed to record 
temperature, local reactions, and systemic events (at the same time each day). The subject will 
also be instructed that, if any event is ongoing after Day 8, to follow the event until resolution 
and report the stop date. The subject will be instructed to bring the Diary Card back to the clinic 
at the next visit.   
Before discharge from the clinic, the subject will be given a pad of EQ-5D-5L questionnaires and 
instructed to complete 1 questionnaire each day of the first genital herpes recurrence. 
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If needed, the subject will be provided with an electronic device for use of the daily electronic 
reporting tool. The subject will be instructed in use of the daily electronic reporting tool. The 
subject will be asked to log into the system to ensure access before leaving the site. 
6.2.2 
Day 8 (± 3 Days) – Clinic Visit 
The following procedures will be performed: 
• Review of daily electronic reporting tool data 
• Collection of completed EQ-5D-5L questionnaires, if completed 
• Review of Diary Card 
• Sample collection:  
- 
Serum for future research 
- 
At selected investigational sites:  whole blood for PBMC isolation for future 
research  
• Assessment of AEs (including SAEs, AESIs, and MAAEs) 
• Assessment of concomitant medications and vaccines 
The subject will be reminded to continue use of the daily electronic reporting tool. 
6.2.3 
Day 29/Month 1 (± 3 Days) – Clinic Visit 
The following procedures will be performed: 
• Review of daily electronic reporting tool data 
• Collection of completed EQ-5D-5L questionnaires, if completed 
• Sample collection: 
- 
Serum for pregnancy test for all women (unless surgically sterilized) 
- 
Serum for future research 
- 
At selected investigational sites:  whole blood for PBMC isolation for future 
research  
• Assessment of AEs (including SAEs, AESIs, and MAAEs) 
• Assessment of concomitant medications and vaccines  
The subject will be reminded to continue use of the daily electronic reporting tool. 
6.3 
Follow-up Period 
6.3.1 
Follow-up Telephone Calls 
Follow-up telephone calls will be made at each of the following time points: 
• Month 2 (Day 57 ± 7 days) 
• Month 4 (Day 113 ± 7 days) 
• Month 8 (Day 225 ± 14 days) 
• Month 10 (Day 281 ± 14 days) 
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The following procedures will be performed: 
• Review of daily reporting tool data (Month 4 only) 
• Assessment of SAEs, AESIs, and MAAEs 
• Assessment of antiviral medication through Month 6 
The subject will be reminded to continue use of the daily electronic reporting tool. 
6.3.2 
Month 3 (Day 85 ± 7 days)  and Month 6 (Day Day 169 ± 14 days) – Clinic 
Visits 
The following procedures will be performed:  
• Review of daily electronic reporting tool data 
• Collection of completed EQ-5D-5L questionnaires, if completed 
• Assessment of SAEs, AESIs, and MAAEs 
• Assessment of antiviral medication  
6.3.3 
Month 9 (Day 253 ± 14 days) and Month 12 (Day 337 ± 14 days) – Clinic 
Visits 
The following procedures will be performed:  
• Assessment of SAEs, AESIs, and MAAEs 
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7 ADVERSE EVENTS 
AEs will be reported in a manner consistent with the FDA Guidance for Industry and 
Investigators, “Safety Reporting Requirements for IND and BA/BE Studies,” December 2012 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM227351.pdf). 
7.1 
Reporting Responsibilities 
All AEs (including SAEs, AESIs, and MAAEs) will be recorded from the maintenance dose to 
Day 29/Month 1. After Day 29/Month 1 to the end of study, only SAEs, AESIs, and MAAEs 
will be recorded. It is the responsibility of the Investigator or Subinvestigator(s) to perform 
periodic assessment of AEs. Data describing AEs will be entered in the subject’s medical record 
and eCRF, and as appropriate, an SAE/AESI report form. SAEs and AESIs will be reported to 
the Sponsor as described in Section 7.6. 
7.2 
Definitions 
7.2.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, 
whether or not related to the IP. 
7.2.2 
Medically Attended Adverse Events 
A MAAE is an AE resulting in hospitalization, emergency room visit, or visit to or from medical 
personnel (other than routine health care visits). If a MAAE is "hospitalization" it should be 
reported as an SAE as described in Section 7.6 below. 
7.2.3 
Adverse Event of Special Interest 
Refer to Appendix 4 for the list of AESIs. 
7.2.4 
Serious Adverse Event 
An AE or suspected adverse reaction is considered serious (an SAE) if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening (An AE is considered life-threatening if, in the view of either the 
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.) 
• Inpatient hospitalization or prolongation of existing hospitalization 
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• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization 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. 
If it is not certain that an event meets the above definitions of an SAE, contact the Medical 
Monitor to discuss. 
7.2.5 
Relatedness (Causality) 
Causality (relationship to GEN-003/placebo) assessment is required for all AEs that occur during 
clinical studies. The following terms will be used during this study:  
• Likely - Reasons to consider an AE likely related to treatment may include, but are not 
limited, to the following: 
- Timing of the event relative to the administration of the IP 
- Location of the AE relative to the site of IP administration 
- Likelihood based on experience with similar products 
- A biologically plausible explanation based on the mechanism of action or mode of 
delivery of the treatment 
- The AE is repeated on subsequent treatments. 
- No other explanation is likely. 
• Unlikely - An AE with no temporal association with the IP but rather related to other 
etiologies such as concomitant medications or conditions or subject's known clinical state 
7.2.6 
Severity 
Severity for all AEs, including laboratory abnormalities, will be reported in accordance with 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (Appendix 2).   
If an appropriate listing is not present in this table for an AE, the AE will be graded as follows: 
• Grade 1 (Mild) - No interference with daily activity 
• Grade 2 (Moderate) - Some interference with daily activity but medical intervention not 
required (e.g., doctor visit and/or prescription medicine); over-the-counter medicine 
permitted 
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• Grade 3 (Severe) - Prevents daily activity and requires medical intervention (e.g., doctor 
visit and/or prescription medicine) 
• Grade 4 (Potentially Life-threatening) - Emergency room visit or hospitalization 
7.3 
Clinical Laboratory Abnormalities 
Any laboratory abnormality deemed clinically significant by the Investigator should be recorded 
as an AE. A clinically significant abnormality is a confirmed abnormality (by repeat test) that is 
changed sufficiently from Screening/baseline so that in the judgment of the Investigator a change 
in management is warranted. This alteration may include monitoring the laboratory test further, 
initiating other diagnostic tests or procedures, changing ongoing treatment, or administering new 
treatment.   
Whenever possible, the underlying medical diagnosis (e.g., anemia) should be recorded as the 
AE term. Repeated additional tests and/or other evaluations required to establish the significance 
and etiology of an abnormal result should be obtained when clinically indicated.  
7.4 
Physical Exam Abnormalities 
Any physical exam abnormality deemed clinically significant by the Investigator at Day 1 should 
be reported as medical history. Any new physical exam abnormality deemed clinically 
significant by the Investigator during the study should be reported as an AE.  
7.5 
Pregnancy 
The ICF will include information regarding reporting of pregnancy to the Sponsor and collection 
of information through the end of pregnancy in both subjects and female partners of male 
subjects. If a female partner becomes pregnant, the Investigator will request consent from the 
partner to collect this information. 
All remaining safety assessments should be performed for a subject who becomes pregnant. All 
pregnancies that occur during the study–including pregnancies in female partners of male 
subjects must be reported to the Sponsor on the Pregnancy eCRF and followed to conclusion. 
The outcome of each pregnancy must also be reported on the Pregnancy eCRF. Pregnancy alone 
is not an AE, nor is an induced elective abortion to terminate a pregnancy without medical 
reason. However, an induced therapeutic abortion to terminate a pregnancy due to complications 
or medical reasons must be reported as an SAE. The underlying medical diagnosis for this 
procedure should be reported as the SAE term. A spontaneous abortion is always considered an 
SAE. 
7.6 
Reporting of Serious Adverse Events and Adverse Events of Special 
Interest 
SAEs and AESIs must be reported to the Sponsor or designee within 1 business day of becoming 
aware of the event by entering the data on the AE eCRF. If at the time the Investigator submits 
an initial SAE/AESI report the event has not resolved, the Investigator must provide a follow-up 
as soon as it resolves (or upon receipt of significant information if the event is still ongoing). All 
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SAEs/AESIs must be followed until resolution/stabilization or until a time that is mutually 
agreed upon between the Medical Monitor and the Investigator. Upon checking serious or AESI 
on the AE eCRF, a notification will be sent to the Medical Monitor and/or designee. Relevant 
eCRFs (including Medical History, Concomitant Medications, and Adverse Events) must also be 
completed to provide supporting documentation for the SAE/AESI. If there are additional 
documents that support the SAE/AESI (e.g., clinic or hospital records or procedure reports), they 
should be uploaded to the AE eCRF. 
After review of the initial SAE/AESI information, the Medical Monitor may request additional 
documentation. 
The Sponsor is responsible for notifying the relevant Regulatory Authorities of certain events. It 
is the Investigator’s responsibility to notify the IRB/EC of all SAEs that occur at his or her site. 
Investigators will also be notified of all unexpected, serious, IP-related events that occur during 
the clinical trial. Each site is responsible for notifying its IRB/EC of these additional SAEs.  
7.7 
Follow-Up of Adverse Events 
A subject who experiences any AE, whether serious or not serious, will be monitored at 
appropriate intervals and receive appropriate treatment and medical supervision as clinically 
indicated. All AEs must be followed until resolution/stabilization or until a time that is mutually 
agreed upon between the Medical Monitor and the Investigator. Clinically significant laboratory 
abnormalities should be confirmed within 48 hours or as soon as clinically indicated and then 
followed weekly until resolution. 
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8 SUBJECT AND STUDY DISCONTINUATION 
Subjects withdrawn from the study will not be replaced, regardless of the reason for withdrawal. 
8.1 
Screening Failures 
Subjects who sign and date the informed consent form (ICF) but who fail to meet the inclusion 
and exclusion criteria (Section 4) are defined as screen failures. A screening log, which 
documents the subject’s initials and reason(s) for screen failure, will be maintained by the 
Investigator for all screen failures. A copy of the log should be retained in the Investigator’s 
study files.   
If a subject fails screening because of Exclusion Criteria 1 (important protocol deviation in Study 
GEN-003-003), 6 (immunocompromise), 7 (AESI), or 8 (other autoimmune disease), then the 
details of the excluding deviation, diagnosis, or medication will be entered in the eCRF. 
8.2 
Premature Discontinuation from Study  
A subject may be prematurely discontinued from the study for any of the following reasons: 
• Withdrawal of consent  
• Loss to follow-up 
• Death 
• Noncompliance or unwillingness to comply with the procedures required by the protocol 
• Investigator discretion  
• Sponsor request 
• Site termination 
• Study termination 
8.3 
Procedures for Premature Discontinuation from Study 
If a subject prematurely discontinues the study prior to Day 29/Month 1, then the procedures 
listed for Day 29/Month 1 (Section 6.2.3) should be performed. 
If a subject prematurely discontinues the study after Day 29/Month 1, then the procedures listed 
for Month 12 (Section 6.3.4) should be performed. 
8.4 
Study or Site Termination 
Conditions may arise during the study that could prompt the study to be halted or the study site 
to be terminated. Conditions that may prompt such considerations include, but are not limited to, 
the following: 
• The discovery of unexpected, serious, or unacceptable risk to the subjects enrolled in the 
study 
• A decision on the part of Sponsor to suspend, discontinue, or shorten the study 
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• Study conduct at the study site may warrant termination under conditions that include, but 
are not limited to, the following: 
- Failure of Investigator(s) to enroll eligible subjects into the study 
- Failure of Investigator(s) to comply with International Council for Harmonisation-Good 
Clinical Practice (ICH-GCP) guidelines, or national guidelines and regulations 
- Submission of false information from the research facility to the Sponsor, the Clinical 
Monitor, the United States Food and Drug Administration (FDA), or institutional review 
board/ethics committee (IRB/EC) 
- Insufficient adherence to protocol requirements 
- A conflict of interest of the Investigator, his/her institution, or site personnel that would 
negatively impact the integrity of the clinical trial 
- Institution or IRB/EC under investigation for cause by a Regulatory Authority 
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9 DATA MONITORING COMMITTEE 
An independent DMC will review this study on an ongoing basis. The DMC will be comprised 
of 3 physicians with expertise in clinical trials for infectious diseases or of vaccines.   
The primary responsibility of the DMC is to safeguard study subjects by reviewing and assessing 
on a periodic basis the clinical safety data being collected during the study. On the basis of these 
evaluations of the data, the DMC will make recommendations to the Sponsor to continue the 
study as planned, or to modify, temporarily suspend, or terminate the study. The DMC will also 
be responsible for identifying issues and making recommendations regarding the monitoring of 
subjects for safety, including collection of additional safety data. 
The Sponsor will notify the DMC Chair of each SAE, AESI, and MAAE. 
The DMC will meet at intervals of a minimum of 3 months until all subjects have completed the 
GEN-003/placebo dosing period. Any additional meetings and the specific safety monitoring 
plan will be detailed in the DMC charter.  
The Sponsor will be responsible for notifying Investigators and Regulatory Authorities of any 
DMC recommendations, as appropriate.   
 
 
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10 STATISTICAL CONSIDERATIONS 
Details of statistical analyses will be provided in a Statistical Analysis Plan (SAP). Any 
deviations from the SAP will be described in the Clinical Study Report. 
10.1 Sample Size 
No formal samples size calculations were performed for this study. 
10.2 Analysis Conventions 
In general, descriptive statistics for continuous variables will consist of subject count, mean 
(geometric mean), standard deviation (SD), median, and range. Descriptive statistics for 
categorical variables will consist of subject counts and percentages.  
All analyses will be presented by treatment group. Sensitivity analyses may also be conducted 
for selected endpoints which incorporate the original treatment group assignments in Study 
GEN-003-003. 
All efficacy, immunogenicity, and safety data will be included in data listings and summaries. 
10.3 Analysis Populations 
The following populations will be used for analysis of the study data. 
• Per-protocol population:  Subjects who received the maintenance dose, reported data in 
the daily electronic reporting period on at least 80% of days, and had no important 
protocol deviations (as defined in Section 11.7). Subjects will be analyzed according to 
the treatment actually received.   
• Modified intent-to-treat population:  All randomized subjects who received the 
maintenance dose. Subjects will be analyzed according to the treatment to which they 
were randomized. 
• Safety population:  All randomized subjects who received at least 1 dose of study 
vaccine. Subjects will be analyzed according to the treatment actually received. 
 
10.4 Subject Disposition 
The number and percentage of subjects enrolled in the study, completing the study, and 
discontinuing the study will be presented in a tabular format. Reasons for screen failure and for                            
discontinuation will also be summarized. 
Important protocol deviations (see Section 11.7) will be listed by subject. 
10.5 Demographic Data and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group. Additionally, 
the number and percent of subjects with past and current medical disorders (i.e., medical history 
coded using the Medical Dictionary for Regulatory Activities [MedDRA]) at Day 1 will be 
presented overall and by treatment group. Prior medications will be coded using the most current 
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WHO Drug Dictionary and summarized by anatomical therapeutic chemical class and preferred 
term with results presented by treatment group. 
10.6 Concomitant Medications 
Concomitant medications will be coded using the most current WHO Drug Dictionary and 
summarized by anatomical therapeutic chemical class and preferred term with results presented 
by treatment group. 
10.7 Primary Efficacy Endpoint – Genital Herpes Lesion Rate  
Genital herpes lesion rates (the proportion of days with genital lesions present) in the 6-month 
period after the maintenance dose will be compared between treatment groups using the 
Wilcoxon rank sum text. 
10.8 Secondary Efficacy Endpoints 
10.8.1 
Frequency of Genital Herpes Recurrences  
The frequency of genital herpes recurrences in the 6-month period after the maintenance dose 
will be calculated as the number of recurrences reported and summarized by mean, SD, median, 
and range.  The median frequencies of recurrences will be compared between treatment groups 
using the Wilcoxon rank sum test. 
10.8.2 
Proportion of Subjects Recurrence-Free  
The proportion of subjects in each treatment group who are genital herpes recurrence-free at 
6 months after the maintenance dose will be tabulated and compared using a chi-square test for 
homogeneity of proportions. 
10.8.3 
Time to First Genital Herpes Recurrence  
Time to first recurrence in the 6-month period after the maintenance dose will be tabulated and 
graphed using the Kaplan-Meier method. The log-rank test will be used to compare the time to 
first recurrence survival curves between the GEN-003 and placebo groups.  
10.8.4 
Duration of Genital Herpes Recurrences 
Duration of genital herpes recurrences over the 6-month period after the maintenance dose will 
be calculated and summarized by mean, SD, median, and range. Median of individual mean 
duration of genital herpes recurrences will be compared using the Wilcoxon rank sum test.   
10.8.5 
Antiviral Medication Use 
Antiviral medications will be coded using the most current WHO Drug Dictionary and 
summarized by anatomical therapeutic chemical class and preferred term with results presented 
by treatment group. 
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10.9 Safety Analysis 
10.9.1 
Reactogenicity 
Local reactions and systemic events within 7 days after the maintenance dose will be 
summarized by treatment group for frequency and severity. 
Antipyretic and analgesic medications taken within 7 days after the maintenance dose will be 
summarized by treatment group. 
10.9.2 
Adverse Events 
AEs (including SAEs, AESIs, and MAAEs) will be coded using MedDRA and summarized by 
treatment group for frequency and severity. No formal statistical testing will be performed. 
10.10 Interim Analysis 
An interim analysis will be conducted after all subjects have completed the Month 6 visit and 
will include analysis lesion rates. The specific contents of the interim analyses will be detailed in 
the SAP. 
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11 ETHICAL AND ADMINISTRATIVE RESPONSIBILITIES 
11.1 Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor, its authorized US 
representative and Investigator abide by GCP as described in ICH Guideline E6, and in US 
regulations described in 21 Code of Federal Regulations (CFR) Parts 50, 54, 56, and 312. 
Compliance with these regulations also constitutes compliance with the ethical principles that 
have their origins in the Declaration of Helsinki. 
11.2 Institutional Review Board/Ethics Committee Approval 
This protocol and the ICF and any subsequent modifications will be reviewed and approved by 
the relevant IRB/EC responsible for oversight of the study. A letter from the IRB/EC indicating 
approval of the study to be conducted by the Investigator will be provided to the Sponsor prior to 
initiation of any enrollment at that site. All reviews and approvals by the IRB/EC will be in 
accordance with 21 CFR Part 56 and ICH-GCP. 
11.3 Informed Consent 
The ICF document must be signed and dated prior to the initiation of study-related tests, and 
prior to administration of IP. The original signed ICF for each participating subject shall be filed 
with records kept by the Investigators. A copy of the ICF must be provided to the subject. If 
applicable, the ICF will be provided in a certified translation of the local language. 
11.4 Confidentiality 
Personal study subject data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, and in accordance with applicable national and/or local laws and 
regulations on personal data protection. 
Monitors, auditors and other authorized agents of the Sponsor, the IRB/EC approving this 
research, and any applicable Regulatory Authorities will be granted direct access to the study 
subjects’ original medical records for verification of clinical trial procedures and/or data, without 
violating the confidentiality of the subjects, to the extent permitted by the law and regulations. In 
any presentation of the results of this study at meetings or in publications, the subjects’ identity 
will remain confidential.    
11.5 Biological Samples 
Biological samples collected for this study will become the property of Genocea and may be 
used for future vaccine and immunology research conducted by or on behalf of Genocea or its 
affiliates, partners, or collaborators. No identifiable personal information will be associated with 
these blood samples. Any samples remaining 10 years after the end of the study will be 
destroyed.  
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11.6 Protocol Amendments 
Any changes to the protocol will be made in writing by the Sponsor in the form of a protocol 
amendment. All protocol amendments will be sent to the Investigator, who is responsible for 
submitting the amendment to the IRB/EC for approval. 
11.7 Protocol Deviations 
There will be no site-specific exceptions or amendments to the written protocol. Strict 
compliance to the current protocol is required. Any unavoidable deviations must be fully 
documented and reported to the Sponsor and IRB/EC (as required). The Investigator is 
responsible for abiding by the IRB/EC rules and regulations for reporting protocol deviations. 
The Investigator will be requested to address each important protocol deviation with a written 
corrective and preventive action plan.  
The following important protocol deviations will be reported in the eCRF: 
• Subject did not meet study eligibility criteria 
• Subject did not receive the correct treatment  
• Subject received a vaccine in an excluded time period 
• Subject used suppressive antiviral therapy 
11.8 Case Report Forms  
An eCRF will be used to record subject data specified by this protocol. The eCRF must be 
completed by designated and trained study personnel. The eCRF will be signed by the 
Investigator or a Subinvestigator listed on the Form FDA 1572. In addition, patient-reported 
genital lesion, genital herpes symptom, and antiviral use information will be recorded by the 
subject in a daily electronic reporting tool. It is the responsibility of the Investigator to ensure 
that both the eCRFs and the daily electronic reporting tool are completed and submitted to the 
Sponsor (or designee) in an accurate and timely manner. The processing of all electronic data 
will include an audit trail (to include changes made, reason for change, date of change and 
person making change).   
11.9 Source Document Maintenance 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents may include, but are not limited to, subject Diary Cards, study 
progress notes, e-mail correspondences, computer printouts, laboratory data, IP accountability 
records, and electronic health records. All source documents produced in this study will be 
maintained by the Investigator(s) and made available for inspection by the Sponsor’s 
representatives, the IRB/EC, and any applicable Regulatory Authorities. 
11.10 Retention of Records 
US regulations (21 CFR Part 312.62) require that records and documents pertaining to the 
conduct of this study and the distribution of IPs (including medical records, eCRFs, ICFs, test 
results, and IP records) be kept on file by the Investigator for 2 years after a marketing 
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application is approved for the IP for the indication for which it is being studied. If no 
application is filed or approved, these records must be kept for 2 years after the investigation has 
been discontinued and the FDA has been notified.   
ICH-GCP requires that documents should be retained until at least 2 years after the last approval 
of a marketing application in an ICH region and there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP.   
No study records should be destroyed without prior authorization from the Sponsor. 
11.11 Study Monitoring 
Site visits will be conducted by an authorized Sponsor representative (the monitor) to inspect 
study data, subjects’ medical records, and eCRFs in accordance with ICH-GCP and national 
regulations and guidelines, as applicable. It will be the monitor’s responsibility to inspect the 
eCRFs at regular intervals throughout the study, to verify the adherence to the protocol and the 
completeness, consistency and accuracy of the data being entered. The monitor should have 
access to laboratory test reports and other subject records needed to verify the entries on the 
eCRFs. 
The Investigator will permit representatives of the Sponsor, the IRB/EC, and any applicable 
Regulatory Authorities to inspect facilities and records relevant to this study. 
11.12 Financial Disclosure 
Investigators participating in this study will provide accurate financial disclosure information to 
the Sponsor, as required by 21 CFR Part 54. Investigators will update the financial information if 
any relevant changes occur during the study and for 1 year following completion of the study. 
11.13 Publication and Disclosure Policy 
Investigators and their staff shall hold confidential, and not disclose directly or indirectly to any 
third party other than those persons involved in the study who have a need to know, the protocol, 
the data arising out of the study, and any other information related to the study or to Sponsor’s 
products or research programs that is provided to the Investigator. All such persons must be 
instructed not to further disseminate this information to others. Investigators shall not use the 
confidential information for any purpose other than the study. The foregoing obligations of 
confidence and non-use assumed by the Investigator shall not apply to: (a) information which at 
the time of disclosure is in the public domain; (b) information which thereafter lawfully becomes 
part of the public domain other than disclosure by or through the Investigator; (c) information 
which, as evidenced by the Investigator’s written records, was known by the Investigator prior to 
Genocea’s disclosure; (d) information which is lawfully disclosed to the Investigator by a third 
party not under any obligation of confidence to Genocea; or (e) information which is required to 
be disclosed by law or government regulatory agency, provided reasonable advance notice of 
such disclosure is given to Genocea.  
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All data and discoveries arising out of the study, patentable or non-patentable, shall be the sole 
property of Genocea Biosciences, Inc. Genocea reserves the right of prior review of any 
publication or presentation of information related to the study. Genocea reserves the right of 
prior review of any publication or presentation of information related to this study. Genocea may 
use these data now or in the future for presentation or publication at Genocea’s discretion or for 
submission to Regulatory Authorities. 
Genocea adheres to the general principles of publication of scientific data as articulated by the 
International Committee of Medical Journal Editors (ICMJE), the Pharmaceutical Research and 
Manufacturers of America (PhRMA) Principles of Conduct of Clinical Trials and 
Communication of Clinical Trial Results, as well as Good Publication Practice as established by 
the International Society for Medical Publication Professionals, and acknowledges its 
responsibility to publish results of Genocea-sponsored clinical trials.  In all cases, study results 
must be reported in an objective, accurate, balanced, and complete manner and must contain a 
discussion of the limitations of the study. Results must be reported regardless of the outcome of 
the study or the country in which the study was conducted. Persons that fulfill the criteria for 
authorship (http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-
the-role-of-authors-and-contributors.html) may be authors on publications based on their 
contributions to the design, conduct, results, and/or analysis of this clinical trial. Consistent with 
ICMJE and PhRMA guidelines, publications should list those people who made significant 
contributions to the publication but do not meet the criteria for authorship, for example, study 
conception and design, conceiving the idea for an article, conducting or managing a study, 
collecting data, performing statistical analysis, analyzing published literature, drafting or 
critically reviewing a manuscript. Investigators will have access to the data from this clinical trial 
for the preparation of scientific presentations and publications, with the understanding that the 
documents are not to be disclosed without prior written approval of Genocea. All results or 
analyses from data generated in this study that are intended for public presentation, including 
scientific meetings, must be shared with Genocea at least 30 days prior to submission (for 
abstracts and manuscripts) and presentation (posters or oral presentation). Publication of data 
subsets from individual institutions participating in multicenter trials should not precede the 
publication of the primary manuscript and—when developed—should always reference the 
primary publication of the entire trial. 
By signing the Investigator Signature Page of this protocol, the Investigator agrees to the release 
of the data from this study and acknowledges the above confidentiality and publication policy. 
The provisions of this statement shall survive the completion of the study.  
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12 REFERENCES 
Awasthi S, Friedman HM. Status of prophylactic and therapeutic genital herpes vaccines. Curr 
Opin Virol. 2014;6:6-12. 
Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-
episode infection. Ann Intern Med; 1994;121:847–54. 
Centers for Disease Control and Prevention. 2015 Sexually transmitted diseases treatment 
guidelines: genital HSV infections https://www.cdc.gov/std/tg2015/herpes.htm. Updated June 8, 
2015. Accessed January 11, 2017.          
Corey L. Herpes simplex virus type 2 and HIV-1: the dialogue between the 2 organisms 
continues. J Infect Dis. 2007;195:1242–4. 
Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of 
genital herpes. N Engl J Med. 2004;350:11–20. 
de Bruyn G, Vargas-Cortez M, Vargas T, et al. A randomized controlled trial of a replication 
defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes 
among immunocompetent subjects. Vaccine. 2006;24:914–20. 
Famvir [prescribing information].  East Hanover, NJ: Novartis Pharmaceuticals Corporation; 
2013. 
Fife KH, Warren TJ, Ferrera RD, et al. Effect of valacyclovir on viral shedding in 
immunocompetent patients with recurrent herpes simplex virus 2 genital herpes: a US-based 
randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc. 2006;81:1321–7. 
Gupta R, Wald A, Krantz E, et al. Valacyclovir and acyclovir for suppression of shedding of 
herpes simplex virus in the genital tract. J Infect Dis. 2004;190:1374–81. 
Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007;370:2127–37. 
Johnston C, Saracino M, Kuntz S, et al. Standard-dose and high-dose daily antiviral therapy for 
short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. 
Lancet. 2012;379:641–7. 
Kimberlin DW, Rouse DJ. Clinical practice. Genital herpes. New Engl J Med. 2004;350:1970–7. 
Looker KJ, Garnett GP, Schmid GP. An estimate of the global prevalence and incidence of 
herpes simplex virus type 2 infection. Bull World Health Organ 2008;86:805-12, A. 
Martens MG, Fife KH, Leone PA, et al. Once daily valacyclovir for reducing viral shedding in 
subjects newly diagnosed with genital herpes. Infect Dis Obstet Gynecol 2009;2009:105376. 
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Skoberne M, Cardin R, Lee A, et al. An adjuvanted herpes simplex virus 2 subunit vaccine elicits 
a T-cell response in mice and is an effective therapeutic vaccine in Guinea pigs. J Virol. 
2013;87:3930–42. 
Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D-adjuvant vaccine to prevent 
genital herpes. N Engl J Med. 2002;347:1652–61. 
Valtrex [prescribing information].  Research Triangle Park, NC: GlaxoSmithKline; 2013.  
Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus 
type 2 with acyclovir. Ann Intern Med. 1996;124:8–15. 
Whitley R. Neonatal herpes simplex virus infection. Curr Opin Infect Dis. 2004;17:243–6. 
World Health Organization. WHO guidelines for the treatment of Genital Herpes Simplex Virus. 
Geneva: World Health Organization, 2016. Available at 
http://apps.who.int/iris/bitstream/10665/250693/1/9789241549875-eng.pdf?ua=1. Accessed 
February 20, 2017. 
 
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Appendix 1 
Schedule of Events  
Study Day/Month 
Study Vaccine (GEN-003/Placebo) Dosing Period 
Maintenance Dose 
 
Day 1 
Day 8 
Day 29/Month 1 
Window (days) 
± 3 
± 3 
 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Informed consent 
X 
 
 
Medical history 
X 
 
 
Serum (S) / urine (U) pregnancy test  
U 
 
S 
Concomitant medication and vaccine assessment 
X 
X 
X 
Eligibility criteria check 
X 
 
 
Weight 
X 
 
 
Serum for research purposes 
X 
X 
X 
PBMCs for research purposes a 
X  
X 
X 
Randomization 
X 
 
 
GEN-003/placebo dosing b 
X  
 
 
Distribution (D) / review (R) of Diary Card 
D 
R 
 
Instruction in daily electronic reporting tool  
X 
 
 
Daily electronic reporting tool 
Subject will report the presence or absence of genital lesions, and severity of genital herpes symptoms on 
each day from Day 1 through Month 6. 
Review of daily electronic reporting tool data 
 
X 
X 
EQ-5D-5L 
Subject will complete the EQ-5D-5L on each day of the first recurrence after the maintenance dose through 
Month 6. 
AE (including SAEs, AESIs, MAAEs) assessment 
X 
X 
X 
AE = adverse event; AESI = adverse event of special interest; EQ-5D-5L = EuroQol – 5 Domains – 5 Levels; MAAE = medically attended adverse event; PBMC 
= peripheral blood mononuclear cell; SAE = serious adverse event. 
a 
At selected sites only 
b     After confirmation of no febrile illness or other acute illness for the past 48 hours  
 
 
 
 
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Study Day/Month 
Follow-up Period 
Month 2 
Month 3 
Month 4 
Month 6 
Month 8 
Month 9 
Month 10 
Month 12 
Window (days) 
Day 57 ± 
7 days 
Day 85 ± 7 
days 
Day 113 ± 7 
days 
Day 169 ± 14 
days 
Day 225 ± 14 
days 
Day 253 ± 14 
days 
Day 281 ± 14 
days 
Day 337 ± 14 
days 
 
Phone 
Contact 
Clinic Visit 
Phone 
Contact 
Clinic Visit 
Phone 
Contact 
Clinic Visit 
Phone 
Contact 
Clinic Visit 
Daily reporting tool 
Subject will report the presence or absence of genital lesions 
and severity of genital herpes symptoms on each day from 
Day 1 through Month 6. 
 
Review of daily electronic reporting 
tool data 
X 
X 
X 
X 
 
EQ-5D-5L 
Subject will complete the EQ-5D-5L on each day of the first 
recurrence after the maintenance dose through Month 6. 
 
SAE/AESI/MAAE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Antiviral and vaccine use 
assessment 
X 
X 
X 
X 
 
AE = adverse event; AESI = adverse event of special interest; EQ-5D-5L = EuroQol – 5 Domains – 5 Levels; MAAE = medically attended adverse event; PBMC = 
peripheral blood mononuclear cell; SAE = serious adverse event. 
a 
At selected sites only 
b     After confirmation of no febrile illness or other acute illness for the past 48 hours and no suspicion of AESI 
 
 
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Appendix 2 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials  
Tables for Clinical Abnormalities 
Local Reaction to Injectable 
Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-threatening 
(Grade 4) 
Pain 
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 
Emergency room (ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to touch 
Discomfort with movement 
Significant discomfort at rest 
ER visit or hospitalization 
Erythema/Redness 
2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Necrosis or exfoliative 
dermatitis 
Induration/Swelling 
2.5 - 5 cm and does not 
interfere with activity 
5.1 - 10 cm or interferes with 
activity 
> 10 cm or prevents daily 
activity 
Necrosis 
 
Vital Signs  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-threatening 
(Grade 4) 
Fever (°C)  
          (°F)  
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats per minute 
101 – 115 
116 – 130 
> 130 
ER visit or hospitalization 
for arrhythmia 
Bradycardia - beats per minute 
50 – 54 
45 – 49 
< 45 
ER visit or hospitalization 
for arrhythmia 
Hypertension (systolic) - mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or hospitalization 
for malignant hypertension 
Hypertension (diastolic) - mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or hospitalization 
for malignant hypertension 
Hypotension (systolic) – mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or hospitalization 
for hypotensive shock 
Respiratory Rate – breaths per 
minute 
17 – 20 
21 – 25 
> 25 
Intubation 
  
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Systemic 
(General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-threatening 
(Grade 4) 
Nausea/vomiting 
No interference with activity or 
1 - 2 episodes/24 hours 
Some interference with 
activity or > 2 episodes/24 
hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
ER visit or hospitalization for 
hypotensive shock 
Diarrhea 
2 - 3 loose stools or < 400 
gms/24 hours 
4 - 5 stools or 400 - 800 
gms/24 hours 
6 or more watery stools or > 
800 gms/24 hours or requires 
outpatient IV hydration 
ER visit or hospitalization 
Headache 
No interference with 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 
ER visit or hospitalization 
Fatigue 
No interference with activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
ER visit or hospitalization 
Myalgia 
No interference with activity 
Some interference with 
activity 
Significant; prevents daily 
activity 
ER visit or hospitalization 
 
Systemic Illness 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-threatening 
(Grade 4) 
Illness or clinical adverse event (as 
defined according to applicable 
regulations) 
No interference with activity 
Some interference with 
activity not requiring medical 
intervention 
Prevents daily activity and 
requires medical intervention 
ER visit or hospitalization 
 
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Tables for Laboratory Abnormalities 
Serum 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
threatening 
(Grade 4) 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia mEq/L 144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia mEq/L 3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia mg/dL 65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
 
100 – 110 
110 – 125 
 
111 – 125 
126 – 200 
 
>125 
>200 
Insulin requirements or 
hyperosmolar coma 
Blood Urea Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorus – 
hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Alkaline phosphate – increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
> 10 x ULN 
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Serum 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
threatening 
(Grade 4) 
Liver Function Tests – ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when accompanied by 
any increase in Liver Function 
Test increase by factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
> 1.75 x ULN 
Bilirubin – when Liver Function 
Test is normal; increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, 
lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
 
Hematology  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) change 
from baseline value - gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) change from 
baseline value – gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25, 000 
> 25,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm3 
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - cell/mm3 1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 
1501 - 5000 
> 5000 
Hypereosinophilic 
Platelets Decreased - cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
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PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x ULN 
 1.11 – 1.20 x ULN 
1.21 – 1.25 x ULN 
> 1.25 ULN 
PTT – increase by factor (partial 
thromboplastin time) 
1.0 – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 – 1.5 x ULN 
> 1.5 x ULN 
Fibrinogen increase - mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or associated with 
gross bleeding or 
disseminated intravascular 
coagulation (DIC) 
 
 
Urine  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life-
threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic) - red blood 
cells per high power field 
(rbc/hpf) 
1 - 10 
11 - 50 
> 50 and/or gross blood 
Hospitalization or packed 
red blood cells (PRBC) 
transfusion 
 
 
 
 
 
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Appendix 3 
Sample Diary Card 
Please assess your symptoms and complete this form each evening (after 4 pm) 
Day Date 
Oral 
Temp 
(°F) 
Systemic Events 
Local Reactions (at the Injection Site) 
Headach
e 
(0 to 3) 
Chills 
(0 to 3) 
Fatigue 
(0 to 3) 
Nausea 
(0 to 3) 
Diarrhea 
(0 to 3) 
Vomiting 
(0 to 3) 
Muscle 
Aches 
(0 to 3) 
Pain 
(0 to 3) 
Tenderness 
(0 to 3) 
Swelling 
(0 to 3) 
Swelling 
(size, 
mm) 
Redness 
(size, mm) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instructions for Scoring Intensity 
Intensity Grading Scale for 
Systemic Events 
 
0 = None 
1 = Mild, no interference with daily 
activity 
2 = Moderate, some interference 
with daily activity 
3 = Severe, significant 
interference, prevents daily 
activity 
Intensity Grading Scale for Pain 
 
0 = None 
1 = Mild, awareness of pain but it 
does not interfere with daily activity 
and no pain medication is taken 
2 = Moderate, awareness of pain 
and there is interference with daily 
activity or requires non-narcotic 
pain medication 
3 = Severe, awareness of pain and 
it prevents daily activity or requires 
use of narcotic pain medication 
Intensity Grading Scale for 
Tenderness 
 
0 = None 
1 = Mild, hurts to touch 
2 = Moderate, hurts with 
movement 
3 = Severe, significant discomfort 
at rest 
Intensity Grading Scale for 
Swelling 
 
0 = None 
1 = Mild, does not interfere with 
daily activity 
2 = Moderate, interferes with daily 
activity 
3 = Severe, prevents daily activity 
Instructions for Measuring Size:  Use the ruler provided and record the number of millimeters across the widest part of the red/swelling area.
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Appendix 4 
Adverse Events of Special Interest 
Gastrointestinal disorders 
• Celiac disease 
• Crohn's disease 
• Ulcerative colitis 
• Ulcerative proctitis 
Liver disorders 
• Autoimmune cholangitis 
• Autoimmune hepatitis 
• Primary biliary cirrhosis 
• Primary sclerosing cholangitis 
Metabolic diseases 
• Addison's disease 
• Autoimmune thyroiditis (including Hashimoto thyroiditis) 
• Diabetes mellitus type I 
• Grave's or Basedow's disease 
Musculoskeletal disorders 
• Antisynthetase syndrome 
• Dermatomyositis 
• Juvenile chronic arthritis (including Still's disease) 
• Mixed connective tissue disorder 
• Polymyalgia rheumatic 
• Polymyositis 
• Psoriatic arthropathy 
• Relapsing polychondritis 
• Rheumatoid arthritis 
• Scleroderma (including diffuse systemic form and CREST syndrome) 
• Spondyloarthritis (including ankylosing spondylitis, reactive arthritis [Reiter's Syndrome] 
and undifferentiated spondyloarthritis) 
• Systemic lupus erythematosus 
• Systemic sclerosis 
Neuroinflammatory disorders 
• Acute disseminated encephalomyelitis (including site-specific variants: e.g., 
noninfectious encephalitis, encephalomyelitis, myelitis, and myeloradiculomyelitis) 
• Cranial nerve disorders, including paralyses/paresis (e.g., Bell's palsy) 
• Guillain-Barre syndrome (including Miller Fisher syndrome and other variants) 
• Immune-mediated peripheral neuropathies and plexopathies (including chronic 
inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and 
polyneuropathies associated with monoclonal gammopathy) 
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• Multiple sclerosis 
• Myasthenia gravis, including Eaton-Lambert syndrome  
• Narcolepsy 
• Optic neuritis 
• Transverse myelitis 
Skin disorders 
• Alopecia areata 
• Autoimmune bullous skin diseases (including pemphigus, pemphigoid, and dermatitis 
herpetiformis) 
• Cutaneous lupus erythematosus 
• Erythema nodosum 
• Morphoea 
• Lichen planus 
• Psoriasis 
• Sweet's syndrome 
• Vitiligo 
Vasculitides 
• Large vessels vasculitis (including giant cell arteritis such as Takayasu's arteritis and 
temporal arteritis) 
• Medium sized and/or small vessels vasculitis (including polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, Wegener's granulomatosis, Churg-Strauss syndrome 
[allergic granulomatous angiitis], Buerger's disease [thromboangiitis obliterans], 
necrotizing vasculitis and antineutrophil cytoplasmic antibody positive vasculitis [type 
unspecified], Henoch­Schönlein purpura, Behcet's syndrome, and leukocytoclastic 
vasculitis) 
Others 
• Antiphospholipid syndrome 
• Autoimmune hemolytic anemia 
• Autoimmune glomerulonephritis (including immunoglobulin A nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
• Autoimmune myocarditis/cardiomyopathy 
• Autoimmune thrombocytopenia 
• Goodpasture syndrome 
• Idiopathic pulmonary fibrosis 
• Pernicious anemia 
• Raynaud's phenomenon 
• Sarcoidosis 
• Sjogren's syndrome 
• Stevens-Johnson syndrome 
• Uveitis 
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Appendix 5 
Genital Herpes Signs and Symptoms Diary 
Genital Herpes Signs and Symptoms Diary 
Version 5.0 
January 17, 2017 
 
Instructions to patients: 
The following questions ask about signs and symptoms of your genital herpes. Signs of genital 
herpes may include having genital lesions (bumps, blisters, sores or scabs) that you may see or 
feel by touch, or drainage or swelling you might have from a genital lesion. These lesions may 
be on your genitals, genital area, thighs or buttocks.  
 
Some people may experience certain symptoms with genital lesions including pain, itching, or 
pain with urination. Please read each question carefully and choose the one best answer for 
each question. Please consider any signs or symptoms due to your genital herpes at their worst, 
in the last 24 hours. 
 
Q1:  Do you have a genital herpes lesion (bump, blister, sore or scab) that you could see or feel 
by touch in the last 24 hours? 
 Yes  
 No  
 
Q1a: If yes, approximately how many genital herpes lesions can you see or feel? 
 1   2-4   5-7   8 or more 
 
Q1b: (if patient answers “Yes” to Q1) Do you have an open genital herpes lesion (bump, 
blister, sore or scab)?  
 Yes  
 No  
 
Q2:  (if patients answers “No” to Q1) Did you experience any signs or symptoms in the last 24 
hours that would indicate you will soon experience a genital herpes recurrence? 
 Yes  
 No  
 
[Q3-Q4 asked ONLY if patient answers “YES” to Q1 or “YES” to Q2] 
[Q5-Q7 asked ONLY if patient answers “YES” to Q1] 
 
Q3:  Rate the severity of any itching you have experienced in the genital area over the last 24 
hours 
 
No 
itch 
 
 
 
 
 
 
 
 
 
Worst 
possible 
itch 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
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Q4: Rate the severity of any pain (soreness or tenderness) you have experienced in the genital 
area over the last 24 hours 
 
No 
pain 
 
 
 
 
 
 
 
 
 
Worst 
possible 
pain 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
Q5:  Rate the severity of any genital lesion pain during urination you have experienced over the 
last 24 hours 
 
No pain 
with 
urination 
 
 
 
 
 
 
 
 
 
Worst 
possible 
pain 
with 
urination 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Q6:  Rate the severity of any genital lesion draining or discharge you have experienced over the 
last 24 hours  
 
No 
draining 
or  
discharge  
 
 
 
 
 
 
 
 
 
Worst 
possible 
draining 
or 
discharge  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Q7:  Rate the severity of any genital lesion swelling you have experienced over the last 24 
hours 
 
No 
swelling 
 
 
 
 
 
 
 
 
 
Worst 
possible 
swelling 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
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Appendix 6 
Protocol Amendments and Summary of Changes 
Amendment 1, Protocol Version 1.1, 14 September 2017 
The overall purpose of the amendment is to: 
• Clarify that prescription medications to treat genital herpes (e.g., antivirals) will not be 
captured with daily electronic reporting tool 
• Added an interim analysis following Month 5 – 6 swab collection period 
• Updated safety reporting from study GEN-003-003 
• Minor edits for clarity and to correct typographical errors 
Summary of Changes 
Section 
Change 
Rationale 
Synopsis – Study Design, ¶ 2, 
and Section 3.1, ¶ 2 
Subjects will use a daily electronic 
tool for reporting the presence or 
absence of genital herpes lesions, 
severity of genital herpes 
symptoms and use of 
prescription medications to 
treat genital herpes from Day 1 
until the end of the study.  
Information on prescription 
medications to treat genital 
herpes will not be captured in 
electronic tool; only in eCRF.  
Synopsis – Exploratory Endpoint 
and Section 2.2.3 
Anogenital HSV-2 shedding rates: 
Proportion of anogenital swabs 
positive for HSV-2 DNA by PCR 
before and after the 
maintenance dose using data 
from GEN-003-003 as subject 
baseline 
Inadvertently left out of original 
protocol. 
Section 1.5.5 - 003-003:  A 
Randomized, Double-blind Study 
to Evaluate a New Formulation of 
GEN-003 in Subjects with Genital 
HSV-2 Infection, ¶ 6 
No AESIs or deaths occurred 
during the study. Six Five SAEs, 
were reported in 4 3 subjects: 
Change to SAE: 
- Post laminectomy syndrome 
requiring hospitalization; 2 months 
later, toxicity to various agents 
ovarian cyst ruptured resulting in 
death 
New SAE: 
- Worsening mitral valve 
regurgitation requiring 
hospitalization for mitral valve 
replacement 
Typo – death 
New information about SAE 
resulting in death and one 
additional SAE was reported 
since the original protocol was 
written.  
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Section 
Change 
Rationale 
Section 6.1 - Daily electronic 
reporting tool 
Each day subjects will report the 
presence or absence of genital 
herpes lesions and genital herpes 
symptoms and the use of 
antivirals. 
Electronic diary will not capture 
daily use of antivirals. 
Section 6.2.1 - Maintenance 
Dose (Day 1) – Clinic Visit, ¶ 5 
If a subject is excluded because of 
exclusion criteria 1 (important 
protocol deviation in Study GEN-
003-003), 6 (immunocompromise), 
7 (AESI), or 8 (autoimmune 
disease), then the details of the 
excluding deviation, diagnosis, or 
medication will be entered in the 
eCRF. 
Correct error in order of 
exclusion criteria numbers.  
Section 7.2.2 - Medically 
Attended Adverse Events 
A An MAAE is an AE resulting in 
hospitalization, emergency room 
visit, or visit to or from medical 
personnel (other than routine 
health care visits). If a MAAE is 
"hospitalization" it should be 
reported as an SAE as 
described in Section 7.6 below. 
Typo 
Clarified reporting of MAAE that 
results in hospitalization. 
Section 10.11 – Interim Analysis 
Added: 
An interim analysis will be 
conducted after all viral 
shedding samples from Month 5 
to 6 swab collection period have 
been tested and will include 
analysis of shedding and lesion 
rates.  The specific contents of 
the interim analyses will be 
detailed in the SAP. 
Added an interim analysis to the 
protocol. 
Original 11.12 – Protocol 
Deviations 
Deleted entire section. 
Already included in Section 11.7. 
Appendix 1 
Subjects will report the presence 
or absence of genital lesions, 
severity of genital herpes 
symptoms, and the use of 
prescription medication to treat 
genital herpes on each day from 
Day 1 through Month 12. 
Electronic diary will not capture 
daily use of antivirals. 
 
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Amendment 2, Protocol Version 2.0, 13 October 2017 
The overall purpose of the amendment is to: 
• Change clinical objectives and endpoint observation period from 12 months to 6 months 
• Eliminate swab collection and shedding analyses 
• Eliminate blood collection for immunology at Months 6 and 12, and eliminate immunology 
analyses 
• Eliminate RGHQoL data collection, and analyses of all quality of life assessments 
• Allow for use of suppressive antiviral medication following the Month 6 visit. 
Summary of Changes 
Section 
Change 
Rationale 
Synopsis and Section 2.1.2 -  
Secondary Efficacy Objectives 
• To evaluate the efficacy of GEN-
003 versus placebo administered 
as a maintenance dose on genital 
herpes recurrence through 6 
months:   
- Reduction of genital herpes 
recurrence frequency   
- Increase of proportion of 
subjects who are genital herpes 
recurrence-free at 12 months 
after the maintenance dose 
- Increase of time to first/next 
genital herpes recurrence  
- Reduction of genital herpes 
recurrence duration 
• To evaluate the efficacy of 
GEN-003 versus placebo 
administered as a maintenance 
dose in reduction of anogenital 
herpes simplex virus type 2 
(HSV-2) shedding rates after 
the maintenance dose 
The Sponsor has stopped 
development of GEN-003 and 
therefore reduced collection and 
analyses of efficacy and viral 
shedding data 
Synopsis and original Section 
2.1.3 -  Exploratory Objectives 
Deleted entire section. 
The Sponsor has stopped 
development of GEN-003 and 
therefore reduced collection and 
all analyses of viral shedding, 
immunogenicity, and quality of 
life data 
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Section 
Change 
Rationale 
Synopsis and Section 3.1 -  
Overall Study Design, ¶2 
 
 
 
¶3 
 
 
 
 
 
 
 
¶4 
 
 
 
 
 
 
¶5 
 
 
 
 
 
 
 
 
 
 
 
¶6 
 
 
 
 
 
 
 
 
 
 
Subjects will use a daily electronic 
tool for reporting the presence or 
absence of genital herpes lesions 
and the severity of genital herpes 
symptoms from Day 1 until the 
end of the study Month 6 Visit. 
Subjects will collect anogenital 
swabs for measurement of 
HSV-2 shedding twice a day for 
28‑ day periods during Months 
5 to 6 and Months 11 to 12. 
Samples will be analyzed for 
HSV-2 DNA by real-time 
quantitative polymerase chain 
reaction (PCR) assay. 
Subjects will complete the 
EuroQol – 5 Domains – 5 Levels 
(EQ-5D-5L) questionnaire on 
each day of the first recurrence 
after the maintenance dose 
through Month 6. and the 
Recurrent Genital Herpes 
Quality of Life Questionnaire 
(RGHQoL) at Month 6 and 
Month 12. 
A serum sample will be collected 
from each subject for evaluation 
of humoral responses future 
research purposes before the 
maintenance dose (Day 1), 7 and 
28 days after the maintenance 
dose (Day 8 and Day 29/Month 
1). , and at Month 6 and Month 
12. Immunoglobulin G (IgG) 
specific to the vaccine antigens 
will be measured by enzyme-
linked immunosorbent assay 
(ELISA), and HSV-2 neutralizing 
antibodies will be measured by 
a colorimetric assay. 
At selected investigational sites, a 
whole blood sample will be 
collected and processed to isolate 
peripheral blood mononuclear 
cells (PBMCs) for evaluation of 
cellular responses future 
research purposes before the 
maintenance dose (Day 1), 7 and 
28 days after the maintenance 
dose (Day 8 and Day 29/Month 
1). , and at Months 6 and 12. 
Secretion of granzyme B (GrB) 
and interferon-gamma (IFN-γ) 
Modify design and procedures 
to reflect reduced data collection 
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Section 
Change 
Rationale 
 
 
¶8 
 
specific to the vaccine-specific 
antigens will be measured by a 
GrB/IFN-γ FluoroSpot assay. 
From Month 2 to Month 12, the 
investigational site will contact 
each subject monthly by 
telephone or site visit for review of 
daily electronic reporting tool data 
and assessment of SAEs, AESIs, 
and antiviral medication (through 
Month 6) and vaccine use. 
Synopsis and Section 2.2.1 – 
Primary Efficacy Endpoint 
• Genital herpes lesion rate 
(proportion of days with lesions 
present) in the 12 6-month period 
after the maintenance dose: 
Based on subject report of genital 
lesions via a daily electronic 
reporting tool 
The Sponsor has stopped 
development of GEN-003 and 
therefore reduced collection and 
analyses of efficacy data 
Synopsis and Section 2.2.2 – 
Secondary Efficacy Endpoints 
• Frequency of genital herpes 
recurrences in the 12 6-month 
period after the maintenance 
dose: Based on subject report of 
genital lesions via a daily 
electronic reporting tool 
• Proportion of subjects genital 
herpes recurrence-free at 12 6 
months after the maintenance 
dose: Based on subject report of 
genital lesions via a daily 
electronic reporting tool 
• 
Time to first/next genital 
herpes recurrence in the 12 6-
month period after the 
maintenance dose: Based on 
subject report of genital lesions 
via a daily electronic reporting tool 
• 
Duration of genital herpes 
recurrences in the 12 6-month 
period after the maintenance 
dose: Based on subject report of 
genital lesions via a daily 
electronic reporting tool 
• Anogenital HSV-2 shedding 
rates: Proportion of anogenital 
swabs positive for HSV-2 DNA 
by PCR after the maintenance 
dose 
The Sponsor has stopped 
development of GEN-003 and 
therefore reduced collection and 
analyses of efficacy and viral 
shedding data 
Synopsis and original Section 
2.2.3 – Exploratory Endpoints 
Deleted entire section. 
The Sponsor has stopped 
development of GEN-003 and 
therefore reduced collection and 
all analyses of viral shedding, 
immunogenicity, and quality of 
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Section 
Change 
Rationale 
life data 
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Section 
Change 
Rationale 
Synopsis – Statistical Methods: 
Efficacy 
Genital herpes lesion rates (the 
proportion of days with genital 
lesions present) in the 12 6-month 
period after the maintenance dose 
will be compared between 
treatment groups using the 
Wilcoxon rank sum text. The 
frequency of genital herpes 
recurrences in the 12-month 
period after the maintenance 
dose will be calculated as the 
number of recurrences 
reported and summarized by 
mean, standard deviation (SD), 
median, and range. The median 
frequencies of recurrences in the 
6-month period will be compared 
between treatment groups using 
the Wilcoxon rank sum test. The 
proportion of subjects in each 
treatment group who are genital 
herpes recurrence-free at 12 6 
months after the maintenance 
dose will be tabulated and 
compared using a chi-square test 
for homogeneity of proportions. 
Time to first recurrence in the 12 
6- month period after the 
maintenance dose will be 
tabulated and graphed using the 
Kaplan-Meier method. The log-
rank test will be used to compare 
the time to first recurrence 
survival curves between the GEN-
003 and placebo groups. Survival 
analysis with Cox model will be 
used to compare the time to 
next genital herpes recurrence. 
Duration of genital herpes 
recurrences over the 12-month 
period after the maintenance 
dose will be calculated and 
summarized by mean, SD, 
median, and range. Median of 
individual mean duration of genital 
herpes recurrences during the 6-
month period will be compared 
using the Wilcoxon rank sum test. 
Deleted remainder of efficacy 
analysis methods. 
The Sponsor has stopped 
development of GEN-003 and 
therefore reduced analyses of 
efficacy data 
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Section 
Change 
Rationale 
Section 3.2.2 – Efficacy 
Endpoints, ¶1, Sentence 1 
 
 
 
 
¶2 
Genital herpes lesion rate in the 
12 6-month period after the 
maintenance dose was selected 
as the primary endpoint because 
lesion rate is the most 
comprehensive measure of 
genital herpes disease burden. 
The secondary efficacy endpoints 
evaluate other clinically important 
measures of vaccine effect, such 
as the frequency and duration of 
genital herpes recurrences. In 
addition, the vaccine’s ability to 
lower HSV-2 shedding rate will 
also be assessed. Viral 
shedding rate is a direct 
measurement of antiviral 
activity that has been used in 
previous studies of both 
vaccines and antiviral 
medications for genital herpes. 
It is an objective measure of 
antiviral activity against HSV-2. 
To reflect change in primary 
endpoint observation period 
 
 
 
 
To reflect that viral shedding will 
no longer be analyzed 
Section 5.5 – Concomitant 
Medications, Sentence 2 
Use of antiviral medications and 
vaccines will be recorded from 
Day 1 through the end of the 
study Month 6. 
Collection of lesion data will end 
at Month 6, therefore subjects 
will be allowed to use antiviral 
medications following the Month 
6 visit 
Section 5.6.1.1 – Suppressive 
Therapy 
Subjects are forbidden from 
taking suppressive antiviral 
therapy during this study through 
the Month 6 Visit.   
Collection of lesion data will end 
at Month 6, therefore subjects 
will be allowed to use antiviral 
medications following the Month 
6 visit 
Section 5.6.1.1 – Treatment of 
Recurrences 
Treatment of recurrences is 
NOT permitted during swab 
collection periods.  Up to 3 days 
of antiviral treatment is permitted 
for recurrences that occur 
outside of swab collection 
periods.   
Genital swabbing has been 
eliminated from the protocol 
Section 5.6.2 - Medications and 
Supplements with Anti-HSV 
Activity 
Use of acyclovir, valacyclovir, 
famciclovir, tenofovir (except for 
postexposure prophylaxis for HIV-
1), lysine, or other medication or 
supplement known or purported to 
affect HSV recurrence frequency 
or intensity is prohibited from 14 
days before the maintenance 
dose to the end of the study 
through the Month 6 Visit (except 
as noted in Section 5.6.1.2 for the 
acute treatment of genital herpes 
recurrences). 
Collection of lesion data will end 
at Month 6, therefore subjects 
will be allowed to use antiviral 
medications following the Month 
6 visit 
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Section 
Change 
Rationale 
Original 5.6.3 – Topical Steroids 
and Antiviral Medications 
Deleted entire section. 
Genital swabbing has been 
eliminated from the protocol; 
section is irrelevant 
Section 6.1 - Definitions and 
Descriptions of Assessments 
and Procedures, Daily Electronic 
Reporting Tool, sentence 3 
Data must be entered daily 
through Month 6 Visit. 
To reflect amended reporting 
period 
Section 6.1 - Definitions and 
Descriptions of Assessments 
and Procedures, Anogenital 
Swabs and RGHQoL 
Deleted 
Genital swabbing and RGHQoL 
have been eliminated from the 
protocol 
Section 6.1 - Definitions and 
Descriptions of Assessments 
and Procedures, EQ-5D-5L, 
sentence 1 
The subject will complete this 
questionnaire on each day of the 
genital herpes first recurrence 
after the maintenance dose 
through Month 6. 
To reflect amended reporting 
period 
Section 6.2.1 – Day 1, ¶6 
Upon determination that a subject 
meets all eligibility criteria, the 
following blood samples will be 
collected: 
- Serum for immunogenicity 
testing future research 
- At selected investigational sites: 
whole blood for PBMC isolation 
for immunogenicity testing 
future research 
Immunogenicity testing has 
been eliminated from the 
protocol 
Section 6.2.2 (Day 8), 6.2.3 (Day 
29), original Section 6.3.4 
(Months 6 and 12) 
Sample collection: 
- Serum for immunogenicity 
testing future research 
- At selected investigational sites: 
whole blood for PBMC isolation 
for immunogenicity testing 
future research 
Immunogenicity testing has 
been eliminated from the 
protocol 
Section 6.3.1 – Follow-up 
Telephone Calls, ¶1 
¶2 
Deleted Month 7 call 
 
The following procedures will be 
performed: 
• Review of daily reporting tool 
data (Month 4 only) 
• Assessment of SAEs, AESIs, 
and MAAEs 
• Assessment of antiviral 
medication and vaccine use 
through Month 6 
No longer required 
 
Reflect new data collection 
periods 
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Section 
Change 
Rationale 
Section 6.3.2 – Months 3 and 6 
The following procedures will be 
performed:  
• Review of daily electronic 
reporting tool data 
• Collection of completed EQ-5D-
5L questionnaires, if completed 
• Assessment of SAEs, AESIs, 
and MAAEs 
• Assessment of antiviral 
medication and vaccine use 
The subject will be reminded to 
continue use of the daily 
electronic reporting tool. 
Combined procedures for 
Months 3 and 6 (changed from 3 
and 9) to reflect new data 
collection periods 
Section 6.3.3 – Months 9 and 12 The following procedures will be 
performed:  
• Assessment of SAEs, AESIs, 
and MAAEs 
Combined procedures for 
Months 9 and 12 (changed from 
6 and 12) to reflect new data 
collection periods and 
elimination of blood sampling 
Original Section 6.3.3 – Months 
5 and 11 
Deleted entire section 
No longer required 
Original Section 6.3.4 – Months 
6 and 12 
Deleted entire section and 
replaced with new section 6.3.3 
See above 
Section 10.4 – Subject 
Disposition, ¶3 
Analysis populations will be 
summarized in a tabular format. 
Data will be presented in listings 
only 
Section 10.7 – Primary Efficacy 
Endpoint 
Genital herpes lesion rates (the 
proportion of days with genital 
lesions present) in the 12 6-month 
period after the maintenance dose 
will be compared between 
treatment groups using the 
Wilcoxon rank sum text. 
To reflect analysis of new 
observation period 
Section 10.8.1 – Frequency of 
Genital Herpes Recurrences, 
sentence 1 
The frequency of genital herpes 
recurrences in the 12 6-month 
period after the maintenance dose 
will be calculated as the number 
of recurrences reported and 
summarized by mean, SD, 
median, and range.   
Reflect analysis of new 
observation period 
Section 10.8.2 – Proportion of 
Subjects Recurrence-Free 
The proportion of subjects in each 
treatment group who are genital 
herpes recurrence-free at 12 6 
months after the maintenance 
dose will be tabulated and 
compared using a chi-square test 
for homogeneity of proportions. 
Reflect analysis of new 
observation period 
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Section 
Change 
Rationale 
Section 10.8.3  – Time to First 
Genital Herpes Recurrence 
Time to first recurrence in the 12 
6-month period after the 
maintenance dose will be 
tabulated and graphed using the 
Kaplan-Meier method. The log-
rank test will be used to compare 
the time to first recurrence 
survival curves between the GEN 
003 and placebo groups. Survival 
analysis with Cox model will 
used to compare the time to 
next genital herpes recurrence. 
Reflect analysis of new 
observation period; time to 
“next” recurrence will not be 
analyzed 
Section 10.8.4 – Duration of 
Genital Herpes Recurrences, 
sentence 1 
Duration of genital herpes 
recurrences over the 12 6-month 
period after the maintenance dose 
will be calculated and 
summarized by mean, SD, 
median, and range. 
Reflect analysis of new 
observation period 
Section 10.8.5 – Anogenital 
Shedding Rate 
Deleted entire section 
Genital swabbing has been 
eliminated from the protocol 
Section 10.9 – Exploratory 
Efficacy Endpoints 
Deleted entire section 
Data collection and analysis 
eliminated from the protocol 
Original Section 10.9.6 – Quality 
of Life 
Deleted entire section 
Data collection and analysis 
eliminated from the protocol 
Section 10.10 – Interim Analysis An interim analysis of lesion 
rates and recurrences will be 
conducted after all viral 
shedding samples from Month 
5 to 6 swab collection period 
have been tested and will 
include analysis of shedding 
and lesion rates on data collect 
to Month 6. The specific contents 
of the interim analyses will be 
detailed in the SAP. 
Genital swabbing has been 
eliminated from the protocol 
Appendix 1 – Schedule of 
Events, Serum and PBMCs 
Serum for immunogenicity 
research purposes 
PBMCs for immunogenicity 
research purposes  
Eliminated at Months 6 and 12 
Immunogenicity testing has 
been eliminated from the 
protocol 
Appendix 1 – Schedule of 
Events, Daily electronic reporting 
tool 
Subject will report the presence or 
absence of genital lesions, and 
severity of genital herpes 
symptoms on each day from Day 
1 through Month 12 6. 
Reflect new data collection 
period 
Appendix 1 – Schedule of 
Events, EQ-5D-5L 
Subject will complete the EQ-5D-
5L on each day of the first 
recurrence after the maintenance 
dose through Month 6. 
Reflect new data collection 
period 
Appendix 1 – Schedule of 
Events, Administration of 
Eliminated 
RGHQoL has been eliminated 
from the protocol 
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Genocea Biosciences, Inc. 
GEN-003-005 
IND #: 14910 
Version 2.0 
Section 
Change 
Rationale 
RGHQoL 
Appendix 1 – Schedule of 
Events, Instruction in anogenital 
swab collection; Distribution, 
reconciliations and processing of 
swabs; Swab collection 
Eliminated 
Genital swabbing has been 
eliminated from the protocol 
 
13 October 2017 
Confidential 
Page 75 of 75