A Phase 1, Open-Label, Dose-Escalation Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of the Sm-p80 + GLA-SE (SchistoShield(R)) Vaccine in Healthy Adults
Phase: PHASE1
Conditions: Schistosomiasis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 18-0018 
Version 4.0 
Phase 1 Trial of Sm-p80 + GLA-SE Vaccine 
04 January 2024 
DMID/NIAID/NIH 
CONFIDENTIAL 
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A Phase 1, Open-Label, Dose-Escalation Trial to Evaluate the 
Safety, Reactogenicity, and Immunogenicity of the Sm-p80 + 
GLA-SE (SchistoShield®) Vaccine in Healthy Adults 
 
 
DMID Protocol Number: 18-0018 
 
DMID Funding Mechanism: Infectious Disease Clinical Research Consortium 
 
Pharmaceutical Support: PAI Life Sciences Inc.; Infectious Disease Research Institute 
 
IND Sponsor: Division of Microbiology and Infectious Diseases, National Institute of Allergy 
and Infectious Diseases, National Institutes of Health 
 
Lead Principal Investigator: Lisa A. Jackson, MD, MPH 
DMID Clinical Project Manager: Ranjodh Gill, BSN, MPH 
Version: 4.0 
04 January 2024 

DMID Protocol 18-0018 
Version 4.0 
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04 January 2024 
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STATEMENT OF ASSURANCE 
 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally-funded human subjects research. Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 

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STATEMENT OF COMPLIANCE 
 
The study trial will be carried out in accordance with the protocol, Good Clinical Practice (GCP) 
and as required by the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection 
of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application), 21 CFR 812 (Investigational Device Exemptions) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 

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Site Inve stigator Signature: 
Signed: 
Date: 
Lisa A. Jackson, MD, MPH 
Senior Investigator, Kaiser Permanente Washington 
Health Research Institute 
 
 
 
 
SIGNATURE PAGE 
 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable United States (US) federal 
regulations and ICH E6 GCP guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ................................................................................................... 2 
STATEMENT OF COMPLIANCE ................................................................................................. 3 
SIGNATURE PAGE ........................................................................................................................ 4 
TABLE OF CONTENTS ................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................ 11 
LIST OF ABBREVIATIONS ........................................................................................................ 12 
PROTOCOL SUMMARY ............................................................................................................. 15 
KEY ROLES ......................................................................................................................... 19 
BACKGROUND AND SCIENTIFIC RATIONALE ........................................................... 20 
Background ................................................................................................................. 20 
2.1.1 Schistosomiasis............................................................................................... 20 
2.1.2 SchistoShield® ............................................................................................... 22 
2.1.3 Preclinical and Safety Studies ........................................................................ 23 
2.1.3.1 Potency of Sm-p80 in Murine Models .............................................. 23 
2.1.3.2 Safety and Immunogenicity of Sm-p80 + GLA-SE in Non-Human 
Primates ............................................................................................. 25 
2.1.3.3 Efficacy of Sm-p80 + GLA-SE in Non-Human Primates ................. 27 
2.1.4 Safety of GLA-SE .......................................................................................... 28 
2.1.5 GLP Toxicity Studies of SchistoShield® ....................................................... 30 
Scientific Rationale ..................................................................................................... 31 
2.2.1 Purpose of Study ............................................................................................ 31 
2.2.2 Study Population ............................................................................................ 32 
Potential Risks and Benefits ....................................................................................... 33 
2.3.1 Potential Risks ................................................................................................ 33 
2.3.2 Potential Benefits ........................................................................................... 34 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES ....... 35 

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Study Design Description ............................................................................................ 35 
Study Objectives ......................................................................................................... 36 
3.2.1 Primary ........................................................................................................... 36 
3.2.2 Secondary ....................................................................................................... 36 
3.2.3 Exploratory ..................................................................................................... 36 
Study Endpoints or Outcome Measures ...................................................................... 36 
3.3.1 Primary ........................................................................................................... 36 
3.3.2 Secondary ....................................................................................................... 36 
3.3.3 Exploratory ..................................................................................................... 37 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ........................................... 38 
Study Product Description .......................................................................................... 38 
4.1.1 Formulation, Packaging, and Labeling........................................................... 38 
4.1.2 Product Storage and Stability ......................................................................... 39 
Acquisition/Distribution .............................................................................................. 40 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product ......................................................................... 40 
Accountability Procedures for the Study Intervention/Investigational Product(s) ...... 41 
Modification of Study Intervention/Investigational Product for a Participant ............ 42 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ..... 43 
Eligibility Criteria ....................................................................................................... 43 
5.1.1 Subject Inclusion Criteria ............................................................................... 43 
5.1.2 Subject Exclusion Criteria .............................................................................. 45 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination 
. ................................................................................................................................. 48 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ........... 48 
5.2.2 Subject Replacement ...................................................................................... 49 
5.2.3 Study Termination .......................................................................................... 49 
STUDY PROCEDURES ....................................................................................................... 51 
Screening, Visit 00 (Day -30 to Day -1) ..................................................................... 51 
Visit 01 Day 01, Enrollment and First Study Product Injection, Clinic Visit ............. 53 

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Planned Study Visits ................................................................................................... 54 
6.3.1 Follow-up ....................................................................................................... 55 
6.3.2 Early Termination Visit .................................................................................. 56 
Unscheduled Study Visits (if needed) ......................................................................... 57 
Protocol Deviations ..................................................................................................... 57 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS ......................... 58 
Clinical Evaluations .................................................................................................... 58 
7.1.1 Assessment of Concomitant Medications/Treatments other than Study 
Product ........................................................................................................... 59 
Laboratory Evaluations ............................................................................................... 60 
7.2.1 Clinical Laboratory Evaluations ..................................................................... 60 
7.2.2 Research Assays ............................................................................................. 60 
7.2.2.1 ELISA (anti Sm-p80 IgG) ................................................................. 61 
7.2.2.2 RNA-Seq ........................................................................................... 61 
7.2.2.3 Laboratory Specimen Preparation, Handling, and Storage ............... 61 
7.2.2.4 Laboratory Specimen Shipping ......................................................... 61 
ASSESSMENT OF SAFETY ............................................................................................... 63 
Assessing and Recording Safety Parameters .............................................................. 63 
8.1.1 Adverse Events (AEs) .................................................................................... 63 
8.1.1.1 Adverse Events Grading ................................................................... 64 
8.1.2 Reactogenicity ................................................................................................ 66 
8.1.3 Serious Adverse Events (SAEs) ..................................................................... 68 
Specification of Safety Parameters ............................................................................. 69 
8.2.1 Solicited Events .............................................................................................. 69 
8.2.2 Unsolicited Events .......................................................................................... 69 
8.2.3 New-Onset Chronic Medical Conditions (NOCMCs).................................... 69 
8.2.4 Medically-Attended Adverse Events (MAAEs) ............................................. 69 
8.2.5 Potentially Immune-Mediated Medical Conditions (PIMMCs) ..................... 69 
Reporting Procedures .................................................................................................. 69 

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8.3.1 Reporting Serious Adverse Events ................................................................. 69 
8.3.2 Regulatory Reporting for Studies Conducted Under a DMID Sponsored IND 
. ....................................................................................................................... 70 
8.3.3 Reporting of Pregnancy .................................................................................. 71 
8.3.4 Disclosure of Study Related Information ....................................................... 71 
Type and Duration of Follow-up of Subjects after Adverse Events ........................... 71 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings ...................................................................................... 72 
Halting Rules .............................................................................................................. 72 
8.6.1 Study Halting Criteria .................................................................................... 72 
8.6.2 Individual Halting Criteria ............................................................................. 74 
8.6.3 Dose Escalation Halting Criteria .................................................................... 75 
Safety Oversight .......................................................................................................... 75 
HUMAN SUBJECTS PROTECTION .................................................................................. 76 
Institutional Review Board/Independent Ethics Committee ........................................ 76 
Informed Consent Process ........................................................................................... 76 
9.2.1 Requirements for Permission by Parents/Guardians and Assent by Children 
(in case of a minor) ......................................................................................... 78 
9.2.2 Other Informed Consent Procedures .............................................................. 78 
Consent for Secondary Research Use of Stored Specimens and Data ........................ 78 
9.3.1 Secondary Use of Stored Specimens and Data ............................................... 78 
9.3.2 Samples for Secondary Research ................................................................... 79 
9.3.3 Data Sharing for Secondary Research ............................................................ 80 
Exclusion of Women, Minorities, and Children (Special Populations) ...................... 80 
Subject Confidentiality ................................................................................................ 80 
Certificate of Confidentiality ...................................................................................... 81 
Costs, Subject Compensation, and Research Related Injuries .................................... 81 
STATISTICAL CONSIDERATIONS .................................................................................. 83 
Study Hypotheses ........................................................................................................ 83 
Sample Size Considerations ........................................................................................ 83 

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Treatment Assignment Procedures .............................................................................. 83 
10.3.1 Randomization Procedures ............................................................................. 83 
10.3.2 Masking Procedures ....................................................................................... 84 
Planned Interim Analyses ........................................................................................... 84 
10.4.1 Interim Safety Review .................................................................................... 84 
10.4.2 Interim Immunogenicity or Efficacy Review ................................................. 85 
Final Analysis Plan ..................................................................................................... 85 
10.5.1 Analysis of Demographics.............................................................................. 85 
10.5.2 Analysis of Safety Data .................................................................................. 85 
10.5.3 Analysis of Immunogenicity Data .................................................................. 86 
10.5.4 RNA-Seq Analysis ......................................................................................... 86 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............... 88 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 89 
DATA HANDLING AND RECORD KEEPING ................................................................. 90 
Data Management Responsibilities ............................................................................. 90 
Data Coordinating Center/Biostatistician Responsibilities ......................................... 90 
Data Capture Methods ................................................................................................ 90 
Types of Data .............................................................................................................. 91 
Study Records Retention ............................................................................................. 91 
CLINICAL MONITORING.................................................................................................. 92 
PUBLICATION POLICY ..................................................................................................... 93 
LITERATURE REFERENCES ............................................................................................ 94 
APPENDICES ...................................................................................................................... 97 
     Schedules of Events ............................................................................... 98 
     List of Potentially Immune-Mediated Medical Conditions (PIMMCs) 
105 
Toxicity Tables ............................................................................... 108 

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LIST OF TABLES 
 
Table 1: Treatment Arms ............................................................................................................... 17 
Table 2: Dose Escalation Schedule. ............................................................................................... 18 
Table 3: Injection Site Reactogenicity Grading ............................................................................. 66 
Table 4: Injection Site Reactogenicity Measurements ................................................................... 66 
Table 5: Subjective Systemic Reactogenicity Grading .................................................................. 67 
Table 6: Quantitative Systemic Reactogenicity Grading ............................................................... 67 
Table 7: Screening Visit Evaluations and Procedures. ................................................................... 98 
Table 8: Schedule of Events and Study Procedures, Study Groups A, B, D, and E ....................... 99 
Table 9: Schedule of Events and Study Procedures, Study Group C ........................................... 102 

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LIST OF FIGURES 
Figure 1: Infographic on the potential impact of the SchistoShield® vaccine. .............................. 20 
Figure 2: Sm-p80-specific Total IgG Titers in Mice ...................................................................... 24 
Figure 3: Sm-p80 + GLA-SE Vaccine-Mediated Efficacy in Mice ............................................... 25 
Figure 4: Kinetics of total Sm-p80-specific antibody in immunized baboons. .............................. 26 
Figure 5: Prophylactic efficacy of the Sm-p80 vaccine in baboons. .............................................. 28 

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LIST OF ABBREVIATIONS 
 
 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASC 
Antibody secreting cell 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMS 
Clinical Material Services 
CRP 
C reactive protein 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLA-SE 
Glucopyranosyl Lipid Adjuvant Stable oil-in-water Emulsion 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HEENT 
Head, ears, eyes, nose, and throat 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
Intracellular cytokine staining 

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IDRI 
Infectious Disease Research Institute 
IEC 
Independent or Institutional Ethics Committee 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MAAE 
Medically attended adverse events 
MOP 
Manual of Procedures 
MPL 
Monophosphoryl Lipid A 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
NOCMC 
New onset chronic medical condition 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral blood mononuclear cell 
PHA 
Phytohemagglutinin 
PHI 
Protected health information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCRI 
Seattle Children’s Research Institute 
SDCC 
Statistical Data Coordinating Center 
SE 
Stable emulsion 
SMC 
Safety Monitoring Committee 
Sm-p80 
S. mansoni calpain protein with a mass of approximately 80 
kDa 
TTUHSC 
Texas Tech University Health Sciences Center 

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US 
United States 
VTEU 
Vaccine and Treatment Evaluation Unit 
WBC 
White blood cell 
WFI 
Water for Injection 

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PROTOCOL SUMMARY 
 
 
 
 
 
Title: 
A Phase 1, Open-Label, Dose-Escalation Trial to Evaluate the 
Safety, Reactogenicity, and Immunogenicity of the Sm-p80 + 
GLA-SE (SchistoShield®) Vaccine in Healthy Adults 
Design of the Study: 
The study is a Phase 1 dose-escalation clinical trial to evaluate 
the safety, reactogenicity, and immunogenicity of the Sm-p80 + 
GLA-SE vaccine candidate in healthy adults. Five treatment 
groups, each including nine subjects, will receive three 
intramuscular (IM) injections of 0.5 mL of the designated study 
product on either Days 1, 29, and 57 or on Days 1, 29, and 180 
(Table 1). Group A (unadjuvanted comparator) will receive 100 
μg Sm-p80 alone on Days 1, 29, and 57, Group B (low dose 
standard schedule) will receive 10 μg Sm-p80 + 5 μg GLA-SE 
on Days 1, 29 and 57, Group C (mid dose delayed booster) will 
receive 30 μg Sm-p80 + 5 μg GLA-SE on Days 1, 29 and 180, 
Group D (mid dose standard schedule) will receive 30 μg Sm- 
p80 + 5 μg GLA-SE on Days 1, 29, and 57, and Group E (high 
dose standard schedule) will receive 100 μg Sm-p80 + 5 μg 
GLA-SE on Days 1, 29 and 57. 
Study Phase: 
1 
Study Population: 
45 healthy adults 18 through 55 years of age in the United States. 
Number of Sites: 
1 
Description of Study 
Product: 
Sm-p80 + GLA-SE, SchistoShield®, consists of Sm-p80, a 
recombinant protein produced in Escherichia coli, and 
Glucopyranosyl Lipid Adjuvant (GLA) formulated in a stable 
emulsion (GLA-SE) as an immunological adjuvant. The Sm-p80 
+ GLA-SE vaccine has not yet been studied in humans. The 
study will evaluate an antigen only formulation with 100 μg Sm- 
p80 and three adjuvanted formulations with varying antigen 

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content (10 μg, 30 μg, or 100 μg Sm-p80, all with 5 μg GLA- 
SE). An injected volume of 0.5 mL will be administered for all 
three doses. All formulations will be evaluated on a Day 1, 29 
and 57 administration schedule; the 30 μg + 5 µg GLA- SE 
formulation will also be evaluated on a Day 1, 29, and 180 
delayed boost schedule. 
Study Objectives: 
Primary: 
• 
To assess the safety and reactogenicity following receipt of 
three doses of 1) 100 µg Sm-p80 (unadjuvanted), 2) 10 µg 
Sm-p80 + 5 µg GLA-SE, 3) 30 µg Sm-p80 + 5 µg GLA-SE, 
and 4) 100 µg Sm-p80 + 5 µg GLA-SE administered 
intramuscularly on Days 1, 29, and 57 and 5) 30 µg Sm-p80 
+ 5 µg GLA-SE administered on Days 1, 29, and 180. 
Secondary: 
• 
To assess anti- Sm-p80 IgG antibody responses from samples 
collected at specified time points. 
Exploratory: 
• 
To assess innate and adaptive immune signatures from 
samples collected at specified time points. 
Duration of Individual 
Subject Participation: 
Approximately 15 months (screening visit through last study 
visit) for subjects with the Day 1, 29 and 57 administration 
schedule and approximately 19 months for subjects with the Day 
1, 29 and 180 administration schedule. 
Estimated Time to Last 
Subject/Last Study Day: 
Approximately twenty months: four weeks initial screening, six 
weeks to progress to enrollment of the delayed booster dose 
cohort (Group C) (Table 2), and study follow-up through day 
545 after enrollment of the last Group C subject. 

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Table 1: Treatment Arms. 
 
Study 
Group 
N Study Product 
Administration Schedule 
A 
9 100 µg Sm-p80 (unadjuvanted) 
Day 1, 29, 57 
B 
9 10 µg Sm-p80 + 5 µg GLA-SE 
Day 1, 29, 57 
C 
9 30 µg Sm-p80 + 5 µg GLA-SE 
Day 1, 29, 180 (delayed booster) 
D 
9 30 µg Sm-p80 + 5 µg GLA-SE 
Day 1, 29, 57 
E 
9 100 µg Sm-p80 + 5 µg GLA-SE 
Day 1, 29, 57 
 
 
 
Dose escalation. The study will be initiated by enrollment of Study Groups A and B, which both 
evaluate first-in-human formulations. Group A will receive high antigen unadjuvanted product 
and Group B will receive low antigen adjuvanted product (Table 1). The safety profile of either 
formulation does not necessarily predict that of the other. Therefore, Groups A and B will be 
enrolled before the first safety data review (Table 2). For each of those Groups, only one subject 
will receive vaccine on the first day of administration of that formulation. 
To progress to the next dose level, the Principal Investigator (PI) will review safety data 
collected through at least seven days after the first injection of the Group A and Group B 
subjects and assess this data according to pre-specified criteria for halting dose escalation 
(Section 8.6.3). If dose escalation halting criteria are not met, Study Groups C and D subjects, 
who will receive the next highest dose of 30 µg Sm-p80 + 5 µg GLA-SE on different schedules, 
will be enrolled. On the first day of administration of that formulation no more than one subject 
from Groups C and D will be vaccinated. Dose escalation to Group E, the highest dose group, 
will follow the same procedures for review of the safety data collected through at least seven 
days after the first injection of the Group C and D subjects. On the first day of administration of 
that formulation no more than one Group E subject will be vaccinated. For both dose escalation 
safety reviews, to allow progression to Groups C and D and then to Group E, if dose escalation 
halting criteria are met, all vaccine administrations will pause. The Safety Monitoring Committee 
(SMC) will then review the safety data and must approve dose escalation before vaccinations can 
resume. 

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Table 2: Dose Escalation Schedule. 
 
Week 
Group A 
Group B 
Group C 
Group D 
Group E 
Number of subjects receiving first study product injections by week 
1 
9 
2 
9 
3 
4 
Review of safety data collected through day 7 after 1st study product injection for Groups A and B 
5 
9 
6 
9 
7 
8 
 Review of safety data collected through day 7 after 1st study product injection for Groups C and D 
9 
10 
9 

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KEY ROLES 
 
 
 
 
 
Lead Principal 
Investigator: 
Lisa A. Jackson, MD, MPH 
Kaiser Permanente Washington Health Research Institute 
DMID Clinical Project 
Manager: 
Ranjodh Gill, MPH 
Parasitology and International Programs Branch, DMID, 
NIAID 
Statistical and Data 
Coordinating Center: 
The Emmes Company, LLC 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background 
2.1.1 
Schistosomiasis 
Schistosoma species have infected humans since 1500 BC and continue to threaten global public 
health with the highest burden in sub-Saharan Africa (Figure 1). Eight hundred million people 
are at risk in 78 countries, and 240 million are already infected. Seroprevalence studies are 
scarce, but available data indicate that up to 90% of persons living in high-risk areas acquire a 
schistosome infection at some point, usually before 10 years of age, resulting in a high 
prevalence in school-aged children. Of deaths caused by parasites, schistosomiasis ranks second 
only to Plasmodium falciparum malaria, killing 280,000 people annually in sub-Saharan Africa 
alone. 
Figure 1: Infographic on the potential impact of the SchistoShield® vaccine. 
 

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Schistosomiasis is caused by a trematode worm of the Schistosoma genus, a parasitic blood 
fluke.[1] During the infectious stages, they are released from snails in fresh water. Prolonged 
infection can result in complex organ manifestations. Intestinal schistosomiasis is caused by S. 
mansoni and occurs in sub-Saharan Africa, the Mediterranean, the Caribbean, and South 
America. S. intercalatum causes intestinal schistosomiasis and occurs in Central Africa. Oriental 
or Asiatic schistosomiasis is caused by the S. japonicum group of parasites (including S. 
mekongi) and is endemic to Southeast Asia. Finally, S. haematobium causes urinary 
schistosomiasis and is endemic to Africa and the Mediterranean. The life cycle of schistosomes 
starts with the release of cercariae by freshwater snails. Human infection occurs when cercariae 
actively penetrate the skin and enter the body. The larvae invade host blood vessels, develop into 
adult schistosomes and multiply. Female schistosomes release eggs into the bloodstream. Eggs 
may be excreted through urine or feces and contaminate water sources, completing the 
schistosome life cycle. Eggs that are not excreted can become lodged in human tissue and trigger 
immune reactions that result in clinical disease. 
Clinical misclassification of schistosomiasis is common. The current diagnostic gold standard is 
microscopic examination of stool or urine for eggs but is not sensitive enough to identify mild 
infections (i.e., adult worms may not have produced detectable eggs) and 20-30% of infections 
may be missed due to intermittent excretion of eggs in stool or urine resulting in a systematic 
underestimation of the burden.[2,3] Adjusting for diagnostic sensitivity, the global burden of 
schistosomiasis estimated in 2007 was 391-587 million cases.[4] The mainstay of 
schistosomiasis control is preventative and therapeutic administration of the anthelminthic 
praziquantel. However, repeated treatment is needed for curative parasite clearance. A single 
infection does not prevent future infection; as such, the cost-effectiveness of mass-treatment 
programs is compromised when reinfection is common. 
To combat the schistosomiasis burden, large-scale prevention strategies (e.g., mass vaccination 
campaigns) that complement treatment programs are necessary. According to the World Health 
Organization, target groups for large-scale, periodic treatment include school-aged children and 
high-risk adults (e.g., fishermen, farmers, irrigation workers, and other persons who have 
increased contact with infested water) or entire communities living in highly endemic areas. 
Periodic praziquantel treatment has been shown to reduce clinical symptoms; however, there 
remains a gap between those who require and those who receive treatment. According to a 2015 
estimate, only 28% of overall cases requiring treatment received care. An alternative or 
supplementary control method is the reduction of intermediate snail hosts using molluscicides, 
but this is even more challenging and costly since frequent application of molluscicides is 
necessary and logistically challenging.[5] 

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Therefore, an efficacious and safe vaccine, giving long-lasting protection against all forms of 
schistosomiasis, will have a profound impact on infection control. Induction of sterile immunity 
is not a prerequisite for a highly effective schistosome vaccine, as schistosome worms do not 
replicate within their definitive hosts. A vaccine that reduces morbidity or even partially reduces 
worm burden will have a major public health impact.[6,7] A combined control approach that 
couples mass treatment with vaccination will significantly reduce worm loads and break the 
transmission cycle, allowing for the eventual elimination of schistosomiasis.[8-10] 
2.1.2 
SchistoShield® 
The proposed vaccine candidate, SchistoShield® (Sm-p80 [antigen] + GLA-SE [adjuvant 
formulation]), targets the Sm-p80 surface membrane antigen, which is the heavy chain of the S. 
mansoni calcium activated neutral protease (calpain), and includes a Toll-like receptor 4 agonist- 
based adjuvant formulation (GLA-SE). Sm-p80 stands for S. mansoni calpain protein with a 
mass of approximately 80 kDa and GLA stands for Glucopyranosyl Lipid Adjuvant-Stable oil- 
in-water Emulsion. The vaccine antigen is an E. coli – produced recombinant Sm-p80 calpain 
protein from S. mansoni, manufactured, filled, and released by PAI Life Sciences Inc. (Seattle, 
WA). The vaccine adjuvant formulation, GLA-SE, is a synthetic Lipid A – like molecule and 
Toll-like receptor 4 agonist formulated in a squalene emulsion manufactured and released by the 
Infectious Disease Research Institute (IDRI) (Seattle, WA). 
 
Development of effective recombinant protein vaccines for S. mansoni is possible for the 
following reasons: 
• 
Unlike protozoan parasites, helminths such as Schistosoma do not undergo significant 
antigenic variation. 
• 
Schistosoma live as two sexes in the circulation, where they are exposed to antibodies and 
their effector functions. 
• 
While both sexes express Sm-p80 on their surface, the female worms – which cause 
pathology due to egg deposition – have a higher density of Sm-p80 on their surface, making 
them most vulnerable to the action of the vaccine. 
• 
While some regions of the targeted deployment countries have both S. mansoni, from which 
Sm-p80 is derived, and S. haematobium, the causative agent of urinary schistosomiasis, our 
data suggest that cross-species efficacy is induced by the vaccine, likely due to the high level 
of homology between the proteins. 

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• 
Safe and effective adjuvants that preferentially induce TH1 responses are now available; the 
proposed GLA-SE adjuvant has been extensively tested with Sm-p80, as well as in thousands 
of human subjects. 
2.1.3 
Preclinical and Safety Studies 
Sm-p80 has been tested for its vaccine efficacy in different vaccine formulations and approaches. 
These include naked DNA, recombinant protein, and DNA prime/protein boost in three 
experimental animal models of infection and disease (mouse, hamster, and baboon). These Sm- 
p80-based vaccines provided comprehensive coverage against different stages of the parasite’s 
life cycle, including its eggs, schistosomula, and adult worms. Sm-p80 is unique in that it has 
demonstrated desirable outcomes of Sm-p80 vaccination including: 1) prophylactic efficacy 
against S. mansoni (intestinal/hepatic schistosomiasis);[9]; 2) reduction in egg-induced 
tissue/organ pathology;[9] 3) post-exposure therapeutic efficacy by elimination of established 
adult worms in chronic disease;[11] 4) cross species-protection against S. haematobium (urinary 
schistosomiasis)[12] and S. japonicum (Asiatic/oriental disease);[13] 5) long lived immunity as 
Sm-p80 specific IgG titers are present in mice for up to 60 weeks and 5-8 years in baboons;[14] 
and 6) maternal transfer of Sm-p80-specific antibodies in baboons.[14] Sm-p80-specific IgE has 
not been detected in high-risk or infected populations from Africa and South America, thus 
reducing the possibility of hypersensitivity following vaccination with the Sm-p80 vaccine in 
humans. The protective immune response to Schistosoma is thought to be antibody mediated 
with cell-mediated help to skew the antibody isotypes to IgG1 and IgG3. 
This section includes descriptions of preclinical and safety/immunogenicity experiments with the 
Sm-p80 recombinant protein antigen. Summaries of the following studies are included: 
• 
Representative preclinical studies in murine models of schistosomiasis that demonstrate 
protective immunity induced by vaccination; 
• 
Safety, immunogenicity, and efficacy studies of the SchistoShield® vaccine in a nonhuman 
primate model. The Sm-p80-based vaccine was evaluated in 40 baboons (Papio anubis), 
natural hosts of schistosomiasis and the most relevant nonhuman primate model of human 
clinical manifestations of both acute and chronic disease. 
2.1.3.1 
Potency of Sm-p80 in Murine Models 
The rSm-p80 antigen was tested for its prophylactic and anti-pathology efficacy in murine 
challenge models. Briefly, groups of mice were immunized three times, four weeks apart. At 
week twelve, four weeks after the last boost, mice were challenged with 150 cercariae of S. 
mansoni via tail immersion. Serum samples were collected via tail bleed before every 
immunization and before challenge. The mice were sacrificed six to eight weeks after challenge. 

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Protection (P) was calculated by comparing worm burdens from vaccinated (V) and control (C) 
animals by a standard formula: %P = [(CV)/C x 100)]. After sacrifice, liver and intestine samples 
were collected from each animal and digested in 4% KOH. The number of eggs present in the 
tissues and percent reduction in egg production was determined. Antibody responses to Sm-p80 
in immunized mice were estimated by an enzyme-linked immunosorbent assay (ELISA). In sera 
collected from these mice distinct Sm-p80-specific antibody titers were obtained for total IgG. 
Animals immunized with adjuvant alone did not exhibit any significant IgG titers. However, 
robust antigen-specific (Sm-p80) IgG titers were detected in the vaccine group. These titers 
reached end-point titers of 1:1,638,400 at weeks 10 and 12 (Figure 2). These results demonstrate 
that the Sm-p80 antigen produced is highly antigenic when given with GLA-SE. 
The SchistoShield® vaccine was able to significantly reduce the number of worms found in 
experimental animals. The levels of protection (62.69%) recorded are high for a murine model. 
The SchistoShield® vaccine was also able to significantly reduce eggs in both liver and intestine. 
Eggs in the liver and intestine were reduced by 92.57% and 87.46%, respectively, compared to 
control animals. Also significant, the vaccine was again able to preferentially kill female worms. 
Specifically, 89% of female worms were killed in the vaccine group (Figure 3). 
Figure 2: Sm-p80-specific Total IgG Titers in Mice 
 

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Figure 3: Sm-p80 + GLA-SE Vaccine-Mediated Efficacy in Mice. 
 
2.1.3.2 
Safety and Immunogenicity of Sm-p80 + GLA-SE in Non-Human Primates 
There were four independent double-blinded trials, with two groups of baboons (control and 
experimental) in each trial. A total of 10 baboons were randomly and equally divided into either 
control (n=5) or experimental (n=5) groups for each trial. Each baboon in the experimental group 
received 250 μg rSm-p80 formulated in 50 μg GLA-SE while baboons in the control group were 
immunized with 50 μg GLA-SE only. The baboon dose of vaccine was higher than that 
envisioned for the human clinical trial since baboons tend to be hyporesponsive to TLR4 
agonists. Humans respond well to the proposed 5 microgram dose of GLA-SE. All animals 
received prime immunization followed by three boosts at four-week intervals. Four weeks 
following the last immunization, each baboon was percutaneously challenged with 1000 S. 
mansoni cercariae. To allow for disease progression, all baboons remained under observation for 
8 weeks. 
In the baboon trials, no notable changes in blood chemistry were identified. Blood chemistry 
evaluations included a complete blood count (including white blood cell [WBC] count, red blood 
cell count, hemoglobin, hematocrit, and platelet count) and chemistries (including alkaline 
phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase, creatine kinase, 
gamma-glutamyl transferase, amylase, lipase, albumin, total protein, globulin, total and 
fractionated bilirubin, blood urea nitrogen, creatinine, cholesterol, glucose, calcium, phosphorus, 
total carbon dioxide, chloride, potassium, sodium, albumin/globulin ratio, anion gap). 
There were also no notable vaccine-related clinical observations. Specifically, the baboons did 
not show any problems in eating, drinking, urinating, or defecating, they were alert and 
responsive and no abnormal animal behaviors were noted. No neurological/motor problems were 
observed and no signs of swelling, hyperemia, or induration at or around the injection site were 
identified. 

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Sm-p80-specific total IgG levels were evaluated in sera of individual animals for all groups of 
vaccinated baboons at baseline and subsequently post-prime (Week 4), post-boosts (Weeks 8, 12, 
and 16), and finally post-challenge (Week 24) by ELISA (Figure 4). None of the animals had any 
antibody response against Sm-p80 at baseline (Week 0). In animals immunized with adjuvant 
alone no significant antibody responses were detected. In contrast, groups immunized with 
SchistoShield® mounted antibody responses following the first vaccination (Week 4) and strong 
antibody titers were observed in all animals post-boosting and remained high after challenge. 
Figure 4: Kinetics of total Sm-p80-specific antibody in immunized baboons. 
 
 
Panels depict the production of Sm-p80-specific total IgG antibodies in control animals (C, GLA-SE) 
and experimental animals (E, rSm-p80 + GLA-SE) in Trials 1, 2, 3, and 4, respectively. Endpoint 
titers were determined for Weeks 0, 4, 8, 12, 16, and 24. 
 
 
The role of anti-Sm-p80 antibodies and complement activation in S. mansoni juvenile worm 
killing was examined in vitro. Data from the cytotoxicity assay showed that pooled sera from 
baboons immunized with Sm-p80/GLA-SE promoted significant in vitro killing of schistosomula 
(43.75%). Addition of active guinea pig complement to the Sm-p80 sera significantly increased 
the percentage of dead schistosomula to 87.72% (p < 0.001). 

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2.1.3.3 
Efficacy of Sm-p80 + GLA-SE in Non-Human Primates 
The cumulative 40-baboon study yielded a statistically significant reduction of 65.71% 
(p<0.0001) in total worm pairs in animals vaccinated with Sm-p80/GLA-SE (Figure 5A); the 
protection was consistent across four independent experiments (Protection: Trial 1, 61.96%; 
Trial 2, 64.16%; Trial 3, 69.35%; Trial 4, 68.17%). Uniquely, the Sm-p80/GLA-SE vaccine can 
eliminate 93.45% (p<0.0001) of female parasites, and this vaccine-mediated sex-preferential 
killing was similar amongst all the experiments (female worm killing: Trial 1, 93.27%; Trial 2, 
91.16%; Trial 3, 94.01%%; Trial 4, 95.19%). Less than 7% of the egg-producing females 
survived the vaccine effect, resulting in minimal pathology in host tissues/organs, as ascertained 
by highly significant (p<0.0001) reduction in egg retention in liver (91.35%), small intestine 
(85.69%), and large intestine (91.14%) in vaccinated animals (Figure 5B). Additionally, egg 
expulsion in feces was reduced by 40-fold in vaccinated animals; 5 eggs per gram in feces was 
the average output in vaccinated animals, compared to 204 eggs per gram release in control 
animals (Figure 5C). Those eggs that were excreted were impaired in their ability to hatch into 
miracidia, the parasite stage that infects snails to continue the life cycle with a 79.21% inhibition 
of hatching for eggs obtained from vaccinated animals (Figure 5D). 
In summary, the four trials demonstrated that the vaccine is highly efficacious in the baboon 
model and leads to profound killing of pathogenic female worms. 

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Figure 5: Prophylactic efficacy of the Sm-p80 vaccine in baboons. 
 
 
2.1.4 
Safety of GLA-SE 
The 5 µg dose of GLA-SE to be used in this trial is comfortably in the mid-range of tested doses 
of the adjuvant and has been shown to be safe and well tolerated in hundreds of human subjects. 
Preclinical Safety 
As reported in the GLA-SE Investigator Brochure (v5, March 2016) many preclinical and 
nonclinical studies in mice, guinea pigs, rats, rabbits, and non-human primates have 
demonstrated the immunostimulatory properties of GLA-SE with no significant safety signals. 
Thousands of mice have been immunized with candidate antigens for infectious disease vaccines 
(e.g., leishmaniasis, tuberculosis, leprosy, malaria, influenza) formulated in GLA-SE. No safety 
issues have been observed when the following parameters were evaluated: clinical observations 
including general health and mortality; injection site reactions; body weights; food consumption; 
and, gross pathology. In addition, the potential for auto-antibody generation following GLA 

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administration was evaluated through extensive immunohistochemistry assays for immune 
complexes and/or autoimmune pathology, and no signs of detrimental autoimmune effects were 
found. Studies have also assayed for anti-nuclear antibody and have not found abnormal levels in 
GLA-immunized mice. 
More than 300 guinea pigs have been immunized with candidate tuberculosis vaccine antigens 
formulated with GLA. Again, no safety issues have been observed when the following 
parameters were evaluated: clinical observations including general health and mortality; injection 
site reactions; body weights; food consumption; and, gross pathology. In addition, a safety study 
was conducted in guinea pigs in which various GLA adjuvant formulations (oil-in-water 
emulsions, aqueous suspensions, liposomes) were administered without antigen by three 
different injection routes (subcutaneous, intramuscular [IM], and intradermal). Administration of 
GLA-SE by all three routes appeared to be safe and well tolerated. 
GLA-SE has been tested in several safety, immunogenicity, and/or efficacy studies in nonhuman 
primates. The safety parameters evaluated included clinical observations, injection site 
evaluations, body weights, body temperatures, hematology, coagulation, clinical chemistry, and 
immunogenicity. In each study the adjuvant was safe, well tolerated, and increased the immune 
response to the co-administered antigen. No treatment-related adverse effects were observed in 
the safety parameters evaluated except for mild injection site reactions and a mild, transient acute 
phase inflammatory response characterized by increases in C-reactive protein (CRP), fibrinogen, 
and neutrophils. 
GLA-SE has been tested in several toxicity studies in rabbits and rats conducted under GLP 
guidelines. Parameters evaluated included the following: morbidity/mortality; clinical signs; 
injection site reactogenicity; body weights; body temperatures; food consumption; 
ophthalmologic evaluations; clinical chemistry; hematology; coagulation; gross necropsy 
observations; organ weights; histopathology; and, immunogenicity. In these studies, GLA-SE 
was found to be safe, well tolerated, and immunostimulatory. No treatment-related adverse 
effects were observed in the parameters evaluated except for reversible injection site reactions 
(erythema, edema, inflammation) and a mild, transient acute inflammatory response (changes in 
hematologic values, increased fibrinogen levels) in some animals receiving GLA adjuvant 
formulations. 
Clinical Experience 
GLA-SE has been evaluated in numerous completed or ongoing clinical trials. These trials have 
investigated GLA-SE formulated with antigens, including recombinant antigens, developed for 
vaccines against a wide variety of diseases, including leishmaniasis,[15] tuberculosis,[16,17] 
influenza,[18,19] schistosomiasis,[20] and malaria[21]. These clinical trials have evaluated 

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GLA-SE at 0.5, 1, 2, 2.5, 5, 10, or 20 µg dose levels. In these studies, over 1100 subjects have 
received at least one study injection containing GLA-SE. Safety data have not revealed any 
significant safety issues at any dose level tested. These studies have revealed a generally 
acceptable safety profile: 
• 
Study injections are generally well tolerated; 
• 
There have been no serious adverse events (SAEs) related to study injection; 
• 
Injection site reactions are common and may include pain, tenderness, erythema, and 
induration; 
• 
Systemic reactions may include headache, fatigue, anorexia, fever, chills, myalgia, and 
arthralgia; 
• 
Transient elevations in CRP levels were noted in a study of GLA-SE administered with the 
Fluzone influenza vaccine; and 
• 
Hematologic changes may occur (including decreases in hemoglobin, WBC, and 
neutrophils). 
These reactions varied from study to study, were generally mild, resolved quickly, and are 
typical of vaccinations by the IM route. GLA-SE often increases the rate and severity of local 
and systemic reactogenicity compared to the antigen alone. This is consistent with the 
nonclinical animal experience and is to be expected of a potent immunostimulant. 
2.1.5 
GLP Toxicity Studies of SchistoShield® 
This GLP toxicology study was to evaluate the systemic toxicity and local tolerance of the 
SchistoShield® vaccine candidate protein antigen Sm-p80, both with and without GLA-SE, 
when administered by IM injection to New Zealand White rabbits. Serum was also collected for 
immunogenicity evaluations. The study was conducted at Battelle - West Jefferson in accordance 
with FDA Good Laboratory Practice regulations (21 CFR Part 58) and the CPMP guidance 
documents (CPMP/ SWP/ 465/ 95 and CPMP/ ICH 302/ 95). Groups of 20 rabbits (10 female 
and 10 male; 80 total for the study) were immunized with one of four formulations including a 
high-dose (100 µg) of protein alone, a mid-dose of 25 µg with 10 µg adjuvant, a high-dose of 
protein plus 10 µg adjuvant, and a saline control. Each group received four injections given on 
Days 0, 14, 28, and 42. The active product dose levels were selected based on intended mid-dose 
and high-dose to be used in human Phase I trials. 
In this GLP study there were no findings definitively attributed to systemic toxicity of Sm-p80 
with or without GLA-SE. All study animals survived until scheduled humane termination. There 
were no changes in body weights, body temperatures, or food consumption attributed to Sm- 

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p80 with or without GLA-SE. Ophthalmic examinations were normal for all animals prior to the 
first dose administration and prior to each scheduled necropsy. Observed ear discolorations and 
skin abrasions were attributed to blood collection and the clipping of injection sites, respectively. 
With regard to local tolerance, injection site observations were generally similar throughout the 
study for male and female rabbits in groups receiving Sm-p80 with or without GLA-SE. There 
were sporadic grades of 1 (very slight) and 2 (slight) edema at the injection site for rabbits in all 
3 active treatment groups, however all were graded 0 by 72 hour post-injection. The immune 
response was highest in rabbits of both sexes that received injections containing both the high 
dose of Sm-p80 (100 μg) with adjuvant (10 μg GLA-SE). Low doses of Sm-p80 plus adjuvant 
(10 μg GLA-SE) produced higher titers than high dose (100 μg) of Sm-p80 alone justifying the 
use of the adjuvant. There were no major histopathological findings in animals humanely 
terminated 2 days following the fourth (final) administration. Slight increases in fibrinogen and 
C-reactive protein were observed in treatments groups on Day 24. 
This toxicity study indicated that the SchistoShield® vaccine is safe and well tolerated in rabbits 
when administered IM for up to four injections at the highest proposed human dose of the Sm- 
p80 antigen given with GLA-SE. No significant local or systematic toxicity was found. As 
previously reported, general safety assessment of the SchistoShield® vaccine in baboons also 
indicated that the vaccine is safe and well tolerated for up to the highest dose of 250 µg of Sm- 
p80 and 50 µg of GLA-SE, further supporting the observation from the GLP-toxicity study in 
rabbits. Based on the N+1 rule, the GLP-toxicity study in rabbits supports the use of the 
SchistoShield® vaccine in the first-in-human clinical trial for up to three injections at the high 
dose of 100 µg Sm-p80 . 
 
Scientific Rationale 
2.2.1 
Purpose of Study 
The promising results of the preclinical evaluations and the urgent need for an effective 
schistosomiasis vaccine support advancement of the SchistoShield® vaccine candidate to an 
initial Phase 1 human trial in healthy volunteers in the United States. The purpose of this trial is 
to determine the safety, reactogenicity, and immunogenicity in 45 healthy adult subjects of the 
candidate investigational schistosomiasis vaccine. The trial will evaluate four study product 
formulations and two administration schedules, as outlined in Table 1. Subjects will receive three 
IM injections of 0.5 mL of the designated study product formulation, on Days 1, 29, and 57 (28 
days apart) or on a delayed booster dose schedule on Days 1, 29, and 180. 
To determine the need for adjuvant, the study will evaluate one group of subjects who receive 
the Sm-p80 antigen without adjuvant (Group A). The 100 μg antigen dose in Group A reflects 
the highest antigen content proposed for administration with adjuvant in this trial (Group E). 

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Groups B, C, D and E will receive study product, at doses of 10 μg, 30 μg, and 100 μg Sm-p80, 
adjuvanted with 5 μg of the GLA-SE adjuvant. The GLA-SE formulation has been used as a 
vaccine adjuvant in 13 clinical trials (seasonal and pandemic influenza, leishmaniasis, 
schistosomiasis, malaria, tuberculosis). Approximately 1100 subjects have received at least one 
study injection containing GLA-SE, with GLA doses ranging from 0.5 to 20.0 µg. This vaccine 
adjuvant is well-tolerated with generally only mild local and systemic adverse events (AEs) and 
no significant AEs related to the product. The adjuvant dose of 5 µg is selected for this trial as 
this dose is in the mid-range of doses evaluated, has been shown to increase antibody levels and 
cellular immune responses, and has been evaluated in multiple clinical trials, including trials 
administering three vaccinations, demonstrating an acceptable safety profile. 
The preclinical studies of SchistoShield® do not inform the selection of antigen dose for this 
study, as non-human primates require much higher doses of antigen and adjuvant than humans 
due to the tolerizing effects of their environments. In the baboon studies, the animals that 
received active study product were given three injections, four weeks apart, of a formulation of 
250 µg Sm-p80 in 250 µg CpG-ODN, a Toll like receptor 9 agonist. In other vaccine trials in 
humans, GLA-SE adjuvant has been administered with antigen doses in the range of 
approximately 10 to 100 µg micrograms. The lower antigen doses appear to be best to elicit T 
cell responses while the higher doses tend to elicit better humoral responses. Since it appears that 
the primary mechanism of action of SchistoShield® is mediated by humoral responses, this study 
will evaluate a range of Sm-p80 doses from 10 to 100 µg. 
Study Groups A, B, D, and E will receive study vaccinations on a Day 1, 29 and 57 schedule (28 
days between vaccinations) while Study Group C will receive study vaccinations on a Day 1, 29 
and 180 delayed booster schedule. The comparison of the same vaccine formulation, 30 μg Sm- 
p80 + 5 μg GLA-SE, given on different schedules to Groups C and D will allow assessment of 
possible differences in immune responses to a schedule with a 5 month versus a 28-day interval 
between the second and third vaccinations. Longer intervals prior to the boost vaccination have 
been associated with enhanced immunogenicity, for example with H5 influenza vaccines given 
as a two-dose series either 28 days or 180 days apart[22] and for recombinant hepatitis B vaccine 
given on a 0, 1, and 2 month versus a 0, 1, and 6 month schedule.[23] 
2.2.2 
Study Population 
 
The study population will include 45 healthy adults 18 through 55 years of age, inclusive, who 
have no prior exposure to schistosomes and have no history of treatment for schistosomiasis. The 
study population will be drawn from the membership of the Kaiser Permanente Washington 
health plan and from the population of the greater Seattle, Washington area and will exclude 
women who are pregnant or who are breast feeding a child. 

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Potential Risks and Benefits 
2.3.1 
Potential Risks 
 
The potential risks of participating in this trial are those associated with having blood drawn, the 
IM injection and possible reactions to the Sm-p80 recombinant antigen, with or without GLA-SE 
adjuvant, and the possibility of a breach of confidentiality. 
 
Drawing blood may cause transient discomfort and fainting. Fainting is usually transient and 
managed by having the subject lie down with legs elevated. Bruising at the blood draw site may 
occur but can be prevented or lessened by applying pressure to the blood draw site for a few 
minutes after the blood is taken. IM injection may also cause transient discomfort and fainting. 
Drawing blood and IM injection may cause infection. The use of aseptic (sterile) technique will 
make infection at the site where blood will be drawn or where the study vaccination will be 
given extremely unlikely. 
 
There is a small amount of risk to subjects who report that they are in good health but who have 
an unknown health problem at the time of screening. This trial will screen by physical exam, 
medical history, vital signs, and clinical laboratory tests, including WBC, hemoglobin, platelets, 
and ALT, as well as screening for HIV, hepatitis B, and hepatitis C infections. 
 
For this first-in-human trial of the SchistoShield® vaccine there is no human safety data with 
which to estimate the potential risks of the study product formulations to be evaluated in this 
trial. Preclinical evaluations, including evaluations in non-human primates, have not identified a 
safety signal associated with administration of the Sm-p80 recombinant protein antigen (Sections 
2.1.3.2 and 2.1.5). 
 
There is potential for AEs to occur more frequently in the adjuvanted vaccine groups [24] than in 
the non-adjuvanted group and there is potentially a higher risk for AEs to occur more frequently 
in the higher dose Sm-p80 antigen groups than in the lower dose antigen groups. GLA-SE 
adjuvant has been evaluated in humans with other vaccine antigens and has been found to have 
an acceptable safety profile, as described in Section 2.1.4. 
Expected AEs associated with GLA-SE administration include injection site reactions that may 
include pain, tenderness, erythema and induration, systemic reactions that may include headache, 
fatigue, anorexia, fever, chills, myalgia, and arthralgia. Transient hematologic changes have been 
observed in preclinical evaluations and in human clinical trials, including decreases in 
hemoglobin, WBC, and neutrophils. Transient elevations of CRP have been noted in preclinical 
evaluations and in one human clinical trial, in which GLA-SE was formulated with the Fluzone 
influenza vaccine. 

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Acute and potentially life-threatening allergic reactions, such as anaphylaxis, are also possible. 
These reactions occur in about 1 in 4 million people given a vaccination. These reactions can 
manifest as skin rash (hives), swelling around the mouth, throat, or eyes (angioedema), difficulty 
breathing (bronchospasm), a fast pulse (tachycardia), or decrease in blood pressure 
(hypotension). If these reactions occur, they can usually be stopped by the administration of 
emergency medications by the study personnel. As with any vaccine or medication, there is a 
very small chance of a death, although researchers do not expect this to occur. 
 
Subjects will be asked to provide protected health information (PHI). All attempts will be made 
to keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the subject’s PHI. All study records will be kept in a locked file 
cabinet or maintained in a locked room at the study site. Electronic files will be password- 
protected. Only people who are involved in the conduct, oversight, monitoring, or auditing of 
this trial will be allowed access to the PHI that is collected. Any publications from this trial will 
not use information that will identify subjects by name. Organizations that may inspect and/or 
copy research records maintained at the participating sites for quality assurance and data analysis 
include groups such as the local IRB, NIAID, and the FDA. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This web site will not include information that can identify subjects. 
 
There may be other risks, discomforts, or side effects that are unknown at this time. 
 
2.3.2 
Potential Benefits 
There is no anticipated direct benefit to subjects resulting from participation in this trial. 
There is potential benefit to society by adding to knowledge of possible interventions that could 
decrease the global morbidity and mortality from schistosomiasis. 

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
This is a Phase 1, open-label, dose-escalation clinical trial to evaluate the safety, reactogenicity, 
and immunogenicity of the Sm-p80 + GLA-SE candidate schistosomiasis vaccine 
(SchistoShield®) in healthy adults 18 through 55 years of age. The Sm-p80 antigen is a 
recombinant protein produced in E. coli and GLA-SE is an immunological adjuvant. 
Five treatment groups, each including nine subjects, will receive three intramuscular (IM) 
injections of 0.5 mL of the designated study product on either Days 1, 29, and 57 or on Days 1, 
29, and 180 (Table 1). Group A (unadjuvanted comparator) will receive 100 μg Sm-p80 alone on 
Days 1, 29, and 57, Group B (low dose standard schedule) will receive 10 μg Sm-p80 + 5 μg 
GLA-SE on Days 1, 29 and 57, Group C (mid dose delayed booster) will receive 30 μg Sm-p80 
+ 5 μg GLA-SE on Days 1, 29 and 180, Group D (mid dose standard schedule) will receive 30 
μg Sm-p80 + 5 μg GLA-SE on Days 1, 29, and 57, and Group E (high dose standard schedule) 
will receive 100 μg Sm-p80 + 5 μg GLA-SE on Days 1, 29 and 57. Dose escalation will proceed 
as described in the Protocol Summary. 
Reactogenicity will be measured by the occurrence of solicited injection site and systemic 
reactions from the time of each study product injection through seven days after each study 
product injection. Unsolicited AEs of all severities, and concomitant medications, will be 
collected from the time of each study product injection through the next 28 days. During periods 
of follow-up outside of the 28-day post-vaccination interval, only SAEs, medically attended 
adverse events (MAAEs), new onset chronic medical conditions (NOCMCs), and potentially 
immune-mediated medical conditions (PIMMCs) will be collected. Clinical laboratory 
evaluations for safety will be performed on venous blood collected prior to, and approximately 
seven days after, each study vaccination. 
Immunogenicity testing will include measuring titers of total IgG against the Sm-p80 protein by 
ELISA. Gene expression will be evaluated using RNA Seq analysis from whole blood. 
For additional details on study procedures and evaluations and study schedule by study 
visits/days, see Sections 6 and 7 and Table 8 and Table 9. 

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Study Objectives 
3.2.1 
Primary 
• 
To assess the safety and reactogenicity following receipt of three doses of 1) 100 µg Sm-p80 
(unadjuvanted), 2) 10 µg Sm-p80 + 5 µg GLA-SE, 3) 30 µg Sm-p80 + 5 µg GLA-SE, and 4) 
100 µg Sm-p80 + 5 µg GLA-SE administered intramuscularly on Days 1, 29, and 57 and 5) 
30 µg Sm-p80 + 5 µg GLA-SE administered on Days 1, 29, and 180. 
3.2.2 
Secondary 
• 
To assess anti- Sm-p80 IgG antibody responses from samples collected at specified time 
points. 
3.2.3 
Exploratory 
• 
To assess innate and adaptive immune signatures from samples collected at specified time 
points. 
 
Study Endpoints or Outcome Measures 
3.3.1 
Primary 
• 
Occurrence of study vaccine-related SAEs from the time of the first study vaccination 
through approximately 12 months after the last study vaccination. 
• 
Occurrence of solicited injection site and systemic reactogenicity events from the time of 
each study vaccination through 7 days after each study vaccination. 
• 
Occurrence of clinical safety laboratory AEs from the time of each study vaccination through 
approximately 28 days after each study vaccination. 
• 
Occurrence of all unsolicited AEs, regardless of the assessment of seriousness or relatedness, 
from the time of each study vaccination through 28 days after each study vaccination. 
• 
Occurrence of SAEs, MAAEs, NOCMCs, and PIMMCs from the time of the first study 
vaccination through approximately 12 months after the last study vaccination. 
3.3.2 
Secondary 
• 
For Sm-p80 IgG antibodies, number of subjects achieving seroconversion, defined as a 
fourfold rise from baseline, at approximately 28 days after the first, second, and third study 
vaccinations. 

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• 
Geometric mean titers of serum Sm-p80 IgG antibodies from samples collected at 7 and 28 
days after each vaccination, and at 124 days after the last vaccination. 
3.3.3 
Exploratory 
• 
Identification and characterization of gene expression changes as measured using RNA-seq 
analysis from whole blood relative to last vaccination. 
o Days 8 and 29 vs. Day 1, and Day 36 vs. Day 29 for all study groups 
o Day 57 vs. Day 29, Day 64 vs. Day 57 for Groups A, B, D, and E 
o Day 187 vs. Day 180 for Group C 
• 
Identification and characterization of gene expression changes as measured using RNA-Seq 
relative to last vaccination that correlate with peak Sm-p80 IgG antibody levels. 
o Days 8 and 29 vs. Day 1, and Day 36 vs. Day 29 for all study groups 
o Day 57 vs. Day 29, Day 64 vs. Day 57 for Groups A, B, D, and E 
o Day 187 vs. Day 180 for Group C 

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STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
The vaccine product is a two-component system comprised of Sm-p80 antigen and GLA-SE 
adjuvant. 
Sm-p80 for injection 
Sm-p80 is a recombinant protein produced in E. coli bacteria. The protein antigen is the large 
subunit of the S. mansoni calcium-activated neutral protease, calpain. The Sm-p80 protein is 
formulated and lyophilized to yield the vaccine antigen, Sm-p80 for Injection. The final 758 
amino acid protein antigen has a predicted mass of approximately 87kDa. 
GLA-SE Adjuvant 
GLA-SE is a synthetic Monophosphoryl Lipid A-like molecule which is a Toll-like receptor 4 
agonist formulated in a SE to produce GLA-SE. 
Sm-p80 + GLA-SE 
Sm-p80 + GLA-SE contains the antigen and adjuvant. After reconstitution of the antigen with 
water-for-injection (WFI) and mixing with the liquid adjuvant, it is ready for administration to 
the study participant. 
4.1.1 Formulation, Packaging, and Labeling 
Sm-p80 for Injection 
Sm-p80 for Injection is formulated as a lyophilized cake in glass vials and appears white to off- 
white cake. Each 3 mL glass vial contains 125 µg of Sm-p80. Reconstitution of Sm-p80 with 
WFI results in a clear, colorless solution. Vials are for single-use only. 
GLA-SE Adjuvant 
GLA-SE Adjuvant is formulated as 20 µg/mL GLA in a 4% SE and is supplied as single use 
glass vials. GLA-SE appears as a milky-white liquid. Each 2 mL vial contains a fill volume of 
0.4 mL. 

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Sm-p80 + GLA-SE for Injection 
Sm-p80 for Injection and GLA-SE adjuvant are added to each other in a 1:1 ratio and mixed by 
inverting the vial or gentle pipetting up and down. This yields a 2% oil emulsion with GLA at 10 
µg/mL and Sm-p80 at the desired concentration for the various dose levels of the antigen. After 
mixing, the dissolved Sm-p80 antigen and the GLA-SE emulsion appears as a translucent milky 
white liquid. 
Sterile Water for Injection, USP 
The sterile WFI is nonpyrogenic and contains no bacteriostatic, antimicrobial agent or added 
buffer. This product will be used to dilute the vaccine (Sm-p80) and will be supplied as a single- 
dose vial. 
Each study product (Sm-p80 and GLA-SE) will be labeled according to manufacturer and 
regulatory specifications and include the statement: “Caution: New Drug-Limited by Federal 
Law to Investigational Use.” 
4.1.2 
Product Storage and Stability 
Sm-p80 for Injection 
Sm-p80 for Injection must be stored between 2°C to 8°C; excursions up to 25°C are permitted 
for 24 hours. 
GLA-SE Adjuvant 
GLA-SE adjuvant is provided as a SE and must be stored between 2°C to 8°C; excursions up to 
25°C are permitted, but the product should never be frozen. cGMP adjuvant lots have been on a 
stability program for over 5 years and are stable for this period when properly stored at 2°C to 8°C. 
Sm-p80 + GLA-SE for Injection 
The vaccine product (antigen + adjuvant) is only produced upon admixture prior to 
administration. A syringe stability study was completed to confirm stability of the admixture for 
at least 4 hours at up to 25°C. 

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Sterile Water for Injection, USP 
The sterile WFI vials are stored at 20°C to 25°C [See USP Controlled Room Temperature]. 
 
Acquisition/Distribution 
Sm-p80 for Injection 
Sm-p80 for Injection will be provided by PAI Life Sciences Inc and distributed through the 
DMID Clinical Material Services (CMS), Fisher BioServices. 
GLA-SE Adjuvant 
The GLA-SE adjuvant is purchased from a commercial supplier (IDRI) and distributed through 
the DMID Clinical Material Services (CMS), Fisher BioServices. 
Sterile Water for Injection, USP 
The sterile WFI, USP will be supplied by the DMID CMS, Fisher BioServices. 
 
Dosage/Regimen, Preparation, Dispensing and Administration of 
Study Intervention/Investigational Product 
 
Preparation 
Study product preparation, including vaccine dilutions, and admixing for the various dosing 
groups, will be performed by the site pharmacist using aseptic technique under a biological 
safety cabinet or laminar flow hood on the same day of study vaccine administration. See the 
protocol-specific MOP for detailed information on the preparation, labeling, and storage of study 
product for each Study Group. 
The research pharmacist will visually inspect the study products upon receipt and prior to use. If 
the study product(s) appear(s) to have been damaged, contaminated or discolored, contain visible 
particulate matter or if there are any concerns regarding its integrity, the pharmacist will not use 
the affected study product(s). The affected study product(s) will be quarantined as per storage 
requirements and labeled as ‘Do Not Use’ (until further notice). The site PI or responsible person 
will immediately contact the DMID Product Support Team (see MOP for contact information) 
and DMID Clinical Project Manager for further instructions before any additional study 
vaccinations are administered. Based on the information collected, DMID and/or the 
manufacturer will determine whether the affected study product(s) can be used. If it cannot be 
used, the site will receive specific instructions on how to return the affected study product(s) to 

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the DMID CMS or destroy it on site. If the study product is unusable, study personnel will use 
another vial from the study supply. Replacement vials may be requested by contacting DMID. 
Additional instructions for quarantine and DMID contact information are provided in the 
protocol-specific MOP. 
For Groups B, C, D, and E the Sm-p80 will be appropriately formulated and mixed with diluted 
GLA-SE adjuvant. Group A participants will receive Sm-p80 (diluted to the appropriate 
concentration) without adjuvant. Once diluted, the unadjuvanted Sm-p80 vaccine must be used 
within 24 hours. The Sm-p80 plus GLA-SE adjuvant admixtures must be used within 4 hours of 
preparation. The four-hour window begins when the final formulated preparation is mixed and 
drawn into a syringe for administration to a study participant. The time of preparation and time 
of administration should be noted in the source documentation. Both the diluted vaccine and 
vaccine plus adjuvant admixture will be held at 2°C to 25°C. Study product will be administered 
within 30 minutes after dispensing from temperature-controlled storage. 
 
Administration 
 
See the protocol-specific MOP for detailed information on the administration of study product 
for each group. Each dose of study vaccine will be administered as a single 0.5 mL IM injection 
in the deltoid muscle of the participant’s arm. 
Participants will be observed in the clinic for a minimum of 30 minutes following the study 
product injection. After 30 minutes, the injection site will be examined and the participant will 
be questioned about the presence of any localized or generalized reactogenicity symptoms. Any 
spontaneous AEs that occur will be assessed. Participants will be instructed to complete a 
symptom Memory Aid for seven days post vaccination to record symptoms and to inform 
investigators immediately if they experience symptoms that may require medical attention. 
Participants may be instructed to return to the clinic if they feel febrile on any individual day or 
if they develop any severe reactions following vaccination. 
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
Once received, study products will be stored in and dispensed by the Investigational Pharmacy. 
The Food and Drug Administration (FDA) requires accounting for the disposition of all 
investigational products. The Investigator is responsible for ensuring that a current record of 
product disposition is maintained, and product is dispensed only at an official study site by 
authorized personnel as required by applicable regulations and guidelines. Records of product 

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disposition, as required by federal law, consist of the date received, date administered, quantity 
administered, and the subject number to whom the drug was administered. 
The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the investigational product. The pharmacy records must be available 
for inspection by the DMID monitoring contractors and are subject to inspection by a regulatory 
agency (e.g., the FDA) at any time. An assigned Study Monitor will review the pharmacy 
records. 
Unused reconstituted investigational product vials will be stored at 2°C to 25°C in the 
Investigational Pharmacy until clinical trial accountability is completed. At study termination, all 
unused investigational product will be disposed in accordance with the MOP following complete 
drug accountability and monitoring. 
 
Modification of Study Intervention/Investigational Product for a 
Participant 
The study product will be administered to enrolled participants according to the study schedule. 
There is no planned modification of a study product administration for participants, with the 
exception that participants who have received a study product injection and who become 
ineligible for further study product injections (Section 5.2.1) will be precluded from these study 
procedures. Every effort will be made to follow vaccinated participants for safety evaluations. 

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SELECTION OF SUBJECTS AND STUDY 
ENROLLMENT AND WITHDRAWAL 
 
The study population of 45 subjects will be enrolled from a population of healthy, Schistosoma- 
naïve subjects aged 18 through 55 years at a single study site in Seattle, Washington. 
Subject Inclusion and Exclusion Criteria must be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID-sponsored studies. 
Questions about eligibility will be directed toward the DMID Medical Officer. 
 
Eligibility Criteria 
5.1.1 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in this 
study. 
1. Male or non-pregnant female 18 through 55 years of age, inclusive, at the time of consent. 
2. Able and willing to participate for the duration of the study and able to understand and comply 
with planned study procedures. 
3. Able and willing to provide written (not proxy) informed consent. 
 
4. Is in good health, as judged by the investigator, and determined by medical history and physical 
examination*. 
* Existing medical diagnoses or conditions (except those in the Subject Exclusion 
Criteria) must be deemed as stable. A stable medical condition is defined as no change in 
prescription medication, dose, or frequency of medication in the last three months (90 
days) and health outcomes of the specific disease are considered to be within acceptable 
limits in the last six months (180 days). Any change due to change of health care 
provider, insurance company, or that is done for financial reasons, as long as in the same 
class of medication, will not be considered a violation of this inclusion criterion. Any 
change in prescription medication due to improvement of a disease outcome, as 
determined by the site PI or appropriate sub-investigator, will not be considered a 
violation of this inclusion criterion. Subjects may be on chronic or as needed (prn) 
medications if, in the opinion of the site PI or appropriate sub-investigator, they pose no 
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Topical, nasal, and inhaled medications (with the exception of some uses of 
corticosteroids as outlined in the Subject Exclusion Criteria), vitamins, and 
contraceptives are permitted. 
5. Women of childbearing potential* must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test within 24 hours prior to each study product injection. 
*Not sterilized via bilateral tubal ligation, bilateral oophorectomy, or hysterectomy, or, if 
menopausal, still menstruating or < 1 year of the last menses 
6. Women of childbearing potential must have used an acceptable form of contraception* in the 
30 days prior to their first study product injection. 
*Acceptable single forms of contraception include abstinence from sexual activity that 
could lead to pregnancy, monogamous relationship with vasectomized partner who has 
been vasectomized for six months or more prior to enrollment, successful Essure® 
placement (permanent, non-surgical, non-hormonal sterilization), intrauterine devices, 
and hormonal methods, including the birth control patch, shot (Depo-Provera), pills, the 
vaginal ring (NuvaRing), and the contraceptive implant (Nexplanon). Acceptable barrier 
methods include diaphragm or cervical cap with spermicide and the contraceptive 
sponge. 
7. Women of childbearing potential must agree to continue use of an acceptable form of 
contraception through 30 days after their last study product injection. 
8. Weight ≥50 kg and body mass index (BMI) < 35.0 kg/m2 
9. Vital signs (oral temperature, pulse, and blood pressure) are all within normal protocol- 
defined ranges.* 
* The normal protocol-defined ranges for vital signs include (a) oral temperature less 
than 38°C (100.4°F), (b) pulse no greater than 100 bpm, (c) systolic blood pressure 85 to 
150 mmHg, inclusive, and (d) diastolic BP ≤ 100 mmHg. 
10. Screening clinical lab values are all within normal protocol-defined reference ranges. 
*The normal protocol-defined ranges for laboratory tests include (a) ALT of < 47 IU/L, 
(b) creatinine less than or equal to the laboratory upper limit of normal, (c) WBC ≥3.80 
x103/UL and ≤13.00 x103/UL, (d) hemoglobin 11.5 g/dL or greater for females or 12.6 
g/dL or greater for males, (e) platelets between 131 x103/UL and 415 x103/UL, inclusive. 

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5.1.2 
Subject Exclusion Criteria 
Subjects must not meet any of the exclusion criteria at baseline to be eligible for enrollment in 
this study. 
1. Has had known schistosomiasis infection or has traveled to an endemic area for 
schistosomiasis infection and, during that travel, was potentially exposed to a Schistosoma 
species. 
2. Has been treated for schistosomiasis. 
3. Has previous exposure to schistosome vaccines or experimental products containing GLA- 
SE. 
4. Female subjects who are breastfeeding a child, or who plan to breastfeed a child from the 
first study product injection through 30 days after the last study product injection. 
5. Asthma, other than mild, well-controlled asthma* 
*Cold or exercise-induced asthma controlled with inhaled medications other than inhaled 
corticosteroids is permissible. Subjects should be excluded if they require daily 
bronchodilator use, or have had an asthma exacerbation requiring oral/parenteral steroid 
use or have used theophylline or inhaled corticosteroids in the past year 
6. Known atherosclerotic cardiovascular disease or history of myocardial infarction, 
pericarditis, or myocarditis. 
7. Diabetes mellitus 
8. History of a psychiatric condition that may make study compliance difficult, such as 
schizophrenia, or poorly controlled bipolar disorder* 
*Includes persons with psychoses or history of suicide attempt or gesture in the 3 years 
before study entry or an ongoing risk for suicide. 
9. Chronic or active neurologic condition (including seizures* and migraine headaches**). 
*Seizure within the past 5 years 
**Four or more migraine headaches in the past 12 months that interfered with normal 
daily activity or any migraine headache in the past 5 years that required emergency or 
inpatient medical care. 
10. Autoimmune disease* 

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*Autoimmune hypothyroidism with or without replacement therapy, and vitiligo or mild 
eczema or psoriasis not requiring chronic therapy, are permissible. 
11. Known or suspected congenital or acquired immunodeficiency including anatomic or 
functional asplenia* or immunosuppression as a result of underlying illness or treatment. 
*Any splenectomy is exclusionary. 
12. Use of alcohol or drugs that, in the opinion of the investigator, may interfere with ability to 
comply with the protocol or increase risk to subject’s health during the study period. 
13. Active neoplastic disease* 
*Subjects with a history of malignancy may be included if treated by surgical excision, or 
by chemotherapy or radiation therapy and has been observed for a period that in the 
investigator’s estimation provides a reasonable assurance of sustained cure (not less than 
36 months). Cervical neoplasia under surveillance and non-melanoma skin cancer are not 
exclusionary. 
14. Chronic topical or systemic corticosteroid use* 
*Corticosteroid nasal sprays for allergic rhinitis are permissible. Persons using a topical 
corticosteroid for a limited duration for mild uncomplicated dermatitis such as poison ivy 
or contact dermatitis prior to enrollment may be enrolled the day after their therapy is 
completed. Oral or parenteral (intravenous, IM, subcutaneous) corticosteroids given for 
non-chronic conditions not expected to recur are permissible if, within the year prior to 
enrollment, the longest course of therapy was no more than 14 days and no oral or 
parenteral corticosteroids were given within 30 days prior to enrollment. Intraarticular, 
bursal, tendon, or epidural injections of corticosteroids are permissible if the most recent 
injection was at least 30 days prior to enrollment. Topical or systemic corticosteroid use 
for study related AEs is not exclusionary. 
15. Known contraindication to repeated phlebotomy* 
*Such as minimal venous access or recent history of anemia 
16. Receipt or planned receipt of inactivated vaccine or allergy desensitization injection within 
14 days before or after a study product injection. 
17. Receipt or planned receipt of live attenuated vaccine within 28 days before or after a study 
product injection. 

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18. Receipt of blood products or immunoglobulin within six months prior to, or donation of a 
unit of blood within two months prior to, the first study product injection. 
19. Receipt of any experimental agent* within 30 days prior to screening or planned receipt prior 
to the last study visit**. 
*Vaccine, drug, biologic, device, blood product, or medication. 
**Receipt of experimental COVID-19 related products are not necessarily exclusionary 
and will be evaluated on a case-by-case basis. 
20. Plan to undergo surgery (elective or otherwise) within six months after study enrollment. 
21. Plans to enroll in another interventional clinical trial* at any time during the study period. 
*Includes trials evaluating interventions such as a drug, biologic, or device. 
22. Positive confirmatory test for HIV infection. 
23. Positive serologic test for hepatitis B surface antigen (HBsAg). 
24. Positive confirmatory test for hepatitis C virus (HCV) infection. 
25. Acute febrile illness (oral temperature ≥ 38°C) or other acute illness within three days prior 
to study product injection.* 
*Note for afebrile, acute illness only: If a subject is afebrile, his/her acute illness is nearly 
resolved with only minor residual symptoms remaining, and, in the opinion of the site PI 
or appropriate sub-investigator, the residual symptoms will not interfere with the ability 
to assess safety parameters as required by the protocol, the subject may receive study 
product injection without further approval from the DMID Medical Officer. 
26. Not willing to avoid donating blood during the study. 
27. Has any condition that would, in the opinion of the site investigator, place the subject at an 
unacceptable risk of injury or render the subject unable to meet the requirements of the 
protocol. 

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Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination 
5.2.1 
Withdrawal from the Study or Discontinuation of the Study Product 
Subjects may voluntarily withdraw their consent for study participation at any time without 
penalty or loss of benefits to which they are otherwise entitled. 
An investigator may also withdraw a subject from receiving the study product for any reason. 
Follow-up safety evaluations will be conducted if the subject agrees. If a subject withdraws or is 
withdrawn prior to completion of the study, the reason for this decision must be recorded in the 
electronic case report forms (eCRFs). 
The reasons, might include, but are not limited to the following: 
• Subject meets individual halting criteria (specified in Section 8.6.2). 
• Subject develops a medical disease or condition, or new clinical finding(s) for which 
continued participation, in the opinion of the investigator might compromise the safety of the 
subject, interfere with the subject's successful completion of this study, or interfere with the 
evaluation of responses. 
• The study is terminated. 
• Presence of signs or symptoms that could confound or confuse assessment of study product 
reactogenicity. 
• As deemed necessary by the site PI or appropriate sub-investigator for noncompliance or 
other reasons. 
• Subject refuses further study product injections. 
• Subject withdraws consent. 
• Subject lost to follow-up. 
The primary reason for withdrawal from this trial will be recorded on the Study Status eCRF. 
Subjects will be encouraged to complete the Early Termination Visit. The Early Termination 
Visit procedures are listed in Section 6.3.2. 
 
Although subjects are free to withdraw at any time or may be withdrawn by the investigator at 
any time, those subjects who received one or more doses of study product will be encouraged to 
remain in this trial for follow-up safety assessments (which may be conducted by phone call 

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rather than in person) continuing through approximately 12 months after their last study 
vaccination. These subjects will also be encouraged to provide venous blood samples for 
humoral immunogenicity assays and clinical safety laboratory testing if within 28 days after the 
last study vaccination. See the protocol-specific MOP for alternate follow-up requirements. 
 
The investigator should be explicit regarding study follow-up (e.g. safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product. If the subject 
consents, every attempt will be made to follow all AEs through resolution. The procedures that 
collect safety data for the purposes of research must be inclusive in the original informed consent 
form (ICF) or the investigator may seek subsequent informed consent using an IRB-approved 
ICF with the revised procedures. 
 
In the case of subjects who fail to appear for a follow-up safety assessment, efforts (i.e., three 
documented contact attempts via phone calls made on separate occasions and followed by a 
certified letter) will be made to locate or recall them, or at least to determine their health status. 
These efforts will be documented in the subject’s study records. 
 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study. 
5.2.2 
Subject Replacement 
Subjects who withdraw, or are withdrawn from this study, or are lost to follow-up after 
administration of the study product will not be replaced. Subjects who withdraw, or are 
withdrawn from this study, or are lost to follow-up after signing the ICF but before 
administration of the study product may be replaced. 
5.2.3 
Study Termination 
The NIAID has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 
• 
Incidence or severity of AEs indicating a potential health hazard. 
• 
Data recording is inaccurate or incomplete. 
• 
The Investigator has not adhered to the protocol or applicable regulatory guidelines in 
conducting the study. 
 
In addition, the study may be discontinued at the discretion of the U.S. FDA or the study site, or 
due to natural disaster. 

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If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB. 

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STUDY PROCEDURES 
 
The Schedules of Events are included as Table 7, Table 8, and Table 9 in Appendix A. Refer also 
to Section 4 and Section 8. 
Clinical assessment of subjects may be performed by any clinician licensed to make medical 
diagnoses and listed on the Form FDA 1572 as the site PI or a sub-investigator. 
 
Screening, Visit 00 (Day -30 to Day -1) 
All subjects will have a screening visit in the 30 days prior to their first study product injection 
visit. Screening laboratory evaluations with abnormal values may be repeated during this period 
only as specified in Section 7.2.1. 
Subjects who are not enrolled within the 30-day window after the screening visit may be 
rescreened to refresh the window. 
Written informed consent will be obtained prior to conducting any screening procedures. A 
single consent form will be used to document consent to screening and to participation in the 
study. 
The following procedures will be performed at the initial screening visit (Table 7): 
• 
Subjects will be provided with a description of this trial (purpose and study procedures) and 
asked to read and sign the ICF. The ICF will be signed prior to performing any study 
procedures, including any screening procedures. 
• 
Demographic information will be obtained by interview of subjects. 
• 
Eligibility criteria will be reviewed with subjects and eligibility assessed by review of the 
inclusion and exclusion criteria. 
• 
A complete medical history will be obtained and all concomitant medications taken in the 
prior 60 days will be identified in order to determine the stability of chronic diseases and 
eligibility. Medications reported in the eCRF are limited to those taken within 30 days prior 
to the first study vaccination. 
• 
Vital signs, including oral temperature, blood pressure, and pulse, will be obtained to ensure 
eligibility. Subjects must not eat or drink anything hot or cold, or smoke, within 10 minutes 
prior to oral temperature measurement. 
• 
Height and weight will be obtained to calculate BMI. 

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• 
A physical examination that assesses general appearance and the following areas/systems: 
skin, lymph nodes, HEENT (head, ears, eyes, nose, and throat), neck, cardiovascular, 
pulmonary, abdomen, extremities, musculoskeletal, and neurological, will be performed by a 
study clinician licensed to make medical diagnoses and listed on the Form FDA 1572 as the 
site PI or sub-investigator. 
• 
Venous blood will be collected for screening laboratory tests (WBC, hemoglobin, platelets, 
creatinine, ALT, HIV-1/HIV-2 testing, anti-HCV antibody, HBsAg, and pregnancy test for 
female subjects of childbearing potential) in volumes as specified in Table 7. 
• 
HIV test counseling will be provided. 
• 
For women of childbearing potential, contraceptive methods will be reviewed to ensure 
eligibility, recent menstrual history will be obtained, and pregnancy avoidance counseling 
will be provided. 
The following procedures will be performed if the screening visit is repeated to re-screen the 
subject if they are not enrolled within the 30-day window: 
• 
Eligibility criteria will be reviewed with subjects and eligibility assessed by review of the 
inclusion and exclusion criteria. 
• 
A complete medical history will be obtained and all concomitant medications taken in the 
prior 60 days will be identified in order to determine the stability of chronic diseases and 
eligibility. Medications reported in the eCRF are limited to those taken within 30 days prior 
to the first study vaccination. 
• 
Vital signs, including oral temperature, blood pressure, and pulse, will be obtained to ensure 
eligibility. Subjects must not eat or drink anything hot or cold, or smoke, within 10 minutes 
prior to oral temperature measurement. 
• 
If indicated, a targeted physical examination will be performed. 
• 
Venous blood will be collected for screening laboratory tests (WBC, hemoglobin, platelets, 
creatinine, ALT, and pregnancy test for female subjects of childbearing potential) in volumes 
as specified in Table 7. Testing for HIV-1/HIV-2, anti-HCV antibody, and HBsAg should be 
repeated only if the previous testing was more than six months earlier. 
• 
For women of childbearing potential, contraceptive methods will be reviewed to ensure 
eligibility, recent menstrual history will be obtained, and pregnancy avoidance counseling 
will be provided. 

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Visit 01 Day 01, Enrollment and First Study Product Injection, 
Clinic Visit 
Prior to the study product injection, the following procedures will be performed: 
• 
Medical history and concomitant medications will be reviewed. 
• 
A targeted physical examination will be performed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator, if 
indicated by medical history. 
• 
Vital signs, including oral temperature, blood pressure, and pulse, will be obtained to ensure 
eligibility and establish baseline. Subjects must not eat or drink anything hot or cold, or 
smoke, within 10 minutes prior to oral temperature measurement. 
• 
Inclusion/exclusion criteria, including the results of all clinical screening laboratory 
evaluations, will be reviewed to verify eligibility 
• 
For women of childbearing potential, contraceptive methods will be reviewed to ensure 
eligibility, recent menstrual history will be obtained, pregnancy avoidance counseling will be 
provided, and a urine pregnancy test will be performed. A test performed on a sample 
obtained within 24 hours prior to vaccination must be negative. 
• 
A pre-administration reactogenicity assessment will be performed to establish baseline. 
• 
Venous blood samples will be obtained for safety labs, PBMC isolation, and immunologic 
assays in volumes as specified in Table 8, for Groups A, B, D, and E, and Table 9 for Group 
C. The clinical safety laboratory results will not be available or reviewed prior to study 
vaccination. 
• 
The assigned study product will be administered IM injection in the deltoid muscle of the 
preferred arm. The site of injection (right or left arm) and time of administration will be 
recorded on the appropriate eCRF. 
• 
Subjects will be observed in the clinic for at least 30 minutes after the injection. The injection 
site will be examined, post-administration reactogenicity assessments will be performed, and 
any AE or SAE will be recorded on the appropriate eCRF prior to discharge from the clinic. 
• 
Subjects will be provided with a web-based electronic Memory Aid (e-Memory Aid) or 
Paper Memory Aid and thermometer for recording daily maximum oral temperature, 
solicited injection site and systemic reactions, unsolicited AEs, and concomitant medications, 
beginning on the evening of Day 1 and continuing daily for the next 7 days. Subjects will be 

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encouraged to take their temperature around the same time each day and also if they feel 
feverish. Subjects will be instructed on how to use the memory aid and how to rate any AEs. 
Subjects will be instructed to notify the study center if they develop any severe reactions and/or 
fever equal to or exceeding 38.0°C (100.4°F). If the investigator deems the reaction warrants 
further evaluation or intervention, the investigator will give further instructions on the proper 
course of action, including a return to the clinic for immediate evaluation if appropriate. 
 
Planned Study Visits 
The second study product injection will be administered at Visit 05, Day 29 (window ± 3 days). 
The third study product injection will be administered at Visit 08, Day 57 (window ± 3 days) for 
subjects in Groups A, B, D, and E and will be administered at Visit 09, Day 180 for Group C. 
At the Second and Third Vaccination Visits, prior to the study product injection: 
• For a subject to receive the study product injection, Individual Halting Criteria will be 
reviewed (refer to Section 8.6.2). 
 
• Interim medical history, including an assessment for new medical conditions, stability of 
chronic diseases, and symptoms suggestive of a MAAE/NOCMC/PIMMC, will be obtained 
by interview of subjects and any changes since the previous clinic visit or contact will be 
noted. 
 
• 
All concomitant medications will be recorded on the appropriate eCRF, if known and not 
previously collected. 
• All newly identified AEs/SAEs/MAAEs/NOCMCs/PIMMCs will be recorded on the 
appropriate eCRF. 
 
• Vital signs, including oral temperature, pulse, and blood pressure, will be obtained prior to 
the study product injection. Subjects must not eat or drink anything hot or cold, or smoke 
within 10 minutes prior to taking oral temperature. 
 
• A targeted physical examination, including an assessment for signs suggestive of a 
MAAE/NOCMC/PIMMC, may be performed, if indicated based on review of interim 
medical history, by a study clinician licensed to make medical diagnoses and listed on the 
Form FDA 1572 as the site PI or sub-investigator. 

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• 
For women of childbearing potential, contraceptive methods will be reviewed to ensure 
eligibility, recent menstrual history will be obtained, pregnancy avoidance counseling will be 
provided, and a urine pregnancy test will be performed. A test performed on a sample 
obtained within 24 hours prior to vaccination must be negative. 
• Pre-administration reactogenicity assessments will be performed to establish baseline. 
 
• Venous blood samples will be obtained for clinical safety labs, PBMC isolation, and 
immunologic assays, in volumes as specified in Table 8, for Groups A, B, D, and E, and 
Table 9 for Group C. The clinical safety laboratory results will not be available or reviewed 
prior to study vaccination. 
 
Subjects will then receive a single dose of study product via IM injection into the deltoid muscle 
of the preferred arm. 
• 
The second or third study product injections may be given in the same arm as the previous 
study product injection as long as there is no interference with the reactogenicity assessment. 
The site of injection (right or left arm) and time of administration will be recorded on the 
appropriate eCRF. Subjects will be observed in the clinic for at least 30 minutes after the 
study vaccination. The injection site will be examined, post-administration reactogenicity 
assessments will be performed, and any AE/SAEs will be recorded on the appropriate eCRF 
prior to discharge from the clinic. 
• 
Subjects will be provided with an e-Memory Aid or Paper Memory Aid and thermometer for 
recording daily maximum oral temperature, solicited injection site and systemic reactions, 
unsolicited AEs, and concomitant medications, beginning on the evening of the day of study 
product injection and continuing daily for the next seven days. Subjects will be encouraged 
to take their temperature around the same time each day and also if they feel feverish. 
Subjects will be instructed on how to use the memory aid and how to rate any AEs. 
• 
Subjects will be instructed to notify the study center if they develop any severe reactions 
and/or fever equal to or exceeding 38°C (100.4°F). If the investigator deems the reaction 
warrants further evaluation or intervention, the investigator will give further instructions on 
the proper course of action, including a return to the clinic for immediate evaluation if 
appropriate. 
6.3.1 
Follow-up 
Follow up visits are scheduled as indicated in the Schedule of Events, Table 8 for Groups A, B, 
D, and E, and Table 9 for Group C. Subjects will be followed for one year after their last study 
vaccination. 

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6.3.2 
Early Termination Visit 
 
The following activities will be performed at the early termination visit on subjects who 
withdraw, or are withdrawn or terminated from this trial and who are willing to participate in the 
visit, clinical evaluations, and study procedures: 
 
• Interim medical history, including an assessment for new medical conditions and symptoms 
suggestive of a MAAE/NOCMC/PIMMC, will be obtained by interview of subjects and any 
changes since the previous clinic visit or contact will be noted. 
 
• Memory Aid information will be reviewed with subjects (if within 7 days after the last study 
vaccination). 
 
• All concomitant medications will be recorded on the appropriate eCRF (if within 28 days 
after the last study product injection). 
 
• AEs will be assessed and recorded as described in Section 3.1. 
 
• Vital signs, including oral temperature, pulse, and blood pressure, may be obtained if 
clinically indicated. 
 
• A targeted physical examination, including an assessment for signs suggestive of a 
MAAE/NOCMC/PIMMC, may be performed, if indicated based on review of interim 
medical history, by a study clinician licensed to make medical diagnoses and listed on the 
Form FDA 1572 as the site PI or sub-investigator. 
 
• The study vaccination site will be examined (if within seven days after the last study product 
injection). 
 
• Post-administration reactogenicity assessments will be performed (if within seven days after 
the last study product injection). 
 
• Approximately 8.5 mL of venous blood will be collected for serum antibody assays (if within 
28 days after the last study vaccination). 
 
• Approximately 7 mL of venous blood will be collected for clinical safety labs (WBC, 
hemoglobin, platelets, ALT, and creatinine), and performed by the clinical laboratory if 
within 28 days after the last study vaccination. 

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Unscheduled Study Visits (if needed) 
Participants may be asked to come in for additional clinic visits if, for example, the need arises 
for follow-up of local or systemic AE such as febrile illnesses, or for requests for repeat blood 
draws for scheduled laboratory testing from the clinical laboratory due to sample hemolysis or 
clotting. 
A supplemental visit eCRF will be filled and signed by the appropriate personnel. All unscheduled 
visits will be entered into Emmes’ Advantage eClinical® internet data entry system on the 
appropriate eCRFs. Please see the MOP for details. 
 
Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol- 
specific MOP requirements. The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff. As a result of deviations, corrective actions should be 
developed by the site and implemented promptly. It is the responsibility of the site PI and other 
study personnel to use continuous vigilance to identify and report protocol deviations. All 
individual protocol deviations will be addressed in subject study records. All protocol 
deviations, either individual, product, or site-specific will be collected and the record stored in a 
sponsor-determined location. Protocol deviations must be sent to the IRB per its guidelines. The 
site PI and other study personnel are responsible for knowing and adhering to their IRB 
requirements. 

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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
 
Complete medical history will be obtained by interview of subjects at the screening visit. 
Subjects will be queried regarding a history of significant medical disorders of the head, eyes, 
ears, nose, throat, mouth, cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, 
kidney, urologic system, nervous system, blood, lymph nodes, endocrine system, 
musculoskeletal system, skin, and genital/reproductive tract. A history of any allergies, cancer, 
immunodeficiency, psychiatric illness, substance abuse, and autoimmune disease will be 
solicited. At follow-up visits after the first study vaccination, an interim medical history will be 
obtained by interview of subjects noting any changes since the previous clinic visit or contact. 
The interim medical history should include an assessment for new medical conditions and 
symptoms suggestive of a MAAE/NOCMC/PIMMC. 
 
Concomitant medications will be collected as described in Section 7.1.1. 
 
At the screening visit a physical examination will be performed on all subjects as described in 
Section 6.1. At subsequent clinic visits, a targeted physical examination may be performed, if 
indicated based on the subject’s interim medical history, by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site PI or sub-investigator. Targeted 
physical examinations should also include an assessment for signs suggestive of a 
MAAE/NOCMC/PIMMC. 
 
Vital signs (oral temperature, pulse, and blood pressure) will be collected at the screening visit, 
at vaccination visits, and at clinic visits scheduled within 7 days after a vaccination. At other 
visits, vital signs will be assessed if clinically indicated. Vital signs assessed on Day 1 prior to 
the first study product injection will be considered as baseline. Subjects must not eat or drink 
anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. Height and 
weight will be collected at the screening visit for the calculation of BMI. 
 
Reactogenicity assessments will include an assessment of solicited AEs occurring from the time 
of each study product injection through seven days after each study product injection, which 
includes an assessment of injection site reactions including pruritus, erythema, induration/ 
swelling, pain, and tenderness as well as systemic reactions including fever, chills, fatigue, 
malaise, myalgia, arthralgia, headache, and nausea or vomiting. Pre-administration 

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reactogenicity assessments will be performed to establish baseline, then the study product 
injection will be given. 
 
Subjects will be observed in the clinic for at least 30 minutes after each study vaccination. The 
injection site will be examined, post-administration reactogenicity assessments will be 
performed, and any AE/SAEs will be recorded on the appropriate eCRF prior to discharge from 
the clinic. The injection site will also be examined approximately 7 days after each study product 
injection. 
 
All subjects will complete a Memory Aid from the time of each study product injection through 
7 days after each study product injection. Subject Memory Aids will be reviewed with the 
subjects for AEs (solicited injection site and systemic reactions and unsolicited AEs) during each 
post-injection clinic or phone visit through 7 days after the injection. 
 
7.1.1 
Assessment of Concomitant Medications/Treatments other than Study Product 
 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
eCRF. Concomitant medications will include all current medications and medications taken in 
the 60 days prior to the first vaccination and those taken from the time of vaccination through 
approximately 28 days after each vaccination, as described in Section 3.1. Medications reported 
in the electronic case report form (eCRF) are limited to those taken within 30 days prior to the 
first study product injection and those taken in the 28-day post-vaccination interval. Prescription 
and over-the-counter drugs will be included as well as herbals, vitamins, and supplements. In 
addition, receipt of non-study vaccines will be solicited from the time of each vaccination 
through approximately 28 days after each vaccination and reported in the eCRF. Use of a new 
medication should prompt evaluation for the occurrence of any MAAE, including a NOCMC. 
 
Medications that might interfere with the evaluation of the investigational product(s) should not 
be used during the trial-reporting period (approximately 12 months after the last study 
vaccination) unless clinically indicated as part of the subject’s health care. Medications in this 
category include the prohibited medications per the Subject Exclusion Criteria (see Section 
5.1.2). In addition, the site PI or appropriate sub-investigator may identify other medications that 
should not be used due to a risk to subject safety or assessment of reactogenicity and 
immunogenicity. 

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Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
 
Subjects will be screened for HIV-1 and HIV-2 infection by a fourth-generation testing 
algorithm, for HCV infection, and for HBsAg. Screening labs also include WBC, hemoglobin, 
platelets, creatinine, and ALT. 
 
Serum (screening visit) and urine (study product injection visits) pregnancy tests will be 
performed. Serum pregnancy tests will be performed by the Quest clinical diagnostic laboratory. 
Urine pregnancy CLIA-waved tests will be performed by research staff at the research site 
specimen processing laboratory. Pregnancy testing will be done at the screening visit and within 
24 hours prior to each study product injection on all women of childbearing potential. Results 
must be negative and known prior to enrollment on Day 1 and administration of each study 
product injection. 
 
Clinical safety laboratory parameters (WBC, hemoglobin, platelets, ALT, and creatinine) will be 
collected from each subject on the day of and prior to each study product injection, 
approximately 7 days after each study product injection, and approximately 28 days after each 
study product injection (which may also serve as the clinical safety laboratory samples for the 
second and/or third study product injection). These evaluations will be performed by the Quest 
laboratory. Venous blood samples will be collected for these safety labs. The results from the 
clinical safety laboratory parameters collected on the day of study product injections will not be 
available or reviewed prior to study product injection. 
 
Laboratory values that are outside the range of eligibility but are thought to be due to an acute 
condition or due to laboratory error may be repeated once. One or more of the laboratory 
parameters may be repeated at any time during the study as determined by the PI, if indicated by 
an AE. A clinically significant abnormal value should be repeated within 10 days if possible and 
followed up as clinically relevant. 
 
The volume of venous blood to be collected for the clinical safety laboratory evaluations is 
presented in Table 8 and Table 9. 
 
7.2.2 
Research Assays 
The research assays to be performed for the immunologic endpoints are specified below. 

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7.2.2.1 
ELISA (anti Sm-p80 IgG) 
Vaccine-specific IgG antibody responses will be assessed by ELISA using serum collected from 
subjects (8.5 ml of blood collected in a serum separator tube) at specific time points selected to 
evaluate the kinetics of the response after each administration, peak response, and durability, 
including prior to each vaccination on the day of vaccination, at 7 and 28 days after each 
vaccination, and at 124 days after the last vaccination. The 28-day post-vaccination sample also 
serves as the day of vaccination sample for a subsequent vaccination given at a 28-day interval. 
This volume is sufficient to provide 1 primary and 1 backup sample for analysis. The goal will 
be to compare the serum IgG titers at each time point among participants who received an Sm- 
p80 study product across treatment groups. Endpoint titer ELISAs will be performed by SCRI as 
follows. Titers of total IgG will be measured against the Sm-p80 protein. Briefly, thawed serum 
samples are serially diluted (12 dilutions at 4-fold each) using robotic liquid handlers on 
duplicate 384-well plates. The serially diluted sera are transferred and incubated on ELISA plates 
coated with Sm-p80 protein. Appropriate standards (pooled participant sera) and controls will be 
included for plate quality control based on criteria established during prior optimizations. 
Following, secondary antibody (HRP-conjugated) incubation, plates will be developed and read 
at OD 450-570nm. Endpoint titer will be calculated for each curve and duplicates will be 
averaged if within established variance limits. 
7.2.2.2 
RNA-Seq 
RNA Sequencing (RNA-Seq) will be performed by Novogene from the whole blood PAXgene 
tubes that will be shipped from TTUHSC. Novogene will perform total RNA extraction, RNA 
quantification and qualification, library preparation, Illumina whole-transcriptome sequencing, 
and raw data quality checking. Novogene will transfer the raw FASTQ files to Emmes. Emmes 
will perform RNA-Seq data analyses, including pre-alignment sequence quality control, 
reference alignment, post-alignment quality control, gene expression quantification, differential 
gene expression analyses, gene cluster and pathway analyses, as well as predictive modeling (see 
Section 10.5.4). 
7.2.2.3 
Laboratory Specimen Preparation, Handling, and Storage 
 
Instructions for specimen preparation, handling, and storage are included in the laboratory 
manual and protocol-specific MOP as appropriate. 
 
7.2.2.4 
Laboratory Specimen Shipping 
Specimens collected during the study will be shipped according to the study MOP. Specimen 
labeling requirements will also be included in the study MOP. 

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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
Safety will be assessed by the frequency and severity of: 
 
1. SAEs occurring from the time of the first study product injection through the end of follow- 
up which is approximately 12 months after the last study product injection. 
 
2. Solicited AEs – reactogenicity events occurring from the time of each study product injection 
through 7 days after each study product injection: 
 
a) Injection site reactions including pruritus, erythema, induration/swelling, pain, and 
tenderness. 
 
b) Systemic reactions including fever, chills, fatigue, malaise, myalgia, arthralgia, headache, 
nausea, and vomiting. 
 
3. Clinical safety laboratory AEs assessed as described in Section 7.2.1. Parameters to be 
evaluated include WBC, hemoglobin, platelets, ALT, and creatinine. 
 
4. Unsolicited AEs – non-serious AEs occurring from the time of each study product injection 
through 28 days after the study product injection. 
 
5. MAAEs, NOCMCs, and PIMMCs occurring from the time of the first study product injection 
through the end of follow-up which is approximately 12 months after the last study product 
injection. 
 
8.1.1 
Adverse Events (AEs) 
The International Conference on Harmonisation (ICH) E6 defines an AE as any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product regardless of its causal relationship to the study treatment. The FDA defines an AE as 
any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product. The occurrence of an AE may come to the attention of study personnel during study 

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visits and interviews of a study recipient presenting for medical care, or upon review by a study 
monitor. 
All AEs, including solicited local (injection site) and systemic (subjective and quantitative) 
reactions, will be captured on the appropriate eCRF. Information to be collected for AEs 
includes event description, date of onset, assessment of severity, relationship to study product 
and alternate etiology (assessed only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as an investigator), date of resolution, seriousness and 
outcome. AEs occurring during the trial collection and reporting period will be documented 
appropriately regardless of relationship. AEs will be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it should be recorded as an AE. 
If an event meets both the criteria of a study endpoint and an AE, the event will be reported 
either as a study endpoint or as an AE (not both). 
8.1.1.1 
Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for 
relationship to study product (see definitions). AEs characterized as intermittent require 
documentation of onset and duration of each episode. The start and stop date of each reported 
AE will be recorded on the appropriate eCRF. 
Severity of Event: 
AEs will be assessed by the investigator using the protocol-defined grading system specified in 
Section 8.1.2 and Appendix C. For events not included in the protocol-defined grading system, 
the following guidelines will be used to quantify severity: 
• Mild (Grade 1): Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s usual 
activities of daily living. 
• Moderate (Grade 2): Events that are usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
• Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. Severe events are usually 
incapacitating. 

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Relationship to Study Product: The assessment of the relationship of an AE to the 
administration of study product is made only by those with the training and authority to make a 
diagnosis and listed on the Form FDA 1572 as an investigator based on all available information 
at the time of the completion of the eCRF. Whether the AE is related or not, is not a factor in 
determining what is or is not reported in this trial. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. 
In a clinical trial, the study product must always be suspect. The relationship to study product 
will be assessed for AEs using the terms related or not related: 
• Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 

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8.1.2 
Reactogenicity 
Reactogenicity events are AEs that are known to occur with this type of study vaccine. The 
following Toxicity Grading Scales will be used to grade solicited local (injection site) and systemic 
(subjective and quantitative) reactions: 
Table 3: Injection Site Reactogenicity Grading 
 
Local (Injection Site) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain – experienced 
without touching the 
injection site 
(spontaneous discomfort) 
Subject is aware of pain 
but it does not interfere 
with daily activity and no 
pain medication is taken 
Subject is aware of pain; 
there is interference with 
daily activity or it 
requires use of pain 
medication 
Subject is aware of pain and 
it prevents daily activity 
Tenderness – hurts only 
when injection site is 
touched or the arm is 
moved 
The area immediately 
surrounding the injection 
site hurts only when 
touched or with arm 
motion, and it does not 
interfere with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
interferes with daily 
activity 
The area immediately 
surrounding the injection 
site hurts when touched or 
with arm motion, and it 
prevents daily activity 
Pruritus (itching) 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
Swelling* 
Does not interfere with 
daily activity 
Interferes with daily 
activity 
Prevents daily activity 
* Will be also measured in cm but size will not be used as halting criteria. 
 
 
Table 4: Injection Site Reactogenicity Measurements 
 
Local (Injection Site) 
Reaction 
Small (Grade 1) 
Medium (Grade 
2) 
Large (Grade 3) 
Erythema (Redness)* 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Induration 
(Hardness)/Swelling* 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
* Will not be used as halting criteria. 

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Table 5: Subjective Systemic Reactogenicity Grading 
 
Systemic (Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Chills 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Myalgia (Body 
Aches/Muscular Pain)* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Arthralgia (Joint Pain)* 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Nausea 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Vomiting 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Headache 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Malaise 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
Fatigue 
No interference with 
daily activity 
Some interference with 
daily activity 
Significant interference, 
prevents daily activity 
* Not at injection site 
 
 
Oral temperature# will be graded as follows: 
Table 6: Quantitative Systemic Reactogenicity Grading 
 
Systemic (Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever* - oral† 
38.0°C – 38.4°C 
100.4°F – 101.1°F 
38.5°C – 38.9°C 
101.2°F – 102.0°F 
>38.9°C 
>102.0°F 
# 
Oral temperature assessed on Day 1 (Visit 01) before the first study product injection will be considered as 
baseline. 
*Note: A fever can be considered not related to the study product if an alternative etiology can be documented. 
† Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes before taking oral temperature. 

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8.1.3 
Serious Adverse Events (SAEs) 
An AE or suspected adverse reaction is considered an SAE if, in the view of either the site 
principal investigator or sponsor, it results in any of the following outcomes: 
• death, 
• a life-threatening AE*, 
• inpatient hospitalization or prolongation of existing hospitalization, 
• a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• a congenital anomaly/birth defect. 
• important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
*Life-threatening AE. An AE is considered “life-threatening” if, in the view of either the site 
principal investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused 
death. 
SAEs will be: 
• Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 or by the 
Institution as the site Principal Investigator or Sub-Investigator. 
• Recorded on the appropriate SAE data collection form and eCRF. 
• Followed through resolution by a licensed study physician (for Investigational New Drug 
Application [IND] studies, a physician listed on the Form FDA 1572 as the site PI or Sub- 
Investigator). 
• Reviewed and evaluated by DMID, the DSMB or SMC (periodic review unless related), and 
the IRB/IEC. 

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Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of: 
8.2.1 
Solicited Events 
Solicited events are AEs that are common and known to occur following administration of study 
product. 
8.2.2 
Unsolicited Events 
Unsolicited events are any other AEs that occur following administration of study product. 
8.2.3 
New-Onset Chronic Medical Conditions (NOCMCs) 
NOCMCs are defined as any new ICD-10 diagnosis that is applied to the subject during the 
duration of the study, after receipt of the study agent, that is expected to continue for at least 3 
months and requires continued health care intervention. 
8.2.4 
Medically-Attended Adverse Events (MAAEs) 
Defined as a hospitalization, ER visit, or an otherwise unscheduled visit to or from medical 
personnel for any reason; and considered related to study product. 
8.2.5 
Potentially Immune-Mediated Medical Conditions (PIMMCs) 
PIMMCs constitute a group of AEs that includes diseases which are clearly autoimmune in 
etiology and other inflammatory and/or neurologic disorders which may or may not have 
autoimmune etiologies. PIMMCs currently in effect are presented in Appendix B List of 
PIMMCs. 
 
Reporting Procedures 
8.3.1 
Reporting Serious Adverse Events 
SAEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
Any AE (including MAAEs, NOCMC, and PIMMCs) that is considered an SAE must be 
submitted immediately (within 24 hours of site awareness) on an SAE form to the DMID 
Pharmacovigilance Group, at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 

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6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into the DCC system. 
Please see the protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible. 
The DMID Medical Monitor and DMID Clinical Project Manager will be notified of the SAE by 
the DMID Pharmacovigilance Group. The DMID Medical Monitor will review and assess the 
SAE for regulatory reporting and potential impact on study subject safety and protocol conduct. 
At any time after completion of the study, if the site principal investigator or appropriate sub- 
investigator becomes aware of an SAE that is suspected to be related to study product, the site 
principal investigator or appropriate sub-investigator will report the event to the DMID 
Pharmacovigilance Group. 
8.3.2 
Regulatory Reporting for Studies Conducted Under a DMID Sponsored IND 
 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
sponsor, will report any suspected unexpected SAE only if there is evidence to suggest a causal 
relationship between the study intervention and the AE. DMID will submit an IND safety report 
to the FDA and will notify the site PI of potential serious risks from clinical studies or any other 
source, as soon as possible. DMID will report to the FDA any unexpected fatal or life- 
threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar 
days after the sponsor’s initial receipt of the information. If the event is not fatal or life- 
threatening the IND safety report will be submitted within 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32. 
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available. 
 
All SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format. 

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8.3.3 
Reporting of Pregnancy 
 
Pregnancies occurring in study subjects will be reported via Advantage eClinical on the 
Pregnancy Report form. No further study vaccinations will be administered to pregnant subjects, 
but with the subject’s permission all protocol-required venous blood samples will be obtained 
and the subject will continue to be followed for safety for the duration of this trial. Efforts will be 
made to follow all pregnancies reported during the course of this trial to pregnancy outcome 
pending the subject’s permission. 
 
The pregnancy will be documented on the Pregnancy Reporting Form provided by Emmes, and 
this form will be used for the pregnancy event data entry into Advantage eClinical. All study 
mandated blood samples will be obtained and the participant will continue in follow-up for 
safety events. Pregnancies will be followed until 30 days after delivery to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. No 
subsequent product injections will be administered to pregnant participants. 
8.3.4 
Disclosure of Study Related Information 
 
Subjects can choose to receive written disclosure of their treatment assignment after the database 
has been locked. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be assessed and followed from initial recognition of the AE through end of the protocol 
defined follow-up period. 
SAEs will be followed up through resolution even if duration of follow-up goes beyond the 
protocol-defined follow-up period. 
Resolution of an AE is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate data 
collection form. 

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Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
The site PI or appropriate co-investigator is responsible for reporting all AEs/SAEs that are 
observed or reported during the study, regardless of the relationship to study product. AEs/SAEs, 
abnormal clinical laboratory test values, or abnormal clinical findings will be documented, 
reported and followed appropriately. 
Clinical safety laboratory results from specimens obtained after the first study product injection 
will be graded as indicated in the Toxicity Tables in Appendix C. Clinical laboratory evaluations 
assessed on the day of and prior to the first study product injection (Day 1) will be considered as 
baseline. 
Systolic and diastolic blood pressures obtained following vaccination will be defined as AEs and 
graded as indicated in the Toxicity Tables in Appendix C below. However, baseline values prior 
to the first vaccination, including values obtained at the screening visit and at Visit 1 prior to 
vaccine administration, may meet the inclusion criteria of systolic blood pressure 85 to 150 
mmHg, inclusive, but fall within values defined as Grade 1 severity in the Toxicity Table. 
Similarly, baseline values may meet the inclusion criteria of diastolic blood pressure ≤ 100 
mmHg but fall within values defined as Grade 1 severity in the Toxicity Table. For those 
participants with baseline blood pressure values that are defined as Grade 1 in the Toxicity 
Table, subsequent, post-vaccination, values will not be defined as an AE unless the post- 
vaccination value meets the criteria for Grade 2 or 3 and therefore represents a change from 
baseline. Those values that represent a change from baseline will be defined as Grade 1 AEs for 
the Grade 2 values and Grade 2 AEs for the Grade 3 values as they represent a change of one two 
grades from baseline, respectively. 
 
Halting Rules 
8.6.1 
Study Halting Criteria 
Further enrollment and study product administrations for all study groups will be halted for SMC 
review and discussion of all appropriate safety data if any of the following halting criteria are 
met one or more subjects in any treatment group experience any of the following AEs from the 
time of first study product administration through 28 days after last study product administration. 
• Any death occurring within 28 days after administration of a study product injection that was 
not the result of trauma or accident, regardless of relatedness to study product. 
• Any subject experiences ulceration, abscess, or necrosis at the injection site considered 
related to study product administration. 

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• Any subject experiences laryngospasm, bronchospasm, or anaphylaxis within 24 hours after 
administration of study product that is considered related to study product. 
• Two or more subjects experience generalized urticaria within 72 hours after administration of 
study product that is considered related to study product. 
• Any other SAE deemed to be related to study product based on close temporal relationship or 
other factors. 
• Three or more subjects in the same dose/schedule study group discontinue study product 
injections due to AEs. 
• Three or more subjects develop same Grade 3 clinical laboratory AE related to the study 
product. 
The study will also be halted for SMC review/recommendation if, within 7 days after 
administration of study product, any of the following occurs: 
• 
 Two or more subjects experience the same Grade 3 study product-related injection site 
reaction (excluding the size of erythema and swelling/induration). 
• 
 Two or more subjects experience the same Grade 3 study product-related subjective 
systemic reaction, for which the severity (grade) is corroborated by study personnel. 
• 
 Two or more subjects experience the same Grade 3 study product-related quantitative 
systemic reaction. 
• 
 Two or more subjects experience the same Grade 3 study product-related laboratory 
abnormality. 
Grading scales for solicited injection site and systemic (subjective and quantitative) reactions are 
included in Section 8.1.2. 
Grading scales for clinical safety laboratory AEs are included in Appendix C. 
If any of the study halting rules are met, the remaining enrollments and study product injections 
will be halted and will not be resumed without a review by and recommendation from the SMC 
to proceed. 
DMID retains the authority to suspend additional enrollment and administration of study product 
during the entire trial, as applicable. 

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The DMID Medical Monitor is empowered to stop enrollment and study product injections if 
AEs that meet the halting criteria are reported. Similarly, the PI may, using discretion, ask for the 
study to be placed on hold and an SMC meeting to be held for any single event or combination 
of multiple events which, in the PI’s professional opinion, jeopardize the safety of the subjects or 
the reliability of the data. 
8.6.2 
Individual Halting Criteria 
The study product injections will be discontinued in an individual if: 
• The subject has a systemic hypersensitivity reaction following a study product injection that 
is judged related to the study product 
• The subject has ulceration, abscess, or necrosis at the injection site related to study product 
administration. 
• Presence of signs or symptoms that could confound or confuse assessment of study vaccine 
reactogenicity. For subjects with injection site or systemic signs or symptoms, or with an 
acute illness, including an oral temperature greater than or equal to 37.8°C, on the day of a 
scheduled study product injection, the study product injection should be postponed/deferred 
until the signs, symptoms, or acute illness have resolved, or are improving as further 
specified below, and if within the acceptable protocol-specified window for that visit No 
exceptions to the protocol-specified window will be made. 
Note for afebrile, acute illness only: If a subject is afebrile, has an acute illness that is 
nearly resolved with only minor residual symptoms remaining, is still within the acceptable 
protocol-specified window for the study product injection and, in the opinion of the site PI or 
appropriate sub-investigator, the residual symptoms will not interfere with the ability to 
assess safety parameters as required by the protocol, the subject may receive the study 
product injection without further approval from the DMID Medical Officer. No exceptions to 
the protocol-specified window will be made. 
• Any clinically significant medical condition that, in the opinion of the participating site PI or 
appropriate sub-investigator, poses an additional risk to the subject if they continue to 
participate in the study. 
• Grade 3 clinical safety laboratory value (according to the Toxicity Tables Appendix C) that 
does not decrease to Grade 2 or less prior to the subsequent study product injection. Any 
clinical safety laboratory parameter may be re-evaluated only once prior to the subsequent 
study product injection. If the clinical safety laboratory value decreases to Grade 2 or less, 
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product injection should be scheduled to occur within the acceptable protocol-specific 
window for that visit. No exceptions to the protocol-specified window will be made. 
• Severe or sustained reaction or disability related to prior administration of study product. 
8.6.3 
Dose Escalation Halting Criteria 
Subjects are scheduled to receive three injections of the assigned study product, given on Days 1, 
29, and 57 or on Days 1, 29, and 180. Dose escalation will proceed as described in the Protocol 
Summary. If one or more dose escalation stopping rules are met the SMC will be convened to 
review the safety information and determine whether dose escalation should proceed. 
• 
Any subject develops a Grade 3 solicited or unsolicited systemic AE or a Grade 3 clinical 
laboratory AE that is judged related to the study product. 
• 
Three or more subjects in the most recently enrolled study group develop the same Grade 3 
solicited injection site AE related to the study product. 
• 
Three or more subjects develop the same Grade 2 or higher solicited or unsolicited systemic 
AE or the same Grade 2 or higher clinical laboratory AE that is judged related to study 
product. 
• 
Any subject has an event meeting an individual halting criterion. 
 
Safety Oversight 
This clinical study will utilize an SMC, which is an independent group of experts that advises the 
DMID. The primary responsibility of the SMC is to monitor subject safety. The SMC is external 
to the DMID and comprises at least three voting members. The SMC will consist of members 
with appropriate phase 1 study expertise to contribute to the interpretation of the data from this 
trial. Its activities will be delineated in a SMC charter that will describe the membership, 
responsibilities, and the scope and frequency of data reviews. The SMC will operate on a 
conflict-free basis independently of the study team. The DMID or the SMC may convene ad hoc 
meetings of the SMC according to protocol criteria or if there are concerns that arise during the 
study and the principal investigator may request an ad hoc SMC meeting through DMID. 
The SMC will review cumulative safety data at time points that may include but not limited to: if 
dose escalation criteria are not met, if halting criteria are met, on an ad hoc basis if a potential 
safety concern is identified, at least annually for safety data review, or for final safety data 
review after completion of the study safety follow-up. These activities will be delineated in the 
SMC charter. 

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

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

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Informed consent forms will be IRB-approved, and subjects will be asked to read and review the 
consent form. Subjects must sign the ICF prior to starting any study procedures being done 
specifically for this trial. 
Once signed, a copy of the ICF will be given to the subject(s) for their records. The subject(s) 
may withdraw consent at any time throughout the course of the trial. The rights and welfare of 
the subject(s) will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if the IRB has 
agreed that persons identified from a patient database (of Kaiser Permanente Washington) may 
be sent recruitment materials, and - if interested - receive further information about the study by 
phone and provide oral consent to respond to questions to determine presumptive eligibility by 
phone. If the IRB has agreed, persons interested in participating in the study who are 
presumptively eligible by the phone screen could provide oral consent to allow review of their 
Kaiser Washington electronic medical record. If that review does not identify exclusionary 
information, a screening clinic visit would be scheduled. At that visit, research staff would obtain 
written consent per the standard informed consent process before conducting protocol-specific 
screening activities. 
New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements. The informed consent document 
will be updated and subjects will be re-consented per IRB requirements, if necessary. Subjects 
will be given a copy of all ICFs that they sign. 
9.2.1 
Requirements for Permission by Parents/Guardians and Assent by Children (in 
case of a minor) 
Not applicable. 
9.2.2 
Other Informed Consent Procedures 
Not applicable. 
 
Consent for Secondary Research Use of Stored Specimens and Data 
9.3.1 
Secondary Use of Stored Specimens and Data 
Secondary Human Subject Research is the re-use of identifiable data or identifiable 
biospecimens that were collected from some other ‘‘primary’’ or ‘‘initial’’ activity, such as the 
data and samples collected in this protocol. This section will detail the samples and data 

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available for secondary research. Any use of the secondary sample or data, however, will be 
presented in a separate protocol and require separate IRB approval. 
9.3.2 Samples for Secondary Research 
Residual samples/specimens are those that are left over after protocol-specified testing and this 
study has been completed. As a condition of study participation, subjects agree that residual 
samples will be stored coded indefinitely at the DMID CMS. On completion of the trial, residual 
specimens may be shared with investigators at the participating site and with other investigators 
at other institutions. The recipients of specimens will be informed that these specimens have a 
NIH certificate of confidentiality. The information provided to the recipient will not contain 
direct identifiable information. 
Samples will be stored indefinitely at a DMID-designated storage facility. Each sample will be 
encoded (labeled) only with a barcode and a unique tracking number to protect subject 
confidentiality. Secondary research with coded samples and data may occur, however, subject 
confidentiality will be maintained as described for this protocol. An IRB review of the secondary 
research using coded specimens is required. 
Residual/Repository Research Samples, upon written request and approval from DMID and any 
approvals required by the site or network, may be shared for secondary research with 
investigators at the participating site, with researchers at other Infectious Disease Clinical 
Research Consortium (IDCRC) sites or other institutions, or company-designated research 
laboratories. The samples will not be sold or used directly for production of any commercial 
product. DMID will authorize shipment from the DMID CMS. 
TTUHSC may receive serum samples and PBMC before the final database lock. The serum 
samples can be aliquoted and stored for secondary research. The PBMC may be received and 
stored for secondary research. TTUHSC will not evaluate the samples until after the final 
database lock and approval received from DMID and the IDCRC per the IDCRC secondary 
research policy. 
Reports from secondary research will not be kept in the subjects’ health records or shared with 
subjects, unless required by law. Reports will not be sent to the specimen repository. 
The subject’s decision can be changed at any time by notifying the study doctors or nurses in 
writing. To participate in this study, subjects must consent for storage of samples for secondary 
use. If the subject subsequently changes his/her decision, the samples will be destroyed if the 
samples have not been used for research or released for a specific research project. 

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9.3.3 
Data Sharing for Secondary Research 
Data from this study may be used for secondary research. All of the individual subject data 
collected during this study will be made available after de-identification. The SAP and Analytic 
Code will also be made available. Data will be available immediately following publication, with 
no end date. Upon written request, with provision of a methodologically sound proposal, and 
approval from DMID and any approvals required by the site or network, data may be shared for 
secondary research with investigators/researchers. The data will be available for only the purpose 
outlined in the approved proposal. 
For access to genomic data in the NIH designated controlled access database, an investigator (or 
data requestor) must submit a Data Access Request which certifies adherence to the NIH 
Security Best Practices for Controlled-Access data subject to the NIH Genomic Data Sharing 
(GDS) Policy. The participating site PI may request removal of data on individual study subjects 
from NIH data repositories in the event that a research subject withdraws or changes his or her 
consent. However, some data that have been distributed for approved research use cannot be 
retrieved. 
 
Exclusion of Women, Minorities, and Children (Special Populations) 
 
 
All healthy adults 18 through 55 years of age, who meet all of the inclusion and none of the 
exclusion criteria (see Section 5.1), regardless of religion, sex, or ethnic background, will be 
included in the study. Due to the nature of the study, and the fact that no benefit of study 
participation exists, children will not be enrolled at this time. Women who are pregnant or plan 
to become pregnant up to 30 days after the last study product injection and persons <18 years of 
age are excluded from the study. 
 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study or the data generated from the study will be released 
to any unauthorized third party without prior written approval of the DMID and the subject. 
Subject confidentiality will be maintained when study results are published or discussed in 
conferences. The study monitor or other authorized representatives of the sponsor or 
governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 

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hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
Certificate of Confidentiality 
As this research is funded by the NIH, it is covered by NIH policy which effectively issues the 
research a Certificate of Confidentiality (COC). By this policy, researchers cannot be forced to 
disclose or provide, in any Federal, State, or local civil, criminal, administrative, legislative, or 
other proceeding, the name of such individual or any such information, document, or 
biospecimen that contains identifiable, sensitive information about the individual and that was 
created or compiled for purposes of the research, unless such disclosure or use is made with the 
consent of the individual to whom the information, document, or biospecimen pertains. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States Government that is used for auditing or evaluation of federally funded projects, like this 
study, or for information that must be released in order to meet the requirements of the FDA. 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing 
information about themselves or their involvement in this research. If any person or agency 
obtains a written consent to receive research information, then the researchers may not use the 
Certificate to withhold that information. 
The Certificate of Confidentiality does not prevent the researchers from reporting without the 
subject’s consent, information that would identify the subject as a participant in the research 
project regarding matters that must be legally reported including: child and elder abuse, sexual 
abuse, or wanting to harm themselves or others. 
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human subjects in research. 
 
Costs, Subject Compensation, and Research Related Injuries 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial. Procedures and treatment for clinical care may be billed to the subject, subject’s 

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insurance or third party. Subjects may be compensated for their participation in this trial. 
Compensation will be in accordance with the local IRB’s policies and procedures, and subject to 
IRB approval. 
If it is determined by the site principal investigator that an injury occurred to a subject as a direct 
result of the tests or treatments that are done for this trial, then referrals to appropriate health care 
facilities will be provided to the subject. Study personnel will try to reduce, control, and treat 
any complications from this trial. Immediate medical treatment may be provided by the 
participating site. No financial compensation will be provided to the subject by the NIAID, NIH 
to the subject, for any injury suffered due to participation in this trial. 

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STATISTICAL CONSIDERATIONS 
 
Study Hypotheses 
This Phase 1, first-in-human study is not designed to test a formal null hypothesis. Rather, it is 
intended to obtain exploratory, initial data on the study product safety and effect of antigen dose 
and inclusion of the GLA-SE adjuvant on humoral immune responses to guide future dose 
selection. 
 
Sample Size Considerations 
This Phase 1 study is not designed for confirmatory testing but rather to detect AEs related to the 
study product. If an AE has a 20% chance of occurring after receiving one of the product 
formulations being tested, then there is an 87% probability that the event would be observed in 
one or more of the 9 subjects in that treatment group in this study. If the event has a 20% chance 
or higher of occurring in any of the product formulations being tested, then there is at >99% 
probability that the event would be observed in one or more of the 45 subjects in any treatment 
group in the study. The below table shows analogous probabilities for events with other 
frequencies. 
 
Probability of event 
after receiving study 
product 
Probability of 
observing event 
among 9 subjects 
Probability of 
observing event 
among 45 subjects 
0.01 
0.086 
0.364 
0.05 
0.370 
0.901 
0.10 
0.613 
0.991 
0.15 
0.768 
0.999 
0.20 
0.866 
>0.99 
0.25 
0.925 
>0.99 
 
Treatment Assignment Procedures 
10.3.1 
Randomization Procedures 
This is a non-randomized trial. Per ICH guideline E6: GCP, screening records will be kept at 
each participating VTEU site to document the reason why an individual was screened, but failed 
trial entry criteria. The reasons why individuals failed screening will be recorded in the 
Statistical Data Coordinating Center’s (SDCC) Advantage eClinical Electronic Data Capture 
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Once consented and upon entry of demographic data and confirmation of eligibility for this trial, 
the subject will be enrolled. All subjects will receive three study product injections; the same 
study product formulation will be given to the subject for each study product injection. In the 
unlikely event that a subject withdraws prior to receiving the first injection, the subject will be 
replaced with a new subject who will be given the same treatment assignment. 
10.3.2 
Masking Procedures 
This is an open-label clinical trial. 
Subjects, investigators, study personnel performing any study-related assessments following 
study vaccine administration are not blinded to study treatment. Laboratory personnel 
performing immunologic assays will receive samples blinded to subject ID number and sample 
visit number. 
The SMC may receive data in aggregate and presented by Study Group. 
 
Planned Interim Analyses 
Interim analyses will be used to terminate this trial in the event that unanticipated safety events 
deemed to be of sufficient concern require such action by the sponsor. These assessments will 
not be made on the basis of testing a formal statistical hypothesis; therefore, p-value adjustment 
will not be made to any analyses. A SMC will be convened by DMID to review study progress 
and participant, clinical, safety, reactogenicity and immunogenicity data as described in Section 
8.7 
To guide protocol development of future studies of the candidate vaccine, interim analyses of 
safety data and immunogenicity assays, including the IgG ELISA assay, will be performed at the 
discretion of the study team prior to completion of follow-up of all subjects. The interim 
immunogenicity analyses report(s) will include between-Group comparisons of those who 
received different Sm-p80 study product formulations and different schedules. The information 
from the report may be used in abstracts and scientific presentations and reports. 
10.4.1 
Interim Safety Review 
An interim safety review may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, dosing compliance, and solicited and unsolicited 
AE/SAEs. Additional data may be requested by the SMC, and interim statistical reports may be 
generated as deemed necessary and appropriate by DMID. The SMC may receive data in 
aggregate and presented by treatment arm. The SMC will meet and review this data at scheduled 
time points or ad hoc as needed during this trial as defined in the SMC charter. As an outcome of 
each review/meeting, the SMC will make a recommendation as to the advisability of proceeding 

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with study vaccinations (as applicable), and to continue, modify, or terminate this trial. 
Additionally, this trial will be monitored to determine if any of the halting rules described in 
Section 8.6 are met. 
10.4.2 
Interim Immunogenicity or Efficacy Review 
Interim immunogenicity analyses of, for example, IgG ELISA responses will be performed for 
each Study Group, as the data is available for each study group. Depending on the timing of data 
availability, a report may cover one or more Study Groups. Immunogenicity reports will be 
provided by the SDCC to the DMID Scientific Lead and CPM, the IDCRC LOU 
representative(s), the study PI and investigators, and the SMC. Reports will include data 
summarized by Study Group. The data will be cleaned but not locked. These reports along with 
interim safety results may be presented in publications, or public forums and used by the product 
developers for internal decision-making. 
 
Final Analysis Plan 
Analyses for this Phase 1 study will be descriptive and are exploratory rather than confirmatory 
in nature. Every attempt will be made to collect all planned measurements. Statistical 
adjustments for missing data are not planned, but sensitivity analyses may be performed if 
warranted. 
An interim CSR will be completed when all primary and secondary endpoint data are available, 
received by the SDCC, cleaned, and locked. Exploratory endpoint data will be included in an 
addendum to the CSR once available, received by the SDCC, cleaned, and locked. Endpoint data 
may be included in publication of manuscript(s) or other reports. 
Separate SAP documents (interim and addendum) will be generated that will contain the details 
of the final analyses that will be performed following database lock. This section outlines the 
major components of the final analyses. 
10.5.1 
Analysis of Demographics 
Descriptive summaries of demographic variables, including age, sex, race, and ethnicity, will be 
summarized by study group. Numeric variables will be summarized by mean and standard 
deviation; categorical variables will be tabulated. 
10.5.2 
Analysis of Safety Data 
All participants who received at least one vaccination will be included in safety summaries. 
Solicited and unsolicited events will be summarized graphically and numerically. Numbers and 
proportions of participants experiencing solicited systemic events will be summarized by 

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symptom, study group and maximum severity. Furthermore, proportions of participants 
experiencing systemic events will be summarized by study day, study group, and maximum 
severity. Solicited injection site events will be summarized in the same way as systemic solicited 
events. 
Numbers and proportions of participants experiencing unsolicited AEs will be summarized by 
MedDRA System Organ Class and Preferred Term, study group, and maximum severity. 
Unsolicited AEs will also be summarized by relationship to study product, study group, and 
maximum severity. 
Detailed listings of MAAEs, NOCMCs, PIMMCs, and all SAEs, will be presented, including the 
most recent dose number, number of days since most recent dose, relationship to study product, 
severity, outcome, MedDRA System Organ Class and Preferred Term, and study group. 
Time trends of laboratory parameter values will be visualized with background shading 
indicating normal and graded ranges for that parameter. 
10.5.3 
Analysis of Immunogenicity Data 
Immunogenicity summaries will include all participants who received at least one study 
vaccination and contributed both pre- and at least one post-study vaccination blood sample for 
immunogenicity testing for which valid results were reported. Antibody levels will be 
summarized graphically and numerically. Individual time trends will be visualized as will 
reverse cumulative distribution plots. Numbers and proportions of participants with 
seroconversion, defined as a fourfold rise from baseline, will be presented along with 95% CIs 
by time point and study group. Statistical summaries will include geometric means, geometric 
mean fold-rise, mean, median, standard deviation, minimum, and maximum by time point and 
study group. 
10.5.4 
RNA-Seq Analysis 
For the transcriptomics exploratory analysis, sequencing quality will be inspected using 
FASTQC. RNA-Seq data will be pre-processed by removing adapters and low-quality reads, 
trimming low quality ends, and mapping sequences to the latest human reference genome using 
splice-aware alignment software such as HISAT2.[25] Gene expression quantification will be 
carried out by using the Subread software [26]using the latest Ensembl[27]gene model 
annotations as a reference. Systematic differences in sequence coverage between samples will be 
accounted for using the TMM method [31]as implemented in the edgeR R package.[28] Principal 
component analysis, non-metric multidimensional scaling, and hierarchical clustering analysis 
will be used to identify potential global outliers and systematic batch effect. Negative binomial 
models as implemented in edgeR [28]will be used to identify genes for each dose group and post- 

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vaccination day that were differentially expressed compared to last vaccination: Days 8 and 29 
vs. Day 1, and Day 36 vs. Day 29 for all study groups, Day 57 vs. Day 29, Day 64 vs. Day 57 for 
Groups A, B, D, and E, Day 187 vs. Day 180 for Group C. To control for testing multiple genes, 
the false-discovery rate based on the Benjamini-Hochberg procedure[32] as implemented in the 
p.adjust R function will be applied. The pvclust [33]R package will be used to identify co- 
expressed DE gene clusters. Mean cluster log2 fold change time trends and associated 95% 
bootstrap confidence intervals (CIs) will be presented by group across post-vaccination days. To 
functionally characterize differently expressed genes, pathway enrichment analysis based on the 
latest MSigDB [34]and KEGG databases[35] as well as Blood Transcription Modules will be 
carried out using the implementation provided by the goseq R package [36]which accounts for 
RNA-Seq gene length bias. Pathway maps color-coded by treatment effect (log2 fold change 
compared to pre-vaccination) will be visualized for significantly enriched KEGG pathways. 
Pathway enrichment trends by group across post-vaccination days will be visualized using 
bubble plots contrasting median pathway response with pathway enrichment as well as time 
trend plots of median pathway responses (based on median average log2 fold changes of all 
pathway members) and associated 95% bootstrap CIs. Regularized linear and/or logistic 
regression analysis as implemented in the glmnet R package [37]will be utilized to identify gene 
expression changes that are predictive of antibody levels that provide protective efficacy ex vivo 
as measured using passive transfer. Cross-validation in combination with bootstrap resampling 
will be used to select optimal models and to assess robustness of variable selections. Please see 
the separate document “Statistical Analysis Plan” for additional information on exploratory 
RNA-Seq analyses. 

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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
 
Each participating site will maintain appropriate medical and research records in compliance 
with ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Each site will permit authorized representatives of the DMID, its 
designees, and appropriate regulatory agencies to examine (and when required by applicable law, 
to copy) clinical records for the purposes of quality assurance reviews, audits, and evaluation of 
the study safety and progress. These representatives will be permitted access to all source data 
and source documents, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. 
This study uses direct data entry for the participating clinic site and the eCRFs serve as the 
source documents for data collected. 
Subjects will use a web-based electronic Memory Aid (e-Memory aid), or paper Memory Aid if 
internet access is not available. Data entered by subjects into the e-Memory Aid are stored in the 
data system for clinic staff review during scheduled visits. The e-Memory Aid is not considered 
source data. After clinic staff review and save the data, the data will be entered into Advantage 
eClinical as source. 

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

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DATA HANDLING AND RECORD KEEPING 
 
Data Management Responsibilities 
 
The site principal investigator is responsible to ensure the accuracy, completeness, and timeliness 
of the data reported. 
 
Data will be entered electronically over the Internet by site study staff into Advantage eClinical, 
developed and maintained by the SDCC. The eCRFs serve as the source documents for data 
collected. Paper case report forms derived from the eCRF are provided by the SDCC and are to 
be used only when Advantage eClinical is unavailable. Details on data handling procedures, 
procedures for data monitoring, and instructions for use of the system and completion of the eCRFs 
are provided in the study MOP, eCRF Instructions, and Advantage eClinical User’s Guide. 
 
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the eCRF. 
 
Data Coordinating Center/Biostatistician Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site principal investigator. During the study, the site principal 
investigator must maintain complete and accurate documentation for the study. 
Emmes will serve as the SDCC for this study, and will be responsible for data management, 
quality review, analysis, and reporting of the study data. 
 
Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) and reactogenicity will be entered into 
eCRFs via a 21 CFR Part 11-compliant internet data entry system provided by Emmes. The data 
system includes password protection and internal quality checks, such as automatic range checks, 
to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
Site staff who are delegated the responsibility by the study PI will be the data originators for 
clinical data entered directly into the eCRF. A list of all authorized data originators, including 
site staff, will be included on the Study Personnel/Signature Responsibility List. 

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

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

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

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centre trial. Vaccine. Oct 27 2017;35(45):6218-6227. doi:10.1016/j.vaccine.2017.09.027 
22. 
Belshe RB, Frey SE, Graham I, et al. Safety and immunogenicity of influenza A H5 
subunit vaccines: effect of vaccine schedule and antigenic variant. J Infect Dis. Mar 1 
2011;203(5):666-73. doi:10.1093/infdis/jiq093 
23. 
Marsano LS, Greenberg RN, Kirkpatrick RB, et al. Comparison of a rapid hepatitis B 
immunization schedule to the standard schedule for adults. Am J Gastroenterol. Jan 
1996;91(1):111-5. 
24. 
Madan A, Segall N, Ferguson M, et al. Immunogenicity and Safety of an AS03- 
Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults. J 
Infect Dis. Dec 01 2016;214(11):1717-1727. doi:10.1093/infdis/jiw414 

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25. 
Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory 
requirements. Nat Methods. Apr 2015;12(4):357-60. doi:10.1038/nmeth.3317 
26. 
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for 
assigning sequence reads to genomic features. Bioinformatics. Apr 1 2014;30(7):923-30. 
doi:10.1093/bioinformatics/btt656 
27. 
Aken BL, Achuthan P, Akanni W, et al. Ensembl 2017. Nucleic Acids Res. Jan 4 
2017;45(D1):D635-D642. doi:10.1093/nar/gkw1104 
28. 
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential 
expression analysis of digital gene expression data. Bioinformatics. Jan 1 2010;26(1):139-40. 
doi:10.1093/bioinformatics/btp616 
29. 
Siddiqui AA, Pinkston JR, Quinlin ML, et al. Characterization of the immune response to 
DNA vaccination strategies for schistosomiasis candidate antigen, Sm-p80 in the baboon. 
Vaccine. Feb 10 2005;23(12):1451-6. doi:10.1016/j.vaccine.2004.09.018 
30. 
Torben W, Ahmad G, Zhang W, et al. Role of antibody dependent cell mediated 
cytotoxicity (ADCC) in Sm-p80-mediated protection against Schistosoma mansoni. Vaccine. 
Nov 6 2012;30(48):6753-8. doi:10.1016/j.vaccine.2012.09.026 
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Robinson MD, Oshlack A. A scaling normalization method for differential expression 
analysis of RNA-seq data. Genome Biol. 2010;11(3):R25. doi:10.1186/gb-2010-11-3-r25 
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Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful 
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Suzuki R, Shimodaira H. Pvclust: an R package for assessing the uncertainty in 
hierarchical clustering. Bioinformatics. Jun 15 2006;22(12):1540-2. 
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Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. 
Molecular signatures database (MSigDB) 3.0. Bioinformatics. Jun 15 2011;27(12):1739-40. 
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Res. Jan 1 2000;28(1):27-30. doi:10.1093/nar/28.1.27 
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Young MD, Wakefield MJ, Smyth GK, Oshlack A. Gene ontology analysis for RNA-seq: 
accounting for selection bias. Genome Biol. 2010;11(2):R14. doi:10.1186/gb-2010-11-2-r14 
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Friedman J, Hastie T, Tibshirani R. Regularization Paths for Generalized Linear Models 
via Coordinate Descent. J Stat Softw. 2010;33(1):1-22. 

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APPENDICES 

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 Schedules of Events 
Table 7: Screening Visit Evaluations and Procedures. 
 
Screen 
Study day 
-30 to 
-1 
Study visit 
00 
Clinical Evaluations and Procedures 
Tube 
Screen 
Sign consent form 
X 
Assessment of eligibility 
X 
Review medical history and con meds and collect demographic information 
X 
Complete physical exam and height and weight, calculate BMI 
X 
Vital signs (blood pressure, pulse, and oral temperature) 
X 
Provide HIV test counseling 
X 
Review of contraceptive/menstrual history; pregnancy avoidance counseling1 
X 
Pregnancy test (serum)1, creatinine, ALT, HIV-1/HIV-2 testing, anti-HCV antibody, HBsAg 
(mL) 
SST 
25.5 
WBC, hemoglobin, platelets (mL) 
EDTA 
4 
Blood Volume (mL) 
29.5 
 
1For women of childbearing potential. 

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Table 8: Schedule of Events and Study Procedures, Study Groups A, B, D, and E 
 
 
Study Product Injection and Follow Up Visits 
Study day 
1 
2 
4 
8 
29 
32 
36 
57 
60 
64 
85 
181 
422 
Days after most recent 
vaccination 
0 
1 
3 
7 
28 
3 
7 
28 
3 
7 
28 
124 
365 
Visit Window (± 
number of days) 
0 
0 
1 
1 
3 
1 
1 
3 
1 
1 
3 
14 
14 
Study visit 
01 
02P 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13P 
Clinical Evaluations 
and Procedures 
Tube 
Assessment of 
eligibility 
X 
Assessment of 
individual halting 
criteria 
X 
X 
Review medical 
history and con meds3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (blood 
pressure, pulse, and 
oral temperature5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
X4 
Enrollment 
X 
Study Product 
Injection1 
I-1 
I-2 
I-3 
Targeted physical 
exam 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
Pre-administration 
reactogenicity 
assessment 
X 
X 
X 
Evaluate study 
product injection site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide and explain 
use of memory aid and 
thermometer 
X 
X 
X 
Review memory aid 
X 
X 
X 
X 
X 
X 
X 
Collection of solicited 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Study Product Injection and Follow Up Visits 
Study day 
1 
2 
4 
8 
29 
32 
36 
57 
60 
64 
85 
181 
422 
Days after most recent 
vaccination 
0 
1 
3 
7 
28 
3 
7 
28 
3 
7 
28 
124 
365 
Visit Window (± 
number of days) 
0 
0 
1 
1 
3 
1 
1 
3 
1 
1 
3 
14 
14 
Study visit 
01 
02P 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13P 
Clinical Evaluations 
and Procedures 
Tube 
Collection of 
unsolicited AEs and 
SAEs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (urine)2 
X 
X 
X 
WBC, hemoglobin, 
platelets (mL) 
EDTA 
3 
3 
3 
3 
3 
3 
3 
Creatinine, ALT6 
SST 
10 
10 
10 
10 
10 
10 
10 
Serum collection for 
antibody assays and 
secondary research 
(mL) 
SST 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
PBMC isolation for 
secondary research 
(mL) 
NaHep/ 
ACD7 
60 
60 
60 
60 
60 
60 
34 
60 
Whole blood 
collection for gene 
expression assays 
PAXGe 
ne 
2.5 
2.5 
2.5 
2.5 
2.5 
2.5 
Total volume per visit 
(mL) 
84 
84 
84 
84 
84 
84 
55.5 
68.5 
Cumulative volume 
(prior 56 days) 
113. 
5 
197. 
5 
281. 
5 
365. 
5 
420 
420 
391. 
5 
68.5 
{ } required at this visit only if clinically indicated 
P=phone assessment 
10.5 mL of the designated study product will be injected IM in the deltoid muscle. Prior to the injection, a pre-administration reactogenicity 
assessment will be performed to establish baseline. After the injection, subjects will be observed for 30 minutes. The injection site will 
be evaluated and vital signs obtained during that period and before the subject leaves the clinic. Subjects will be provided with a 
Memory Aid and thermometer for recording daily maximum oral temperature, solicited injection site and systemic reactions, unsolicited 
AEs, and concomitant medications, beginning on the evening of the day of study product injection and continuing daily for the next 
seven days. Subjects will be encouraged to take their temperature around the same time each day and also if they feel feverish. Subjects 
will be instructed on how to use the memory aid and how to rate any AEs. Subjects will also be instructed to notify the study center if 
they develop any severe reactions and/or fever ≥ 38°C (100.4°F). 

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2For women of childbearing potential. Must be confirmed as negative prior to injection of study product. The visit will also include review of 
contraceptive/menstrual history and pregnancy avoidance counseling. 
 
3After Study Visit 11 (or Study Day 85 if Study Visit 11 is not attended), through the end of study follow-up (Day 422), only SAEs, MAAEs, 
NOCMCs, and PIMMCs will be collected. Other unsolicited AEs and concomitant medications will not be collected. 
4Vital signs will be assessed only if clinically indicated. 
 
5Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
 
6 Blood collection volumes shown are the maximum that may potentially be drawn from the participant at each visit based on collection tube 
availability. 
7ACD collection tubes can be used to collect blood that will be processed for PBMC if appropriate NaHep tubes are unavailable. 

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Table 9: Schedule of Events and Study Procedures, Study Group C. 
 
Study day 
1 
2 
4 
8 
29 
32 
36 
57 
180 
183 
187 
208 
304 
545 
Days after most recent vaccination 
0 
1 
3 
7 
28 
3 
7 
28 
151 
3 
7 
28 
124 
365 
Visit Window (± number of days) 
0 
0 
1 
1 
3 
1 
1 
3 
7 
1 
1 
3 
14 
14 
Study visit 
01 
02P 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14P 
Clinical Evaluations and Procedures 
Tube 
Assessment of eligibility 
X 
Assessment of individual halting criteria 
X 
X 
Review medical history and con meds3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (blood pressure, pulse, and oral 
temperature5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
X4 
Enrollment 
X 
Study Product Injection1 
I-1 
I-2 
I-3 
Targeted physical exam 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
{X} 
Pre-administration reactogenicity assessment 
X 
X 
X 
Evaluate study product injection site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide and explain use of memory aid and 
thermometer 
X 
X 
X 
Review memory aid 
X 
X 
X 
X 
X 
X 
X 
Collection of solicited AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Study day 
1 
2 
4 
8 
29 
32 
36 
57 
180 
183 
187 
208 
304 
545 
Days after most recent vaccination 
0 
1 
3 
7 
28 
3 
7 
28 
151 
3 
7 
28 
124 
365 
Visit Window (± number of days) 
0 
0 
1 
1 
3 
1 
1 
3 
7 
1 
1 
3 
14 
14 
Study visit 
01 
02P 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14P 
Clinical Evaluations and Procedures 
Tube 
Collection of unsolicited AEs and SAEs3 
X 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
X 
Pregnancy test (urine)2 
X 
X 
X 
WBC, hemoglobin, platelets (mL) 
EDTA 
3 
3 
3 
3 
3 
3 
3 
3 
Creatinine, ALT6 
SST 
10 
10 
10 
10 
10 
10 
10 
10 
Serum collection for antibody assays and secondary 
research (mL) 
SST 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
8.5 
PBMC isolation for secondary research (mL) 
NaHep/ACD7 
60 
60 
60 
60 
60 
60 
60 
34 
60 
Whole blood collection for gene expression assays 
PAXGene 
2.5 
2.5 
2.5 
2.5 
2.5 
2.5 
Total volume per visit (mL) 
84 
84 
84 
84 
84 
84 
84 
55.5 
68.5 
Cumulative volume (prior 56 days) 
113.5 
197.5 
281.5 
365.5 
420 
84 
168 
223.5 
68.5 
 
 
{ } required at this visit only if clinically indicated 
P=phone assessment 
10.5 mL of the designated study product will be injected IM in the deltoid muscle. Prior to the injection, a pre-administration reactogenicity assessment will be performed to establish baseline. After the 
injection, subjects will be observed for 30 minutes. The injection site will be evaluated and vital signs obtained during that period and before the subject leaves the clinic. Subjects will be 
provided with a Memory Aid and thermometer for recording daily maximum oral temperature, solicited injection site and systemic reactions, unsolicited AEs, and concomitant medications, 

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beginning on the evening of the day of study product injection and continuing daily for the next seven days. Subjects will be encouraged to take their temperature around the same time each day 
and also if they feel feverish. Subjects will be instructed on how to use the memory aid and how to rate any AEs. Subjects will also be instructed to notify the study center if they develop any 
severe reactions and/or fever ≥ 38°C (100.4°F). 
2For women of childbearing potential. Must be confirmed as negative prior to injection of study product. The visit will also include review of contraceptive/menstrual history and pregnancy avoidance 
counseling. 
 
3After Study Visit 8 (or Study Day 57 if Study Visit 8 is not attended), through the time of the third study vaccination at Study Visit 09, only SAEs, MAAEs, NOCMCs, and PIMMCs will be collected. 
Other unsolicited AEs and concomitant medications will not be collected during this period. Collection of unsolicited AEs and concomitant medications will then resume at the time of the third 
vaccination and continue through Study Visit 12 (or Study Day 208 if Study Visit 12 is not attended), after which only SAEs, MAAEs, NOCMCs, and PIMMCs will be collected. 
4Vital signs will be assessed only if clinically indicated. 
 
5Subjects must not eat or drink anything hot or cold, or smoke within 10 minutes prior to taking oral temperature. 
 
6 Blood collection volumes shown are the maximum that may potentially be drawn from the participant at each visit based on collection tube availability. 
 
7ACD collection tubes can be used to collect blood that will be processed for PBMC if appropriate NaHep tubes are unavailable. 

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 List of Potentially Immune-Mediated Medical Conditions 
(PIMMCs) 
Gastrointestinal disorders 
 
• 
Celiac disease (gluten-sensitive enteropathy) 
• 
Inflammatory bowel disease (Crohn’s disease, ulcerative colitis or proctitis) 
 
Liver disorders 
 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
 
Metabolic diseases 
 
• 
Primary adrenal insufficiency (Addison’s disease) 
• 
Chronic lymphocytic thyroiditis (Hashimoto’s disease) (Not exclusionary for enrollment) 
• 
Diabetes mellitus type I 
• 
Graves’ or Basedow’s disease 
 
Musculoskeletal disorders 
 
• 
Antisynthetase syndrome 
• 
Dermatomyositis 
• 
Juvenile chronic arthritis/juvenile idiopathic arthritis (including juvenile Still’s disease 
[macrophage activating syndrome]) 
• 
Mixed connective tissue disorder 
• 
Polymyalgia rheumatica 
• 
Polymyositis 
• 
Psoriatic arthritis 
• 
Relapsing polychondritis 
• 
Rheumatoid arthritis 
• 
Scleroderma, including diffuse systemic form and CREST syndrome 

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• 
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., non- 
infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitis) 
• 
Possibly immune-mediated cranial nerve disorders (e.g., Bell’s palsy) 
• 
Guillain-Barré 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 
• 
Multiple sclerosis 
• 
Optic neuritis 
• 
Transverse myelitis 
• 
Myasthenia gravis, including Lambert-Eaton myasthenic syndrome (LEMS) 
 
Skin disorders 
 
• 
Alopecia areata 
• 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis 
herpetiformis 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Localized scleroderma (morphea) 
• 
Lichen planus 
• 
Psoriasis (May not be exclusionary for enrollment, see Section 5.1.2) 
• 
Acute febrile neutrophilic dermatosis (Sweet’s syndrome) 
• 
Vitiligo (May not be exclusionary for enrollment, see Section 5.1.2) 
 
Vasculitides 
 
• 
Large artery vasculitis: Takayasu’s arteritis and giant cell arteritis (temporal arteritis) 
• 
Small and medium-sized artery vasculitis: 

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Others 
o Polyarteritis nodosa 
o Mucocutaneous lymph node syndrome (Kawasaki disease) 
o Microscopic polyangiitis 
o Granulomatosis with polyangiitis (Wegener's granulomatosis) 
o Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) 
o Thromboangiitis obliterans (Buerger’s disease) 
o Necrotizing vasculitis (systemic necrotizing vasculitis) 
o Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis 
o IgA vasculitis (Henoch-Schonlein purpura) 
o Behcet's syndrome 
o Leukocytoclastic vasculitis (hypersensitivity vasculitis) 
 
• 
Antiphospholipid syndrome 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune glomerulonephritis (including IgA 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 
• 
Sjögren’s syndrome 
• 
Stevens-Johnson syndrome 
• 
Uveitis 

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Toxicity Tables 
 
 
Parameters for solicited AEs are reported in Table 3, Table 4, Table 5, and Table 6. 
 
 
Pulse and Blood Pressure 
 
Physiologic Parameter 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Tachycardia - beats per minute 
101 - 115 
116 - 130 
> 130 
Hypotension (systolic) mm Hg1 
85 – 89 
80 – 84 
<80 
Hypertension (systolic) mm Hg2 
141 – 150 
151 – 155 
> 155 
Hypertension (diastolic) mm Hg3 
96 – 100 
101 – 105 
>105 
 
 
The inclusion criteria for systolic blood pressure includes values from 85 through 150, inclusive 
and for diastolic blood pressure includes values ≤ 100. 
 
1Subjects with baseline (prior to first vaccination) Grade 1 values of 85-89 mm Hg are defined 
with a hypotension (systolic) AE only due to post-vaccination values ≤ 84 mm Hg and the AE is 
Defined as Grade 1 based on values of 80 through 84 and Grade 2 based on values less than 80. 
 
2Subjects with baseline (prior to first vaccination) Grade 1 values of 141-150 mm Hg are defined 
with a hypertension (systolic) AE only due to post-vaccination values over 150 mm Hg and the 
AE is Defined as Grade 1 based on values of 151 through 155 mm Hg and Grade 2 based on 
values over 155. 
 
3Subjects with baseline (prior to first vaccination) Grade 1 values of 96-100 mm Hg are defined 
with a hypertension (diastolic) AE only due to post-vaccination values ≥ 101 mm Hg and the AE 
is Defined as Grade 1 based on values of 101 through 105 mm Hg and Grade 2 based on values 
over 105. 

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Clinical Safety Laboratory Values 
 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
WBC 103/UL (Decrease) 
2.50 – 3.50 
1.50 – 2.49 
<1.50 
WBC 103/UL (Increase) 
13.01 – 15.00 
15.01 – 20.00 
>20.00 
HgB g/dL (Decrease) (Female) 
11.0 – 11.49 
9.5 – 10.9 
<9.5 
HgB g/dL (Decrease) (Male) 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
Platelets 103/UL (Decrease) 
120 – 130 
100 – 119 
<100 
Platelets 103/UL (Increase) 
416 – 550 
551– 750 
>750 
Chemistry 
ALT IU/L (Increase) 
47 – 105 
106 – 175 
>175 
Creatinine mg/dL (Increase) 
> ULN – 1.7 
1.8 – 2.0 
>2.0 
 
ULN = upper limit of normal range 

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Clinical Adverse Events 
CARDIOVASCULAR 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Arrhythmia 
asymptomatic, transient 
signs, no Rx required 
recurrent/persistent; 
symptomatic Rx 
required 
Hemorrhage, Blood Loss 
Estimated 
blood loss < 
100 mL 
Estimated blood loss > 
100 mL, no transfusion 
required 
Transfusion 
required 
RESPIRATORY 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Cough 
Transient- no 
treatment 
Persistent cough; 
Interferes with 
daily activities 
Bronchospasm, Acute 
transient; no 
treatment; 71% 
- 80% FEV1 of 
peak flow 
requires treatment; 
normalizes with 
bronchodilator; FEV1 
60% - 70% (of peak flow) 
no normalization 
with 
bronchodilator; 
FEV1 <60% of 
peak flow 
Dyspnea 
Does not 
interfere with 
usual and 
social 
activities 
Interferes with usual and 
social activities, no 
treatment 
Prevents daily and 
usual social activity 
or requires 
treatment 
GASTROINTESTINAL Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Vomiting 
No 
interference 
with activity or 
1 - 2 
episodes/24 
hours 
Some interference with 
activity or > 2 episodes/24 
hours 
Prevents daily 
activity or requires 
IV hydration 

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Diarrhea 
2 - 3 loose or 
watery stools 
or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 gms/24 
hours 
6 or more loose or 
watery stools or > 
800gms/24 hours or 
requires IV 
hydration 
SYSTEMIC 
REACTIONS 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Allergic Reaction 
pruritus 
without rash 
localized urticaria 
generalized 
urticaria; 
angioedema or 
anaphylaxis 
All Other conditions 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
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