A Phase I Safety and Immunogenicity Trial of IHV01 in HIV-1 Uninfected Volunteers
Phase: PHASE1
Conditions: HIV Infection
Sponsor: University of Maryland, Baltimore

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IHV01 
 
 
 
A PHASE I SAFETY AND IMMUNOGENICITY TRIAL OF IHV01 IN HIV-1 
UNINFECTED VOLUNTEERS 
 
 
DATE: 
3/27/17 
 
SPONSOR: 
 Institute of Human Virology (IHV) 
725 West Lombard Street 
Baltimore, MD 21201 
Director: Robert Gallo, M.D. 
Contact: Shyamasundaran Kottilil M.B.B.S., Ph.D. 
Tel: 410-706-4613 
 
MEDICAL MONITOR: 
Kirsten Lyke, M.D. 
Center for Vaccine Development 
685 West Baltimore Street , Room 480 
Baltimore, MD 21201-1509 
Tel: 410-706-7376 
 
PRINCIPAL INVESTIGATOR: Charles E. Davis Jr., M.D. 
Institute of Human Virology (IHV) 
725 West Lombard Street 
Baltimore, MD 21201 
Tel: 410-706-4608 
Fax: 410-706-3243 
 
CO-INVESTIGATORS: 
Joel Chua, M.D. 
David J. Riedel, M.D. 
 
 
STUDY SITE: 
Institute of Human Virology (IHV) 
725 West Lombard Street 
Baltimore, MD 21201 
Phone: 410-706-1684 
 
MANUFACTURER: 
Profectus Biosciences 
 
PROTOCOL NUMBER: 
FLSC-001 
 
IND NUMBER: 
16505 
 
CONFIDENTIAL 

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INVESTIGATOR’S AGREEMENT 
 
 
 
I have received, read the Investigator’s Brochure for IHV01 and agree to conduct the study as 
outlined. By my signature below, I attest that I have read, understood, and agree to abide by all 
conditions, instructions, and restrictions contained in this protocol (including appendices). I will 
not initiate this study without approval from the appropriate Institutional Review Board (IRB) 
and I understand that any changes in the protocol must be approved in writing by Profectus 
BioSciences, Inc. and the IRB before they can be implemented, except where necessary to 
eliminate immediate hazards to the volunteer.  I agree to maintain the confidentiality of all 
information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
Signature of Investigator 
 
 
 
 
Date 

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PROCEDURES IN CASE OF EMERGENCY 
 
 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
Address and Telephone number 
Clinical Study Leader 
Charles E. Davis Jr., M.D. 
Institute of Human Virology 
725 West Lombard St, Room N555 
Baltimore, MD 21201 
410-706-4608 
Responsible Physician 
Charles E. Davis Jr., M.D. 
Institute of Human Virology 
725 West Lombard St, Room N555 
Baltimore, MD 21201 
410-706-4608 
Drug Safety Physician 
Kirsten Lyke, M.D. 
Center for Vaccine Development 
685 West Baltimore St, Room 480 
Baltimore, MD 21201 
410-706-7376 
24-Hour Emergency Contact 
Charles E. Davis Jr., M.D. 
Institute of Human Virology 
725 West Lombard St, Room N555 
Baltimore, MD 21201 
301-775-7618 

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2. 
SYNOPSIS 
 
Name of Sponsor/Company: Sponsor: Institute of Human Virology 
Manufacturer: Profectus Biosciences 
Name of Investigational Product: IHV01 
Name of Active Ingredient: Full Length Single Chain (FLSC), Aluminum Phosphate 
 
Title of Study: A Phase I Safety and Immunogenicity Trial of IHV01, in HIV-1 Uninfected 
Volunteers 
Study center(s): Institute of Human Virology 
Principal Investigator: Charles E. Davis Jr., M.D. 
 
Investigators:  Joel Chua, M.D. 
                          David J. Riedel, M.D. 
Studied period (years): 1 year 
Estimated date first patient enrolled: November 2015 
Estimated date last patient completed:  May 2018 
Phase of development: I 
Objectives: 
Primary: 
To evaluate the safety and tolerability of intramuscular administration of the IHV01 at three different 
doses. 
Secondary: 
 
To evaluate the immunogenicity of three different doses of the IHV01, a full length single chain 
(FLSC) gp120-CD4 complex vaccine. This will be assessed by the following parameters: 1) anti- 
FLSC antibodies, and 2) anti gp-120 (BaL), and 3) competitive titers to CD4i epitopes. 
Methodology: Single center, randomized, dose escalation, placebo-controlled, double-blind trial 
Number of patients (planned): 60 
 
Diagnosis and main criteria for inclusion: Inclusion/Exclusion Criteria as in Section 7.1 and 
Section 7.2. 
Investigational product, dosage and mode of administration: 
IHV01 in sequential dose escalation of 75 ug, 150 ug and 300 ug administered intramuscularly. 
Duration of treatment: 

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Volunteers will be immunized with candidate vaccine or placebo on Days 0, 28(week 4), 56(week 8), 
and 168(week 24). Volunteers will continue to undergo active protocol follow up visits on Days 
182(week 26), 196(week 28), 252(week 36). 294 (week 42) and 336 (week 48). The total trial time 
expected per volunteer is 48 weeks.  The protocol recruitment period is expected to be approximately 
36 weeks. The total trial duration is estimated to be approximately 72-96 weeks. 
Reference therapy, dosage and mode of administration: 
Placebo consisting of preservative free normal saline in volumes equal to the investigational product 
administered intramuscularly. 
Criteria for evaluation: 
 
 
Safety: 
1. Monitoring and assessment of hematological, chemical, and immunologic parameters (See 
Section 11.1.5, Section 12.1, and Table 4). 
2. Monitoring participants for local and systemic adverse reactions after each injection and for 12 
months after the first injection (Section 11.2). 
a. Local reactogenicity signs and symptoms 
b. Systemic reactogenicity signs and symptoms 
c. Adverse and serious adverse experiences 
Immunogenicity: 
See Section 12.1 and Section 12.2. 
Statistical methods: 
Each safety parameter assessed will be compared between vaccine recipients and placebo recipients 
as determined by Student’s T test and chi-square analyses.  In addition safety parameters with be 
compared between vaccine dose groups as well as to placebo recipients. Further analyses as 
described in Section 13. 

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TABLE OF CONTENTS 
1. TITLE PAGE ........................................................................................................................1 
INVESTIGATOR’S AGREEMENT ............................................................................................2 
PROCEDURES IN CASE OF EMERGENCY ...........................................................................3 
2. SYNOPSIS ............................................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................6 
3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................10 
4. INTRODUCTION ..............................................................................................................12 
4.1. Name and Description of the Investigational Product  .................................................... 12 
4.2. Trial Design Overview  ................................................................................................... 12 
4.3. Rationale for testing IHV01 vaccine (FLSC) in a phase 1 clinical trial  ......................... 12 
4.4. Findings from nonclinical studies that potentially have clinical significance  ................ 13 
4.4.1. Immunological markers of protection  ................................................................ 13 
4.4.2. Safety/Toxicity Data  ........................................................................................... 14 
4.5. Findings from clinical trials that are relevant to the proposed trial  ................................ 15 
4.5.1. Correlates of protection  ...................................................................................... 15 
4.5.2. Potential Risks  .................................................................................................... 15 
5. TRIAL OBJECTIVES AND PURPOSE ..........................................................................17 
5.1. Purpose  ........................................................................................................................... 17 
5.2. Primary Objective - Safety  ............................................................................................. 17 
5.3. Secondary Objectives - Immunogenicity  ....................................................................... 17 
6. INVESTIGATIONAL PLAN ............................................................................................18 
6.1. Overall Study Design  ...................................................................................................... 18 
6.1.1. Study Procedures  ................................................................................................ 18 
6.1.1.1. Study Entry  ............................................................................................... 18 
6.1.1.2. Study Duration  .......................................................................................... 18 
6.1.1.3. Study Evaluations  ..................................................................................... 18 
6.1.1.4. Missed Visits  ............................................................................................. 23 
6.1.1.5. Replacement  .............................................................................................. 23 
6.1.1.6. Pregnancy  .................................................................................................. 24 
6.1.1.7. Off-study evaluations  ................................................................................ 24 
6.2. Number of Volunteers  .................................................................................................... 24 
6.3. Treatment Assignment  .................................................................................................... 24 
6.4. Dose Escalation Criteria  ................................................................................................. 25 
6.4.1. Safety Criteria for Adjustment or Stopping Doses  ............................................. 25 
6.4.2. Pharmacokinetic Criteria for Adjustment or Stopping Doses  ............................ 25 
6.5. Criteria for Study Termination  ....................................................................................... 25 
7. SELECTION AND WITHDRAWAL OF VOLUNTEERS ...........................................31 
7.1. Volunteer Inclusion Criteria  ........................................................................................... 31 
7.2. Volunteer Exclusion Criteria  .......................................................................................... 31 

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7.3. Volunteer Withdrawal Criteria  ....................................................................................... 32 
7.3.1. Reasons for Withdrawal for Study  ..................................................................... 32 
7.3.1.1. Conditions mandating withdrawal from the Study  ................................... 32 
7.3.1.2. Conditions permissible to withdraw from the Study  ................................ 33 
7.3.2. Withdrawal Procedures  ....................................................................................... 33 
7.3.2.1. Volunteer Withdraws  ................................................................................ 33 
7.3.2.2. Volunteer Withdrawn by Investigator  ....................................................... 33 
7.3.2.3. Volunteer Withdrawn for Vaccine Related Toxicity  ................................ 33 
7.3.2.4. Volunteer Withdrawn by Investigator for other reasons  ........................... 33 
7.3.3. Reasons to Halt Study  ........................................................................................ 34 
7.3.4. Reasons for Discontinuation of all Immunizations in the Study  ........................ 34 
8. 
TREATMENT OF VOLUNTEERS  ................................................................................ 35 
8.1. Description of Study Drug  .............................................................................................. 35 
8.2. Concomitant Medications  ............................................................................................... 36 
8.3. Treatment Compliance  ................................................................................................... 36 
8.4. Randomization and Blinding  .......................................................................................... 36 
8.4.1. Blinding  .............................................................................................................. 36 
8.4.2. Blinding and Code Breaking Procedures  ............................................................ 36 
8.5. Identification of participants as volunteers in HIV vaccine trial  .................................... 37 
8.6. Detection of intercurrent HIV-1 infections. .................................................................... 37 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT  ................................................. 39 
9.1. Study Drug  ...................................................................................................................... 39 
9.2. Study Drug Packaging and Labeling  .............................................................................. 39 
9.3. Study Drug Storage ......................................................................................................... 39 
9.4. Study Drug Preparation  .................................................................................................. 39 
9.4.1. FLSC 75 ug (Group 1)  ....................................................................................... 39 
9.4.2. FLSC 150 ug (Group 2)  ..................................................................................... 39 
9.4.3. FLSC 300 ug (Group 3)  ...................................................................................... 39 
9.4.4. Placebo (Groups 1-3)  .......................................................................................... 40 
9.5. Administration  ................................................................................................................ 40 
9.6. Study Drug Accountability  ............................................................................................. 41 
9.7. Study Drug Handling and Disposal  ................................................................................ 41 
10. 
CLINICAL SAMPLE COLLECTION  ........................................................................... 42 
10.1. Blood Sample Collection  ........................................................................................... 42 
10.2. Urine Sample Collection  ............................................................................................ 42 
10.3. Sample Analysis  ........................................................................................................ 42 
11. 
ASSESSMENT OF SAFETY  ........................................................................................... 43 
11.1. Safety Parameters  ...................................................................................................... 43 
11.1.1. Demographic/Medical History  ........................................................................... 43 
11.1.2. Vital Signs  .......................................................................................................... 43 
11.1.3. Weight and Height  .............................................................................................. 43 
11.1.4. Physical Examination  ......................................................................................... 43 
11.1.5. Laboratory Assessments  ..................................................................................... 43 

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11.1.5.1. Hematology  ............................................................................................... 44 
11.1.5.2. Blood Chemistry  ....................................................................................... 44 
11.1.5.3. Urinalysis  .................................................................................................. 44 
11.1.5.4. Virus Serology  .......................................................................................... 44 
11.1.5.5. Pregnancy Screen  ...................................................................................... 44 
11.1.5.6. Assessment of Vaccine Reactogenicity  .................................................... 44 
11.2. Adverse and Serious Adverse Events  ........................................................................ 45 
11.2.1. Definition of Adverse Events  ............................................................................. 45 
11.2.1.1. Adverse Event (AE)  .................................................................................. 45 
11.2.1.2. Serious Adverse Event (SAE)  ................................................................... 45 
11.2.1.3. Other Adverse Event (OAE)  ..................................................................... 46 
11.3. Relationship to Study Drug  ........................................................................................ 46 
11.4. Recording Adverse Events  ......................................................................................... 46 
11.5. Reporting Adverse Events  ......................................................................................... 47 
11.5.1. Adverse Events  ................................................................................................... 47 
11.5.2. Serious Adverse Events  ...................................................................................... 48 
11.6. Data Safety Monitoring Board  ................................................................................... 48 
12. 
ASSESSMENT OF IMMUNOGENICITY  ..................................................................... 50 
12.1. Endpoint Evaluations of Immunogenicity  ................................................................. 50 
12.1.1. Immunogenicity Endpoint  .................................................................................. 50 
12.1.2. Secondary Immunogenicity Endpoints  ............................................................... 50 
12.1.3. Exploratory/Developmental Immunogenicity Endpoints  ................................... 50 
12.2. Immunogenicity Assays  ............................................................................................. 50 
12.2.1. Endpoint Assay  ................................................................................................... 50 
12.2.2. Secondary Endpoint Assay  ................................................................................. 51 
12.2.3. Developmental Assays  ....................................................................................... 51 
12.2.4. Assay Timepoints  ............................................................................................... 51 
12.2.5. Data Analysis  ...................................................................................................... 52 
13. 
STATISTICS  ..................................................................................................................... 53 
13.1. Determination of Sample Size  ................................................................................... 53 
13.2. Statistical Methods  ..................................................................................................... 53 
13.3. Volunteer Population  ................................................................................................. 53 
13.3.1. Population analyzed  ............................................................................................ 53 
13.3.1.1. Definitions of Populations  ........................................................................ 53 
13.3.1.2. Full Analysis Set  ....................................................................................... 54 
13.3.1.3. Safety Analysis Sets  .................................................................................. 54 
13.3.1.4. Immunogenicity Analysis Sets  .................................................................. 54 
13.4. Primary Criterion Analysis  ........................................................................................ 54 
13.5. Secondary Criterion Analysis  .................................................................................... 54 
13.6. Level of significance  .................................................................................................. 55 
13.7. Criteria for Termination of the Trial  .......................................................................... 55 
13.8. Procedures for Missing or Spurious Data  .................................................................. 55 
13.9. Changes in Statistical Methods  .................................................................................. 55 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  ............................................. 56 

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14.1. Study Monitoring  ....................................................................................................... 56 
14.2. Audits and Inspections  ............................................................................................... 56 
14.3. Institutional Review Board (IRB)  .............................................................................. 56 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE  .............................................. 57 
15.1. Study Monitoring  ....................................................................................................... 57 
15.2. Laboratory  .................................................................................................................. 57 
15.3. Handling of Biologic Samples  ................................................................................... 57 
16. 
ETHICS  .............................................................................................................................. 58 
16.1. Ethics Review  ............................................................................................................ 58 
17. 
ETHICAL CONDUCT OF THE STUDY  ....................................................................... 59 
17.1. Written Informed Consent  ......................................................................................... 59 
18. 
DATA HANDLING AND RECORDKEEPING  ............................................................ 60 
18.1. Inspection of Records  ................................................................................................ 60 
18.2. Retention of Records  ................................................................................................. 60 
18.3. Data Recording  .......................................................................................................... 60 
18.4. Data Control Methods  ................................................................................................ 60 
19. 
PUBLICATION POLICY  ................................................................................................ 61 
20. 
LIST OF REFERENCES  ................................................................................................. 62 
21. 
APPENDICES  ................................................................................................................... 66 
APPENDIX 1. 
DETAILED REACTOGENICITY FORM  .......................................... 67 
APPENDIX 2. 
TABLE FOR GRADING SEVERITY OF ADULT ADVERSE 
EXPERIENCES  ....................................................................................................... 68 
APPENDIX 3. 
INVESTIGATIONAL DRUG ACCOUNTABILITY 
POLICY/PROCEDURE  ......................................................................................... 76 
 
 
 
LIST OF TABLES 
 
Table 1: 
Emergency Contact Information ................................................................................... 3 
Table 2: 
Abbreviations and Specialist Terms ........................................................................... 10 
Table 3: 
Study Design  .............................................................................................................. 26 
Table 4: 
Schedule of Assessments  ........................................................................................... 27 
Table 5: 
Blood Draw Flow Sheet  ............................................................................................. 29 
Table 6: 
Investigational Product  .............................................................................................. 36 
Table 7: 
Placebo Groups  .......................................................................................................... 40 
LIST OF FIGURES 
Figure 1: 
Algorithm to detect inter-current HIV-1 infections .................................................... 38 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
 
Table 2: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
Ab 
Antibody 
ACTG 
AIDS Clinical Trials Group 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Asparatate aminotransferase 
BP 
Blood pressure 
CBC 
Complete Blood Count
CMI 
Cell Mediated Immune 
CPT 
Cell Preparation Tube 
CRF 
Case Report Form 
CTL 
Cytotoxic T Lymphocyte 
DNA 
Deoxyribonucleic Acid 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
FLSC 
Full Length Single Chain gp120-CD4 complex Vaccine 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator's Brochure 
ICC 
Intracellular Cytokine Cytometry 
ICH 
International Conference on Harmonization 
IHV 
Institute of Human Virology 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IRB 
Institutional Review Board 
OAE 
Other significant adverse event 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 

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Abbreviation or Specialist Term 
Explanation 
PI 
Principal Investigator 
The investigator who leads the study conduct at an individual study 
center.  Every study center has a principal investigator. 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
SAE 
Serious adverse event 
SHIV 
Simian/HIV virus 
SIV 
Simian Immunodeficiency virus 
SD 
Standard deviation 
UMMC 
University of Maryland Medical Center 
WB 
Western-Blot 

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4. 
INTRODUCTION 
 
4.1. 
Name and Description of the Investigational Product 
 
The investigational product is IHV01 which consists of the Full Length Single Chain (FLSC) 
gp120-CD4 chimera subunit vaccine formulated in Aluminum phosphate adjuvant (Alum). The 
formulation consists of 0.3 mg/ml of FLSC, 2.4 mg/ml of Alum, 5 mM NaOAc, 40 mg/mL 
mannitol, pH 6.2. The product intended use is as a prophylactic vaccine to prevent infection with 
HIV. FLSC is encoded by a synthetic gene, which contains a human codon-optimized HIV(BaL) 
gp120 sequence (an R5-tropic envelope), followed human CD4D1D2, connected together by a 
flexible 20 amino acid (S-G-A) linker that covalently links the gp120 and CD4 portions. The gp120 
sequences are translated as the N terminus of the chimera and the CD4 sequences at the C terminus. 
This construction allows the gp120 and CD4 moieties to form a stable intrachain binding 
interaction that forms a transition state structure that presents conserved, conformational domains 
involved in the early HIV replication process (Fouts, Tuskan et al. 2000). 
 
4.2. 
Trial Design Overview 
 
This study is designed to evaluate the safety of the IHV01 vaccine and will be a randomized, 
placebo-controlled, modified double-blinded dose escalation study in 60 healthy adult volunteers. 
Although there is a great deal of experience with protein vaccines, the optimal dose of IHV01 
given intramuscularly is not known. Therefore, this trial is designed as a dose escalation trial in 
order to determine the optimal dose to move forward with in future clinical trials. This dose will 
be chosen after reviewing the safety and immunogenicity data from this trial. Alum has been 
chosen as an adjuvant due to the extensive amount of safety data available. The study will have 3 
arms including placebo, 75 µg dose, 150 µg dose, and 300 µg dose and will last for 336 days (48 
weeks). Volunteers will be immunized on Day 0, Day 28(4 weeks), Day 56(8 weeks), and Day 
168(24 weeks). Each dose group will have 15 vaccine and 5 placebo recipients. The dosage 
schedule in this trial was based on the animal data and data with other envelope protein vaccines, 
and is patterned after the schedule utilized in the RV144 trial in Thailand. From this trial, an 
optimal dose of the candidate vaccine will be chosen for use in future trials. It is anticipated that 
the trial will be enrolled and completed 18 months after it is open to enrollment. 
 
4.3. 
Rationale for testing IHV01 vaccine (FLSC) in a phase 1 clinical trial 
 
The challenge for HIV vaccine development stems from evolutionary pressures that abrogate the 
immunogenicity of conserved, functional epitopes on the envelope spike that are potential targets 
for cross-reactive antibodies. Large areas are masked by a “glycan shield” of carbohydrate 
molecules (Leonard, Spellman et al. 1990; Kwong, Wyatt et al. 1998; Wei, Decker et al. 2003) 
and extensive conformational flexibility (sometimes termed “conformational masking”) (Myszka, 
Sweet et al. 2000; Kwong, Doyle et al. 2002; Chen, Vogan et al. 2005) that dampen 
immunogenicity of the conserved functional domains. The remaining immunogenic domains 
(“variable” or “V” loops) tolerate a high degree of sequence variability (Hahn, Gonda et al. 1985; 
Saag, Hahn et al. 1988; Wyatt, Kwong et al. 1998; Hartley, Klasse et al. 2005) and generate “type- 
specific” neutralizing antibodies (Putney, Matthews et al. 1986; Rusche, Javaherian et al. 1988; 
Fung, Sun et al. 1992; Sattentau 1996) that are not cross-reactive. The IHV01 vaccine (FLSC) 
design approach solves these problems by “locking” the conformation of the envelope into a highly 

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immunogenic moiety that induces antibodies that target highly conserved epitopes on gp120. Such 
antibodies would be highly cross-reactive and potentially useful for HIV vaccine development (see 
Section 4.4 and Section 4.5). 
 
There is a growing body of evidence supporting the FLSC approach. In particular, the anti-CD4i 
epitope antibodies raised by FLSC have the potential to facilitate “non-neutralizing” control of 
infection via Fc-Receptor-dependent mechanisms that have been correlated with protection in past 
studies (Ferrari, Pollara et al. ; Sun, Asmal et al. ; Gomez-Roman, Patterson et al. 2005; Hessell, 
Hangartner et al. 2007; Florese, Demberg et al. 2009; Hessell, Rakasz et al. 2009; Hidajat, Xiao et 
al. 2009; Rerks-Ngarm, Pitisuttithum et al. 2009; Xiao, Zhao et al. 2010; Barouch, Liu et al. 2012; 
Haynes, Gilbert et al. 2012; Robb, Rerks-Ngarm et al. 2012; Barouch, Stephenson et al. 2013; 
Lewis 2013; Tomaras, Ferrari et al. 2013; Vargas-Inchaustegui and Robert-Guroff 2013). 
Antibodies to certain CD4i epitopes are especially potent mediators of ADCC activity against 
freshly targeted host cells and chronically infected cells (Ferrari, Pollara et al. 2011; Guan, Pazgier 
et al. 2013; Pollara, Bonsignori et al. 2013). Serum antibodies exhibiting Fc-mediated antiviral 
activity were correlated with the rate of acquiring HIV infection after gp120 immunization in 
vaccinees from the Vax004 trial (Wilflingseder, Banki et al. 2007); similar correlates were 
observed in Thai volunteers receiving the ALVAC-HIV/AIDSVAC B/E prime/boost regimen 
(Rerks-Ngarm, Pitisuttithum et al. 2009; Haynes, Gilbert et al. 2012). Specifically, ADCC activity 
was correlated with reduced risk of infection in vaccinees with lower IgA responses. Since plasma 
IgA poorly mediates ADCC, these data suggest that IgG-dependent ADCC is beneficial as long as 
it is not dampened by competitive plasma IgA responses (Haynes, Gilbert et al. 2012; Tomaras, 
Ferrari et al. 2013). In accordance with these findings, we have determined that similar responses 
raised in nonhuman primates by rhFLSC can be correlated with resistance to heterologous virus 
challenge (DeVico, Fouts et al. 2007; Fouts, Bagley et al. 2015) (see Investigator’s Brochure 
Section 4 and 6.1). 
 
4.4. 
Findings from nonclinical studies that potentially have clinical 
significance 
 
4.4.1. 
Immunological markers of protection 
 
Proof of concept studies show that rhFLSC can elicit protection against SHIV acquisition under 
experimental conditions that mimic those likely to confront the deployment of an effective HIV 
vaccine. These include transmitting viruses that are heterologous to the vaccine and are difficult 
to neutralize. They also show that parenteral immunization can protect against mucosal 
acquisition, which a probable requirement for an effective HIV vaccine. Proof-of-concept 
challenge studies also showed that the immune response that provided the best protection in either 
challenge model was directed to the CD4 induced epitopes that were preferentially presented by 
the FLSC. These characteristics included a ratio of serum antibodies titers to FLSC/gp120 > 2 and 
the presence of antibodies titers > 1:100 directed to CD4i epitopes defined by human MAbs 17b, 
19e, A32, and N12-i2. Since the FLSC/aluminum phosphate formulation was not evaluated in 
these studies, a study was performed with cynomolgus monkeys to evaluate the immune response 
generated with clinical formulation. One group of animals was immunized with rhFLSC also 
formulated in aluminum phosphate to account for any immunogenicity generated to the 
heterologous CD4 used in the human FLSC. Cynomolgus macaques were also selected because 
the region of their CD4 is homologous to the rhesus CD4 used in rhFLSC.  The immune response 

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generated by the aluminum phosphate formulation was robust with antigen specific serum 
antibody responses directed towards epitopes presented by FLSC. All immunized animals 
presented FLSC/gp120 ratio >2. Animals immunized with FLSC presented a higher ratio as 
compared to those immunized with rhFLSC most likely because a portion of the antibody response 
in the FLSC groups is directed to the heterologous human CD4. All groups also presented 
competitive serum antibodies directed to CD4i epitopes recognized by 17b, 19e, A32, and N12-i2 
that were >200 EU and, in some animals, were >1000 EU. Collectively, these data demonstrate 
that the immune response generated by the FLSC/ aluminum phosphate formulation will induce a 
CD4i directed immune response that similar to that generated by FLSC in our proof-of-concept 
studies. 
 
These proof-of-concept challenge studies and the immunogenicity studies in cynomolgus 
macaques are summarized in Investigator’s Brochure Section 4 and 6.1. 
 
4.4.2. 
Safety/Toxicity Data 
 
The safety of FLSC absorbed to aluminum phosphate was evaluated in a GLP-compliant, repeat- 
dose toxicity study in rabbits (Study Number 5000069) and in an immunotoxicity study in 
cynomolgus monkeys (Study Number VTR-0018). 
 
In the repeat dose toxicity study in rabbits, FLSC was absorbed to aluminum phosphate and 
dosages of 300 μg/2.4 mg or 900 μg/7.2 mg FLSC/Adjuvant were intramuscularly injected once 
every three weeks (Days 1, 22, 43, 64 and 85) for 5 total administrations. For the 
immunotoxicology study, cynomolgus monkeys were repeatedly intramuscularly vaccinated with 
FLSC or rhesus FLSC (containing HIV gp120 and rhesus CD4). After the third and fourth 
vaccination, neoantigen KLH was administered. The FLSC contains the D1D2 domains of human 
CD4 that is only 88% identical to that of cynomolgus and rhesus monkey CD4s. The rhesus CD4 
D1D2 amino acid sequence is 100% identical to the cynomolgus CD4 D1D2 sequence, which 
allows for the evaluation of the induction of antibodies that may cross-react with the endogenous 
cynomolgus CD4 protein. The rhFLSC was used as a mimic for the test of FLSC in humans. Prior 
to the pivotal study, a pilot study verified that inhibition of CD4 activity in the cynomolgus monkey 
negatively affected the immune response against KLH (Study Number VTR-0016 (Study VTR- 
0018, Appendix 16)). Measures of autoimmune responses to CD4 that may be deleterious included 
drop in CD4 count, significant impact in the serum response to neoantigen KLH, and drop in in 
vitro proliferation of cells after addition of immune sera in a mix lymphocyte reaction assay. 
 
The toxicology studies showed that repeated intramuscular vaccinations with 300 or 900 μg FLSC 
(with aluminum phosphate adjuvant) was well tolerated in rabbits (up to 5 administrations) and 
cynomolgus monkeys (up to 4 administrations). The majority of the effects observed in the rabbit 
toxicity study can be attributed to general inflammation occurring with intramuscular vaccine 
administration and/or an active immune response towards the antigen. No deleterious effects on 
the immune system were detected in the cynomolgus monkey with repeat administration of up to 
900 μg FLSC (with aluminum phosphate adjuvant). Of most concern is the potential test article 
related reduction in platelet count with FLSC; however, this finding only occurred in the rabbit 
with repeat administration of the high dose of FLSC (900 μg), which is 12-fold greater than the 
proposed starting dose of 75 μg FLSC in the clinic and 3-fold greater than the proposed maximum 
clinical dose of 300 μg FLSC. Thus, the safety risk of 4 intramuscular administrations of FLSC 
(with aluminum phosphate adjuvant) to the patient is low. 

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4.5. 
Findings from clinical trials that are relevant to the proposed trial 
 
4.5.1. 
Correlates of protection 
 
While the need for a preventive HIV vaccine effective worldwide becomes more urgent every 
year, the correlates of immunity or protection are still not well understood. This makes it difficult 
to determine the optimal characteristics of an HIV vaccine candidate. At this point, the general 
consensus view is that a successful HIV vaccine candidate must raise humoral immune responses 
that recognize conserved domains on the viral envelope and mediate various antiviral effector 
mechanisms. This view is reinforced by the RV144 clinical trial, which demonstrated modest 
protection against HIV infection in Thailand that correlated with anti-gp120 antibody responses 
(Rerks-Ngarm, Pitisuttithum et al. 2009; Haynes, Gilbert et al. 2012). Such mechanisms could 
include 1) direct neutralizing activity, as passive transfer of broadly neutralizing antibodies affords 
protection against infection in nonhuman primate models (Mascola, Lewis et al. 1999; Baba, Liska 
et al. 2000; Hessell, Hangartner et al. 2007); 2) ADCC activity, given its past associations with 
protection against HIV, SHIV or SIV infection (Ferrari, Pollara et al. ; Sun, Asmal et al. ; Gomez- 
Roman, Patterson et al. 2005; Hessell, Hangartner et al. 2007; Florese, Demberg et al. 2009; 
Hessell, Rakasz et al. 2009; Hidajat, Xiao et al. 2009; Rerks-Ngarm, Pitisuttithum et al. 2009; 
Xiao, Zhao et al. 2010; Barouch, Liu et al. 2012; Haynes, Gilbert et al. 2012; Robb, Rerks-Ngarm 
et al. 2012; Barouch, Stephenson et al. 2013; Tomaras, Ferrari et al. 2013); and/or a variety of 
other Fc receptor-dependent effector mechanisms including trogocytosis, phagocytosis and 
antibody-dependent cell-mediated viral inhibition or ADCVI (Forthal, Landucci et al. 2001; 
Ackerman and Alter 2013; Kramski, Parsons et al. 2013; Lewis 2013; Pollara, Bonsignori et al. 
2013; Vargas-Inchaustegui and Robert-Guroff 2013). As discussed in the Investigator’s Brochure 
Section 4 and 6.1, we have determined that rhFLSC elicits humoral responses against conserved 
domains, associated with specificities and effector mechanisms that correlate with protection in 
animal models (DeVico, Fouts et al. 2007; Fouts, Bagley et al. 2015). These findings warrant 
clinical tests of FLSC in human trials to determine if these and other responses correlated with 
control or prevention of HIV infection are elicited. 
 
4.5.2. 
Potential Risks 
 
In theory, it is possible that immunization with gp120-CD4 complexes could induce auto-anti- 
CD4 responses. These could be antibody responses, T cell responses, or both. It is well established 
in the older immunological literature that it is possible to break tolerance to self-antigens by adding 
T helper epitopes. In principle, gp120 T helper epitopes could collaborate with auto-anti-CD4 B 
cells or CTL precursors to break tolerance to CD4 epitopes. In this regard, it is interesting to note 
that immunization of a chimp with soluble human CD4 elicited an antibody response against an 
epitope that is not present on cell surface CD4 although the sera were able to block infection of 
chimpanzee or human lymphocytes with HIV-1 (Watanabe, Boyson et al. 1992). Similar results 
were obtained in rhesus macaques immunized with human CD4 (Watanabe, Chen et al. 1991; 
Watanabe, Levine et al. 1991). These studies used soluble human CD4 that differs in the 
extracellular domain from chimp CD4 by 4 residues and macaque CD4 by 37 residues raising the 
question of whether tolerance was actually broken in these studies and whether it would be broken 
if macaques were deliberately immunized with human CD4. Deliberate immunization of 
cynomologus macaques with human CD4 showed that the antibody response was selectively 
directed against human epitopes (Truneh, Frescatore et al. 1990). We were able to verify this result 

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in our immunotoxicology study using FLSC (Study Number VTR-0018). There was no evidence 
in this study that immunization of cynomolgus macaques with a homologus CD4 contained in 
rhFLSC broke tolerance. While these findings strongly indicate that the CD4 moiety of FLSC will 
be poorly immunogenic in humans, the risk of inducing auto-anti-CD4 antibodies drives the design 
of the phase 1 safety studies. 
 
It is worthwhile to consider what would happen if an auto-anti-CD4 antibody response occurs in a 
clinical setting. In this regard, the expanding literature on the therapeutic use of anti-CD4 
antibodies is informative. There are two non-exclusive mechanisms whereby passive 
immunization with anti-CD4 antibodies modulates disease. First, some anti-CD4 antibodies cause 
depletion of CD4+ T cells that is variable in duration as a function of the protocol and isotype of 
the antibody (Mourad, Preffer et al. 1998; Mason, Aldrich et al. 2002). Alternatively, anti-CD4 
antibodies can coat CD4+ T cells without depleting them from the peripheral circulation (Mourad, 
Preffer et al. 1998; Mason, Aldrich et al. 2002). In both cases, clinical effects can be observed 
(Larche, Robinson et al. 2003) but there is evidence in rheumatoid arthritis that coating is more 
important than depletion for clinical effect (Mason, Aldrich et al. 2002). Very recently, non- 
depleting anti-CD4 antibodies that block HIV-1 infection in vitro have been developed for passive 
immunization against HIV-1 (Reimann, Khunkhun et al. 2002). Thus, it is reasonable to expect 
that if immunization with FLSC were to break tolerance to CD4 both depleting and non-depleting 
anti-CD4 antibodies are possible outcomes. Each of these possibilities were addressed in the 
immunotoxicology study (Study Number VTR-0018). No autoimmune responses to CD4 after 
repeated immunization with FLSC or rhFLSC were observed. 

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5. 
TRIAL OBJECTIVES AND PURPOSE 
 
5.1. 
Purpose 
 
The purpose of this study is to perform a randomized, double-blinded, placebo-controlled dose 
escalation Phase I clinical trial to evaluate the safety, tolerability and immunogenicity of the full 
length single chain (FLSC) gp120-CD4 complex vaccine in HIV-1 uninfected healthy adult 
volunteers. 
 
5.2. 
Primary Objective - Safety 
 
To evaluate the safety and tolerability of intramuscular administration of the full length single 
chain (FLSC) gp120-CD4 complex vaccine at three different doses. 
 
5.3. 
Secondary Objectives - Immunogenicity 
 
To evaluate the immunogenicity of three different doses of the full length single chain (FLSC) 
gp120-CD4 complex vaccine assessed by the following parameters:1) anti-FLSC antibodies, and 
2) anti gp-120 (BaL), and 3) competitive antibodies titers to CD4i epitopes. 

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6. 
INVESTIGATIONAL PLAN 
 
6.1. 
Overall Study Design 
 
This will be a randomized, placebo-controlled, modified double-blinded study in 60 healthy adult 
volunteers. The study will evaluate the safety and immunogenicity of the full length single chain 
(FLSC) gp120-CD4 complex vaccine formulated with alum at three different doses. The study 
will have 3 arms as outlined below in Figure 1 and will last for 336 days (48 weeks). Volunteers 
will be immunized on Day 0, Day 28(4 weeks), Day 56(8 weeks), and Day 168(24 weeks). 
 
6.1.1. 
Study Procedures 
 
6.1.1.1. 
Study Entry 
 
Volunteers who satisfy the entry criteria will be fully informed about the study by the investigator 
or his/her designee and asked whether they wish to participate. The information given to the patient 
or his/her legal representative will be in a language understandable to the volunteer or the 
representative. All questions will be answered prior to the volunteer signing consent. Written 
consent will be obtained from the volunteer or his/her legal representative prior to performing any 
study related procedures. This includes obtaining consent for the acquisition and review of the 
volunteer’s prior medical history (and old medical record if appropriate and available). A copy of 
the informed consent will be given to the volunteer or his/her legal representative. 
 
All volunteers having completed informed consent procedures will undergo a baseline screening 
evaluation within 30 days of initial immunization with the experimental candidate vaccine (or 
placebo). The CD4 cell count will be repeated on the day of initial immunization. These two 
observation points will define protocol baseline evaluation. 
 
6.1.1.2. 
Study Duration 
 
Each volunteer will complete a pre-immunization screening evaluation within 30 days prior to 
receiving the immunization series. Study procedures are outlined in Table 4. Volunteers will be 
immunized with candidate vaccine or placebo on Days 0, 28 (week 4), 56 (week 8), and 168 (week 
24). Volunteers will continue to undergo active protocol follow up visits on Days 182 (week 26), 
196 (week 28), 252 (week 36), 294 (week 42) and 336 (week 48). The total trial time expected 
per volunteer is 336 days (48 weeks). The protocol recruitment period is expected to be 
approximately 16 weeks. The total trial duration is estimated to be approximately 72 weeks (18 
months). 
 
6.1.1.3. 
Study Evaluations 
 
See also the Schedule of Assessments in Table 4. 
 
 
 
1. Study Visit 0, Day –30 to Day –3 (Week –4 to 0): Screening Visit 

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A screening evaluation will be performed within 3-30 days of the first immunization to 
determine eligibility for the study and to collect blood for baseline safety evaluation and 
immunological exams. 
 
a. Obtain informed consent for study prior to screening 
b. Obtain and record medical history including allergies, medications, and concomitant 
illnesses, and review of systems 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Perform complete physical examination, including vital signs, temperature, weight 
and height. 
e. Collect blood for CBC with differential, serum chemistries, liver function 
tests(including AST, ALT, alkaline phosphatase, total bilirubin), PT/PTT, CD4 cell 
count, Hepatitis B surface antigen, Hepatitis C antibody, HIV-1 ELISA/Western Blot, 
HIV-1 quantitative RNA PCR, and, in women, serum human chorionic gonadotropin 
(HCG) assay (See Table 4 and Section 11). 
f. Collect urine for urinalysis 
g. Collect blood for baseline immunologic exams (See Table 5 and Section 12) 
 
 
2. Study Visit 1, Day 0 (Week 0): First Immunization 
 
a. Obtain interim medical history since screening visit 
b. Perform physical examination, including vital signs, temperature, weight and height. 
c. Conduct urine pregnancy test (female volunteers). 
 
If volunteer continues to meet inclusion/exclusion criteria he/she will be given a volunteer 
number, randomized, and the following will be done: 
 
d. Collect blood for safety labs (CBC with differential, serum chemistries, LFT’s, CD4 
cell count, and Quantitative HIV-1 RNA PCR) (Table 4, Table 5 and Section 11). 
e. Collect blood for immunologic studies (Table 4 and Table 5 and Section 12). 
f. Administer first injection of the study vaccine as an intramuscular injection in the 
deltoid muscle as per Section 9.5. 
g. Record vital signs and examine injection site for local reactions at 15 and 30 minutes 
post-injection. 
h. Observe and instruct while volunteer takes own temperature and assesses local 
reactions (as a guide for subsequent evaluations at home). 
i. Counsel volunteer regarding avoiding HIV risk behaviors 
j. Dispense diary for immunization reactions (Appendix 1) and digital thermometer. 
Give instructions for diary completion and thermometer use. 
 
 
3. Follow-up Phone contact by study nurse (24-48 hours after first immunization) 
 
a. Obtain interim history including:  local and systemic reactions, post-injection oral 
temperature, Adverse Events, and concomitant medication. 

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4. Study Visit 2, Day 14 (Week 2): Follow-up Clinical Visit 
 
a. Obtain interim medical history including: review of volunteer diary, adverse events, 
concomitant medications, and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4, Table 5 and 
Section 11). 
 
5. Study Visit 3, Day 28 (Week 4): Second Immunization 
 
a. Obtain interim medical history including:, adverse events, concomitant medications, 
and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Conduct urine pregnancy test (female volunteers). 
d. Collect blood for safety labs (Table 4, Table 5 and Section 11). 
e. Collect blood for immunologic studies (Table 4 and Table 5 and Section 12). 
f. Administer second injection of the study vaccine as an intramuscular injection in the 
deltoid muscle as per Section 9.5. 
g. Record vital signs and examine injection site for local reactions at 15 and 30 minutes 
post-injection. 
h. Observe and instruct while volunteer takes own temperature and assesses local 
reactions (as a guide for subsequent evaluations at home). 
i. Counsel volunteer regarding avoiding HIV risk behaviors 
j. Dispense diary for immunization reactions (Appendix 1). Give instructions for its 
completion and for digital thermometer use. 
 
6. Follow-up Phone contact by study nurse (24-48 hours after second immunization) 
 
a. Obtain interim history including:  local and systemic reactions, post-injection oral 
temperature, Adverse Events, and concomitant medication. 
 
7. Study Visit 4, Day 42 (Week 6): Follow-up Clinical Visit 
 
a. Obtain interim medical history including: review of volunteer diary, adverse events, 
concomitant medications, and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
8. Study Visit 5, Day 56 (Week 8): Third Immunization 
 
a. Obtain interim medical history including:, adverse events, concomitant medications, 
and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Conduct urine pregnancy test (female volunteers). 

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d. Collect blood for safety labs (Table 4, Table 5 and Section 11). 
e. Collect blood for immunologic studies (Table 4 and Table 5 and Section 12). 
f. Administer third injection of the study vaccine as an intramuscular injection in the 
deltoid muscle as per Section 9.5. 
g. Record vital signs and examine injection site for local reactions at 15 and 30 minutes 
post-injection. 
h. Observe and instruct while volunteer takes own temperature and assesses local 
reactions (as a guide for subsequent evaluations at home). 
i. Counsel volunteer regarding avoiding HIV risk behaviors 
j. Dispense diary for immunization reactions (Appendix 1).  Give instructions for its 
completion and digital thermometer use. 
 
 
9. Follow-up Phone contact by study nurse (24-48 hours after third immunization) 
 
a. Obtain interim history including:  local and systemic reactions, post-injection oral 
temperature, Adverse Events, and concomitant medication. 
 
 
10. Study Visit 6, Day 70 (Week 10): Follow-up Clinical Visit 
 
a. Obtain interim medical history including: review of volunteer diary, adverse events, 
concomitant medications, and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
 
11. Study Visit 7, Day 84 (Week 12): Follow-up Clinical Visit 
 
a. Obtain interim medical history including:, adverse events, concomitant medications, 
and safety labs. 
b. Perform directed physical examination as indicated, including vital signs and 
temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
 
 
12. Study Visit 8, Day 112 (Week 16): Follow-up Clinical Visit 
 
a. Obtain interim medical history including:, adverse events, concomitant medications, 
and safety labs. 
b. Perform directed physical examination as 
Indicated, including vital signs and temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 

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13. Study Visit 9, Day 168 (Week 24): Fourth Immunization 
 
a. Obtain interim medical history including:, adverse events, concomitant medications, 
and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Conduct urine pregnancy test (female volunteers). 
e. Collect blood for safety labs (Table 4, Table 5 and Section 11). 
f. Collect blood for immunologic studies (Table 4 and Table 5 and Section 12). 
g. Administer fourth injection of the study vaccine as an intramuscular injection in the 
deltoid muscle as per Section 9.5. 
h. Record vital signs and examine injection site for local reactions at 15 and 30 minutes 
post-injection. 
i. Observe and instruct while volunteer takes own temperature and assesses local 
reactions (as a guide for subsequent evaluations at home). 
j. Dispense diary for immunization reactions (Appendix 1) Give instructions for its 
completion and for thermometer use. 
 
 
14. Follow-up Phone contact by study nurse (24-48 hours after fourth immunization) 
 
a. Obtain interim history including:  local and systemic reactions, post-injection oral 
temperature, Adverse Events, and concomitant medication. 
 
 
 
15. Study Visit 10, Day 182 (Week 26): Follow-up Clinical Visit 
 
a. Obtain interim medical history including: review of volunteer diary, adverse events, 
concomitant medications, and safety labs. 
b. Perform exam of previous injection site and directed physical examination as 
indicated, including vital signs and temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
 
 
16. Study Visit 11, Day 196 (Week 28): Follow-up Clinical Visit 
 
a. Obtain interim medical history including:, adverse events, concomitant medications, 
and safety labs. 
b. Perform directed physical examination as indicated, including vital signs and 
temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
 
 
17. Study Visit 12, Day 252 (Week 36): Follow-up Clinical Visit 

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a. Obtain interim medical history including: adverse events, concomitant medications, 
and safety labs. 
b. Perform directed physical examination as indicated, including vital signs and 
temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
 
18. Study Visit 13, Day 294 (Week 42): Follow-up Clinical Visit 
 
a. Obtain interim medical history including: adverse events, concomitant medications, 
and safety labs. 
b. Perform directed physical examination as indicated, including vital signs and 
temperature. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Collect blood for safety labs and immunologic studies (Table 4 and Table 5 and 
Section 11 and Section 12). 
 
 
 
19. Study Visit 14, Day 336 (Week 48): Follow-up Clinical/End of Study Visit 
 
a. Obtain interim medical history including: review adverse events, concomitant 
medications, and safety labs. 
b. Perform complete physical examination, including vital signs, temperature, weight 
and height. 
c. Counsel volunteer regarding avoiding HIV risk behaviors 
d. Conduct urine pregnancy test (female volunteers). 
e. Collect blood for safety labs (Table 4 and Section 11). 
f. Collect urine for urinalysis. 
g. Collect blood for immunologic studies (Table 4 and Table 5 and Section 12). 
 
6.1.1.4. 
Missed Visits 
 
A volunteer is considered to have missed a visit if (s)he is not seen in 7 days of a scheduled 
study visit through the first 3 immunizations and within ± 28 days of a scheduled study visit after 
the third immunization visit. Volunteers who miss one of the immunization visits will be kept on 
the study if (s)he is willing and it is deemed appropriate by the investigator. Volunteers who miss 
2 immunization visits will be removed from the study and may be replaced at the discretion of the 
investigator. 
 
6.1.1.5. 
Replacement 
 
A volunteer who drops out of the study for any reason other than toxicity (an SAE related to the 
study drug) may be replaced. No replacements will be allowed when the enrollment is closed. 
Volunteers who fail to return for two clinic visits after day 14 may be considered to be dropouts 
and can be replaced at the discretion of the Investigator. Volunteers who miss one of the first 3 
immunization visits can be replaced at the discretion of the Principal Investigator. They will 

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continue to be evaluated for safety and will be evaluable for immunogenicity up to their last 
vaccine administration date. Volunteers who miss 2 immunization visits will be removed from 
the study and may be replaced at the discretion of the investigator. Volunteers with missed 
vaccination visits will be included in all safety analyses. 
 
6.1.1.6. 
Pregnancy 
 
In the event of pregnancy while the volunteer is on study, no further immunizations will be given 
regardless of outcome. The volunteer will be followed for all remaining scheduled visits according 
to the schedule of procedures for safety evaluation. The site will maintain contact with pregnant 
volunteers to obtain pregnancy outcome information. 
 
6.1.1.7. 
Off-study evaluations 
 
In the event a volunteer discontinues participation in the study prematurely, the initial off study 
evaluation will be treated as an end of study visit and consist of a complete physical examination, 
follow-up clinical assessment, selected blood chemistry and hematology evaluations, CD4+ count, 
ultra-sensitive viral load, PBMC and sera for immunogenicity assays (batched), PMBC stored (< 
-135C) for assessment of chemokine receptor expression and chemokine production capacity. 
Patients who withdraw prematurely from the study (prior to the completion of the 32 weeks of 
study) will have all safety tests performed as soon as possible. Follow up off study evaluations 
may be conducted if agreed to by volunteer per schedule visit outline in Table 4 to allow for 
additional safety and immunogenicity evaluation to be completed. However, immunization will 
not be permitted once a volunteer has discontinued participation in the study. The Investigator 
will attempt to complete all discharge procedures and will follow each dropout (by telephone if 
necessary) for adverse experiences through 24 weeks after his/her first vaccine injection. 
 
6.2. 
Number of Volunteers 
 
The study population will consist of 60 healthy volunteers without HIV-1 infection who are 
available for at least 48 weeks of follow-up. Individuals of all races and groups may participate 
as long as the inclusion/exclusion criteria are met. The inclusion/exclusion criteria have been 
chosen to minimize risk to all participants. Therefore, those individuals with conditions that might 
place them at increased risk have been excluded. 
 
Pregnant women and children are excluded from the trial as the safety of this vaccine has not 
previously been evaluated in humans and the effects on children or the unborn child are not known. 
 
6.3. 
Treatment Assignment 
 
The volunteers in this study will enroll in each group of the study sequentially as this is a dose 
escalation study. Each volunteer will undergo randomization as described in Section 8.4. Each 
group will be fully enrolled prior to the enrollment of the next group. The description of the FLSC 
vaccine is noted in Section 8 and Section 9 and the clinical formulation of the products are listed 
in Section 9. Volunteers in all arms will be immunized by intramuscular injection on Days 0, 28 
(week 4), 28 (week 4), 56 (week 8), and 168 (week 24). Following completion of the immunization 
schedule, all volunteers will be followed (for an additional 24 weeks) until the end of the trial at 
48 weeks as detailed in Section 6.1.1.3. 

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6.4. 
Dose Escalation Criteria 
 
Requirements to begin immunizations in the higher dose groups (Groups 2 and 3) are listed below. 
 
1. Safety data including the visit 4 data (2 weeks after the second immunization) in the 20 
volunteers in the lower dose group has been collated and then reviewed by the DSMB. 
 
2. DSMB review is completed, no safety concerns are noted, and approval to enroll the next 
group is granted. 
 
6.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
 
1. If more than 5 volunteers in any group have an unexplained CD4 cell count decline 
(confirmed by assays at least 4 weeks apart) of greater than 30 percent and corroborated 
by a similar CD4% decline (>30%), immunizations in that study group will be stopped. 
No further immunizations will be allowed until after all data are reviewed by the IHV 
DSMB and the DSMB authorizes immunizations to continue in this group.  Follow-up 
visits for safety will continue during this time. Note that an unexplained drop in CD4 cell 
count is defined as a decline that cannot be explained by an intercurrent illness or other 
event known to cause decreased CD4 cell counts. 
 
2. The entire study will be stopped if five or more vaccine related severe (grade 3 or 4) 
adverse events occur in any group. 
 
3. The volunteer will have immunizations stopped upon the occurrence of an unexpected 
Grade IV event felt by the investigator to be related to the study vaccine.  No further 
immunizations will be allowed until after all data are reviewed by the IHV DSMB and 
the DSMB authorizes immunizations to continue in this group. Follow-up visits for 
safety will continue during this time. 
 
4. The entire study immunizations will be stopped upon the occurrence of one unexpected 
serious adverse event felt to be related to the study vaccine. 
 
6.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
 
Not applicable. 
 
6.5. 
Criteria for Study Termination 
 
Criteria for Termination of Study immunizations in all volunteers. 
 
1. The entire study will be stopped upon the occurrence of an unexpected Grade 3 or 4 event 
thought to be related to the study vaccine in 5 volunteers as noted in Section 6.4.1.  If 
after review by the DSMB, these events are determined by the DSMB to be study vaccine 
related, the volunteers would be continued to be followed on the study for safety, but no 
further immunizations would occur in any of the groups. 
 
2. Individual volunteers may have immunizations halted as listed in Section 6.4.1. 

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Table 3: 
Study Design 
 
Phase 1 FLSC Study Immunization Schedule/Volunteer Allocation 
Group 
Route of 
Administration 
N 
Vaccine/ 
Control 
Vaccine Dose 
Vaccination Schedule in Months (Days) 
0 
1(28) 
2(56) 
6(168) 
1 
IM 
15 
0.25 ml 
(75 ug) 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
 
 
5 
0.25 ml 
Saline 
Saline 
Saline 
Saline 
2 
IM 
15 
0.5 ml 
(150 ug) 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
 
 
5 
0.5 ml 
Saline 
Saline 
Saline 
Saline 
3 
IM 
15 
1.0 ml 
(300 ug) 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
FLSC/ 
ALPO4 
 
 
5 
1.0 ml 
Saline 
Saline 
Saline 
Saline 
TOTALS 
60 

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Table 4: 
Schedule of Assessments 
 
STUDY VISIT 
0 
01  
02 
03  
04 
05  
06 
07 
08 
09  
10 
11 
12 
13 
143 
STUDY DAY 
 
-30 TO –3 
0 
1-2 
14 
28 
29- 
30 
42 
56 
57- 
58 
 
70 
84 
112
168 
169- 
170 
182
196
252
294
336 
STUDY WEEK 
-4 TO -0 
0  
2 
4  
6 
8  
10 
12 
16 
24  
26 
28 
36 
42 
48 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunization 
 
X  
 
X  
 
X  
 
 
 
X  
 
 
 
 
 
Complete Medical History and 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Interval Medical History and 
Directed Physical 
Examination(as indicated) 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Phone Interview 
 
 
X  
 
X  
 
X  
 
 
 
X 
 
 
 
 
 
Dispense diary 
 
X  
 
X  
 
X  
 
 
 
X  
 
 
 
 
 
Monitor Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for Screening Labs: 
CBC with diff 
Serum Chemistry, LFT’s 
PT/PTT 
Hepatitis B Surface Antigen 
Hepatitis C Antibody1 
CD4 cell count 
HIV-1 RNA PCR 
HIV-1 ELISA/Western blot 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test (serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (urine) 
 
X  
 
X  
 
X  
 
 
 
X  
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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STUDY VISIT 
0 
01  
02 
03  
04 
05  
06 
07 
08 
09  
10 
11 
12 
13 
143 
Blood for Safety Labs: 
CBC with diff 
Serum Chemistry, LFT’s 
CD4 cell count 
HIV-1 RNA PCR2 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Blood for Serologic 
Assays/Serum storage 
 
X 
X4  
X4 
X4  
X4 
X4  
 
X4 
X 
X4 
X4  
X4 
X 
X4 
X 
X4 
Blood for Cellular Immune 
Response Assays/Storage 
 
X 
X4  
X4 
X4  
X4 
X4  
 
X4 
X 
X4 
X4  
X4 
X 
X4 
X 
X4 
Total blood volume(ml) 
 
75 ml 
64 
ml 
X 
64 
ml 
84 
ml 
X 
64 
ml 
84 
ml 
X 
64 
ml 
84 
ml 
64 
ml 
90 
ml 
X 
64 
ml 
94 
ml 
64 
ml 
64 
ml 
102 
ml 
Approximate Visit Duration 
(minutes) 
 
60 
60 
10 
30 
60 
10 
30 
60 
10 
 
30 
60 
30 
60 
10 
30 
30 
30 
30 
60 
Footnotes: 
1. If positive Hepatitis C antibody and documentation of negative Hepatitis C PCR can be provided, the volunteer may enroll. 
2. HIV RNA PCR will be performed at the screening and end of study visit. Blood will be stored for the PCR at subsequent visits but the assay will not be 
performed unless there is a concern for acute infection. 
3. Visit 14 procedures will also be carried out in the case of early withdrawal/discontinuation. 
4. Initially the planned assay days are those marked with a superscript. The other days will be stored for future studies. 

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Table 5: 
Blood Draw Flow Sheet 
 
STUDY VISIT 
0 
01  
02 
03 
 
04 
05  
06 
07 
08 
09  
10 
11 
12 
13 
142 
STUDY DAY 
-30 
TO -3 
 
0 
1- 
2 
14 
28 
29- 
30 
42 
56 
57- 
58 
70 
 
84 
112 
168 
169- 
170 
182 
196 
252 
294 
336 
STUDY WEEK 
-4 TO 
0 
 
0 
 
2 
4 
 
6 
8 
 
10 
 
12 
16 
24  
26 
28 
36 
42 
48 
Immunization 
 
X 
 
 
X 
 
 
X  
 
 
 
X  
 
 
 
 
 
Blood for Screening Labs: 
CBC with diff 
Serum Chemistry, 
LFT’s, 
PT/PTT 
Hepatitis B Surface 
Antigen 
Hepatitis C Antibody 
CD4 cell count 
HIV-1 RNA PCR 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Safety Labs: 
CBC with diff 
Serum Chemistry, 
LFT’s 
CD4 cell count 
HIV-1 RNA PCR2 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pregnancy Test (serum) 
3 ml  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff 
 
3 ml 
 
3 ml  
3 ml 
3 ml  
3 
ml 
3 
ml 
 
3 ml 
3 
ml 
3 ml 
3 
ml 
 
3 ml 
3 
ml 
3 
ml 
3 
ml 
3 
ml 
Serum Chemistry, LFT’s, 
 
3 ml 
 
3 ml  
3 ml 
3 ml  
3 
ml 
3 
ml 
 
3 ml 
3 
ml 
3 ml 
3 
ml 
 
3 ml 
3 
ml 
3 
ml 
3 
ml 
3 
ml 
PT/PTT 
 
3 ml  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
ml 

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STUDY VISIT 
0 
01  
02 
03 
 
04 
05  
06 
07 
08 
09  
10 
11 
12 
13 
142 
HIV-1 RNA Quantitative 
PCR 
 
5 ml 
 
5 ml  
5 ml 
5 ml  
5 
ml 
5 
ml 
 
5 ml 
5 
ml 
5 ml 
5 
ml 
 
5 ml 
5 
ml 
5 
ml 
5 
ml 
5 
ml 
HBsAg, Hep C Ab 
5 ml  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 ELISA/Western 
blot 
 
5 ml  
 
 
 
 
 
 
 
 
 
 
5 
ml 
 
 
 
 
 
5 
ml 
CD4 cell count 
 
3 ml 
 
3 ml  
3 ml 
3 ml  
3 
ml 
3 
ml 
 
3 ml 
3 
ml 
3 ml 
3 
ml 
 
3 ml 
3 
ml 
3 
ml 
3 
ml 
3 
ml 
PBMC stored 
 
30 ml 
30 
ml 
 
30ml 
50 
ml 
 
30 
ml 
50 
ml 
 
30 
ml 
50 
ml 
30 
ml 
50 
ml 
 
30 
ml 
50 
ml 
30 
ml 
30 
ml 
50 
ml 
Serum stored1 
 
15 ml 
20 
ml 
 
20 
ml 
20 
ml 
 
20 
ml 
20 
ml 
 
20 
ml 
20 
ml 
20 
ml 
20 
ml 
 
20 
ml 
30 
ml 
20 
ml 
20 
ml 
30 
ml 
Total blood volume(ml) 
 
75 ml 
64 
ml 
X 
64 
ml 
84 
ml 
X 
64 
ml 
84 
ml 
X 
64 
ml 
84 
ml 
64 
ml 
90 
ml 
X 
64 
ml 
94 
ml 
64 
ml 
64 
ml 
102 
ml 
Total Study Blood 
Volume (over 48 
weeks): 
 
 
1125 ml 
Footnotes: 
1. If positive Hepatitis C antibody and documentation of negative Hepatitis C PCR can be provided, the volunteer may enroll. 
2. HIV RNA PCR will be performed at the screening and end of study visit . Blood will be stored for the PCR at subsequent visits but the assay will not be 
performed unless there is a concern for acute infection. 
3. Visit 14 procedures will also be carried out in the case of early withdrawal/discontinuation. 

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7. 
SELECTION AND WITHDRAWAL OF VOLUNTEERS 
 
7.1. 
Volunteer Inclusion Criteria 
 
All of the following inclusion criteria must be fulfilled for patients to be eligible for participation in the proposed 
clinical protocols. 
 
1. Age: 18 to 45 years of age. 
 
2. Sex: Male or Female (female volunteers of child-bearing potential must have a negative serum beta human 
chorionic gonadotropin(pregnancy) test at time of screening and entry into the study and provide assurance 
of the use of effective(as judged by the investigator) birth control methods or abstinence beginning at least 
60 days prior to the study and during the study 
 
3. Documented HIV-1 seronegative by ELISA 
 
4. Be in good general health without clinically significant medical history, physical examination findings, or 
clinically significant abnormal laboratory results(i.e., chronic medical conditions as noted in the exclusion 
criteria such as cancer as well as any conditions that in the opinion of the investigator might pose a risk to 
the volunteer) 
 
5. No  identifiable  risk  factor  for  acquisition  of  HIV  infection(i.e.,  intravenous  drug use/needle  sharing, 
unprotected sex with multiple partners) 
 
6. Negative b-HCG pregnancy test on the day of initial vaccination (women only); 
 
7. Negative screen for Hepatitis B surface antigen (HBsAg); 
 
8. Negative screen for antibodies to Hepatitis C virus (Patient may enroll if patient can provide documentation 
of negative HCV PCR.) 
 
9. Participant must have a CD4 count within the normal range of the clinical laboratory utilized for the study 
and a CD4 percentage within 20% of the normal range of the clinical laboratory 
 
10. Laboratory parameters must be within pre-specified limits as defined by exclusion criteria. 
 
11. Volunteers must be willing and able to provide written informed consent to participate in the study. 
 
12. Available for at least 48 weeks of follow-up. 
 
7.2. 
Volunteer Exclusion Criteria 
 
Any volunteer who fulfills any of the following criteria will not be eligible for entry. 
 
1. High risk behavior for acquisition of HIV within 24 weeks of study entry(i.e., intravenous drug use/needle 
sharing, unprotected sex with multiple partners) 
 
2. Volunteers with an acute and clinically significant medical event (as determined by the investigator) within 
the past 30 days of screening. 
 
3. Have active tuberculosis or other systemic infectious process by review of systems and physical examination 
 
4. Have a history of immunodeficiency, autoimmune disease, or use of immunosuppressive medications 
 
5. Current treatment for malignancy other than basal or squamous cell carcinoma of the skin or carcinoma in 
situ of the cervix 
 
6. Is pregnant 

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7. History of any chronic illness that would interfere with conduct or completion of study(as determined by the 
investigator) 
 
8. Have evidence of psychiatric, medical and/or substance abuse problems during the past 24 weeks that the 
investigator believes would adversely affect the volunteer’s ability to participate in the trial 
 
9. Have occupational or other responsibilities that would prevent completion of participation in the study 
 
10. Have received any live, attenuated vaccine except rabies vaccine within 60 days of study entry 
 
11. Vaccine (FDA approved; e.g. influenza, pneumovax, etc) administration within 30 days of immunization 
with the study vaccine. NOTE: Medically indicated subunit or killed vaccines (e.g., Hepatitis A or Hepatitis 
B) should be given prior to trial initiation or after completion of the study immunizations. If patient requires 
immunization, injections should be given more than 2 weeks prior or 2 weeks after study immunization 
 
12. Have used experimental therapeutic agents within 30 days of study entry 
 
13. Have received blood products or immunoglobulins in the past 12 weeks 
 
14. Have a history of anaphylaxis or other serious adverse reactions to vaccines 
 
15. Have previously received an HIV vaccine 
 
16. Volunteers with any of the following laboratory parameters at the screening visit (within 30 days of 
immunization): Hemoglobin <10 (without having received a blood or RBC transfusion within 30 days prior 
to laboratory test); neutrophil count <750 cells/mm3; platelet count <50,000/mm3; serum creatinine > 2.0 
mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limits of 
normal; total bilirubin > 1.5 mg/dL 
 
17. Pregnant women or women who are breast-feeding; female volunteers of childbearing potential who are not 
using or willing to use effective (as judged by the investigator) contraceptive methods or abstinence while 
enrolled in this study. 
 
18. Use of any immune modulators or suppressors within 45 days of study entry including but not limited to 
agents such as interleukins(e.g. IL-2), interferons (e.g. IFN-), high dose systemic steroids(e.g. ≥ 20 mg 
prednisone equivalent/day) for > 30 days, thalidomide, filgrastim (G-CSF), sargramostim (GM-CSF), 
dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex, polyribonucleoside, ditiocarb 
sodium, cyclosporin, mycophenolate mofetil, methotrexate, and cancer chemotherapy. 
 
19. No other investigational agent within 30 days of study entry 
 
20. Any other condition which, in the opinion of the investigator, might interfere with completion of the study 
or evaluation of the results 
 
21. Have active Hepatitis B virus infection (positive HBsAg) or Hepatitis C infection(defined as positive 
antibodies.  Patient may enroll if patient can provide documentation of negative HCV PCR.)) 
 
7.3. 
Volunteer Withdrawal Criteria 
 
7.3.1. 
Reasons for Withdrawal for Study 
 
Volunteers have the right to withdraw from the study at any time for any reason. 
 
7.3.1.1. 
Conditions mandating withdrawal from the Study 
 
Individual volunteers will be withdrawn from further immunizations on the study for the following reasons: 

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 Experiencing a grade 4 toxicity/adverse event or serious adverse event considered by the principal 
investigator to be related to study vaccine 
 
 Becoming pregnant during the study 
 
 Requiring cytotoxic chemotherapy or immunomodulatory therapy during the course of the study 
 
 Missing 2 immunization visits (injections) 
 
Note that those withdrawn for toxicity reasons will continue to be followed for safety as described in Section 6.1.1.7. 
 
7.3.1.2. 
Conditions permissible to withdraw from the Study 
 
 Protocol violations 
 
 Intercurrent illness 
 
 Administrative reasons 
 
 Adverse events requiring discontinuation of any study drug; 
 
 At the discretion of the investigator in situations where the volunteer is unable to comply, including situations 
involving unmanageable drug or substance abuse; patients lost to follow-up. 
 
7.3.2. 
Withdrawal Procedures 
 
In the event that the volunteer withdraws from the study, the investigator will record the reason for and the date of 
the withdrawal and make every effort to complete an off study evaluation as noted below. The procedures outlined 
for Reporting of Adverse Experiences must be followed if the patient is withdrawn due to a serious adverse event. 
Volunteers may be withdrawn from the vaccine or from the study at any time without prejudice to their subsequent 
medical care. The sponsor should be notified of all study withdrawals within 24 hours. Study completion is defined 
as completion of protocol-specified procedures through 48 weeks.  See Section 6.1.1.7 as well. 
 
7.3.2.1. 
Volunteer Withdraws 
 
If the volunteer withdraws consent, he/she will be asked to complete an end of study visit. If he/she agrees, the end 
of study visit will be performed as described in Section 6.1.1.7. If he/she does not agree, no further study activity 
will occur. 
 
7.3.2.2. 
Volunteer Withdrawn by Investigator 
 
If the volunteer is withdraw by the investigator, he/she will be asked to complete an end of study visit.  If he/she 
agrees, the end of study visit will be performed as described in Section 6.1.1.7.  If he/she does not agree, no further 
study activity will occur. 
 
7.3.2.3. 
Volunteer Withdrawn for Vaccine Related Toxicity 
 
Should a volunteer be discontinued from the study for toxicity reasons, the volunteer will continue to have safety 
visits performed until the end of the study as in Section 6.1.1.7. 
 
7.3.2.4. 
Volunteer Withdrawn by Investigator for other reasons 
 
The Volunteer will be asked to undergo an end of study visit. If he/she agrees, the end of study visit will be performed 
as in Section 6.1.1.7.  If he/she does not agree, no further study activity will occur. 

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7.3.3. 
Reasons to Halt Study 
 
If 5 or more volunteers in any group have an unexplained CD4 cell count decline (confirmed by assays at least 4 
weeks apart) of greater than 30 percent and corroborated by a similar CD4% decline (>30%), immunizations in that 
study group will be stopped. No further immunizations will be allowed until after all data are reviewed by the IHV 
DSMB and the DSMB authorizes immunizations to continue in this group. Follow-up visits for safety will continue 
during this time. Note that an unexplained drop in CD4 cell count is defined as a decline that cannot be explained by 
an intercurrent illness or other event known to cause decreased in CD4 cell counts. Other reasons are noted in 
Section 6.4.1 and Section 6.5. 
 
7.3.4. 
Reasons for Discontinuation of all Immunizations in the Study 
 
All immunizations across the entire study will be stopped upon the occurrence of 5 or more unexpected Grade 3 or 
4 events felt to be related to the study vaccine in any group or a serious adverse event felt to be related to study 
vaccine in one volunteer as noted in Section 6.4.1 and Section 6.5. Follow-up visits for safety will continue to occur 
as per study protocol. No further enrollments will occur. 

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8. 
TREATMENT OF VOLUNTEERS 
 
8.1. 
Description of Study Drug 
 
The FLSC final product consists of 0.3 mg/ml of purified FLSC Drug Substance formulated with Aluminum 
Phosphate (AlPO4) at 2.4 mg/mL in binding buffer (mannitol 40 mg/mL; sodium acetate 5 mM, pH 6.2. Aluminum 
ion concentration is 1.2 mg/mL and 1.3 mL product is vialed in 2cc glass vials. 

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Table 6: 
Investigational Product 
 
 
Investigational Product 
Product Name: 
IHV01 
0.9% Sodium Chloride Inj., USP 
Dosage Form: 
1 ml single dose vial 
Liquid 
Unit Dose 
300 ug/vial 
10 ml/ single dose vial 
Route of Administration 
Intramuscular 
Intramuscular 
Physical Description 
FLSC 0.3 mg/ml, 
Aluminum Phosphate 2.4 
mg/ml, 
Mannitol 40 mg/ml, 
Sodium Acetate 5 mM 
NaCl 9 mg/ml 
Preservative Free 
Manufacturer 
Profectus Biosciences 
Hospira, Inc.* 
*The company the saline is purchased from may change depending on what vendor the institution is using at the time that the trial begins. 
 
8.2. 
Concomitant Medications 
 
Concurrent medications (with the exception of those noted in the Exclusion Criteria) will be permitted as medically 
necessary during the study. Changes in medication treatment during this protocol will be permitted if clinically 
indicated at the discretion of the patient’s primary care physician. All changes in medications will be recorded. 
Medically indicated vaccines (FDA approved; e.g. influenza, pneumococcal, etc.) should be administered either 30 
days prior to or following study vaccine administration to minimize potential confusion of adverse experiences due 
to the study vaccine vs the other vaccine. 
 
8.3. 
Treatment Compliance 
 
Adherence with the protocol will be assessed by the study personnel at each clinic visit. Careful review of the 
volunteers’ interim medical history will be performed. If appropriate, corroboration of any outside medical clinic or 
hospital visits will be obtained with the volunteer’s consent. 
 
8.4. 
Randomization and Blinding 
 
Volunteers will be randomized using block randomization in a 3:1 ratio of FLSC:placebo. They will be block 
randomized in groups of 4 with each study group. This will be done by the research pharmacist utilizing random # 
generator called Stat Trek. There will be 5 groups of 4 volunteers in each randomized block (each block will have 3 
FLSC recipients and 1 placebo recipient). 
 
8.4.1. 
Blinding 
 
Both the investigator and the volunteer will be blinded to the study drug/placebo but not to the group assignment as 
it is a dose escalation trial. The syringes containing the study drug/placebo will be covered by the study pharmacist 
to insure blinding of the study. 
 
 
 
8.4.2. 
Blinding and Code Breaking Procedures 
 
Dose labels will not allow for identification of treatment. The investigator and volunteer will not know which 
treatment is administered. The pharmacist responsible for product preparation will prepare the appropriate product 

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for the volunteer as indicated by the block randomization and cover the syringe to prevent identification. The 
nurse/physician responsible for injection and the volunteer will not know which product is injected as the syringes 
will be blinded (a film will be affixed on each syringe by the staff responsible for product preparation). 
 
Consequently, two sealed envelopes for each volunteer containing emergency decoding information for each 
volunteer will be issued by the research pharmacist. The emergency decoding information indicates the treatment 
corresponding to each randomization number. One envelope will be retained by the investigator and the other one 
by the research pharmacy/medical monitor. 
 
The code can be broken by opening the individual envelope for the volunteer. The vaccine/diluent injected will be 
indicated in the envelope. The code may be broken only in case of a Serious Adverse Event and if identification of 
the treatment can influence the treatment of the adverse event. 
 
In case of code breaking, the name of the person who requests it, the date and reason must be written on the list. The 
event must be immediately reported on the CRF. The sponsor will immediately be informed by phone or by fax. 
 
At the end of the trial the emergency decoding information will be returned to the sponsor and checked. In the 
absence of any problem, codes will be broken at the time of the analysis, when the data base is validated and locked. 
 
8.5. 
Identification of participants as volunteers in HIV vaccine trial 
 
All volunteers will receive an individual identification card indicating their status as an HIV-1 vaccine trial 
participant. All volunteers will be counseled periodically regarding the potential for testing positive on routine 
screening tests for HIV-1 as a consequence of participation in this trial and receiving these vaccine products. All 
volunteers will be offered further confirmatory testing and certification as to the nature of their vaccine trial 
participation whenever needed to address complications arising at home, at work or in the community that could 
arise from routine screening from HIV-1. 
 
8.6. 
Detection of inter-current HIV-1 infections. 
 
Each volunteer will be counseled at each visit and an algorithm followed to identify inter-current HIV-1 infections. 
The algorithm is shown in Figure 1 and uses FDA approved serological and nucleic acid diagnostic kits at each step. 
If an individual is determined to have an inter-current infection with HIV-1 they will be excluded from further 
immunizations and counseled about their medical options. Enrollment in the trials does not include subsequent care 
for an inter-current HIV-1 infection. The volunteer will be counseled on how to access that care if they choose to 
do so. 

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Figure 1: 
Algorithm to detect inter-current HIV-1 infections 
 
FDA Approved 
Serological Test 
+ 
- 
 
Confirmatory  FDA Approved 
Serological Test 
- 
+ 
+ 
- 
FDA Approved 
Western Blot 
+ 
- 
 
 
 
Not 
Infected 
 
FDA approved viral load test 
 
+ 
 
FDA approved viral load test 
- 
on new specimen 
 
- 
 
 
 
Repeat FDA approved 
viral load test 
+ 
+ 
Infected 

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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
 
9.1. 
Study Drug 
 
The FLSC final product consists of 0.3 mg/ml of purified FLSC Drug Substance formulated with Aluminum 
Phosphate (AlPO4) at 2.4 mg/mL in binding buffer (mannitol 40 mg/mL; sodium acetate 5 mM, pH 6.2. Aluminum 
ion concentration is 1.2 mg/mL and 1.3 mL product is vialed in 2cc glass vials. 
 
9.2. 
Study Drug Packaging and Labeling 
 
The information to appear on each study medication vial label will be: 
 
 
 
 
 
 
 
 
 
 
 
 
The placebo will be preservative free saline provided by the IHV research pharmacy. 
 
9.3. 
Study Drug Storage 
 
FLSC will be stored between +2C and +8C as directed by the manufacturer. 
 
9.4. 
Study Drug Preparation 
 
The product preparation and the injection will be performed in different places. The product preparation must be 
performed in the absence of the investigator and of the nurse responsible for injection. This will be performed by a 
pharmacist or nurse.  If it is a nurse, the nurse must not be performing other duties with the study. 
 
9.4.1. 
FLSC 75 ug  (Group 1) 
 
Before injection, the FLSC vial will be removed from the refrigerator and swirled until a uniform solution results. 
Once the FLSC is in a uniform solution, 0.25 ml (75ug) of FLSC will be withdrawn from the viral using a 22-25 
gauge, 25 mm (1 inch) needle with a 1-mL sterile disposable syringe. The syringe will then be covered with a 
film/aluminum foil to prevent visualization of the product. 
 
9.4.2. 
FLSC 150 ug  (Group 2) 
 
Before injection, the FLSC vial will be removed from the refrigerator and swirled until a uniform solution results. 
Once the FLSC is in a uniform solution, 0.5 ml (150ug) of FLSC will be withdrawn from the viral using a 22-25 
gauge, 25 mm (1 inch) needle with a 1-mL sterile disposable syringe. The syringe will then be covered with a 
film/aluminum foil to prevent visualization of the product. 
 
9.4.3. 
FLSC 300 ug (Group 3) 
 
Before injection, the FLSC vial will be removed from the refrigerator and swirled until a uniform solution results . 
Once the FLSC is in a uniform solution, 1.0 ml (300ug) of FLSC will be withdrawn from the viral using a 22-25 
gauge, 25 mm (1 inch) needle with a 1-mL sterile disposable syringe. The syringe will then be covered with a 
film/aluminum foil to prevent visualization of the product. 

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9.4.4. 
Placebo (Groups 1-3) 
 
Before injection, depending on the group (see Table 7), the saline will be withdrawn using a 22-25 gauge, 25 mm (1 
inch) needle with a 1-mL sterile disposable syringe. The syringe will then be covered with a film/aluminum foil to 
prevent visualization of the product. 
 
Table 7:            Placebo Groups 
 
Group Number 
Volume of Saline 
1 
0.25 ml 
2 
0.5 ml 
3 
1.0 ml 
 
9.5. 
Administration 
 
Immunizations will be administered on an outpatient basis on Day 0, Day 28, Day 56, and Day 168. Evaluations 
listed on the study schema will be conducted prior to immunization with the study vaccine. Total time required in 
the clinic for an immunization visit will be approximately one hour, unless the subject experiences an Adverse Event 
which requires additional treatment. The volunteer will be instructed to call a designated staff member immediately 
if an Adverse Event should occur after the volunteer leaves the clinic. 
 
The intramuscular route will be used in all cases. At all stages of the preparation, aseptic procedures must be 
followed. After cleansing the site of injection with a suitable antiseptic, the injections will be given as an 
intramuscular injection in the deltoid muscle of the volunteer's non-dominant arm (unless preferred otherwise by the 
patient) with a 22 gauge 25 mm (1 inch) needle. All of the product contained in the syringe will be injected. As noted 
in Section 9.4, according to the group number, drug product or diluent will be given as an intramuscular injection in 
the deltoid muscle of the volunteer's non-dominant arm per institutional protocol. The study vaccine may be given 
in the deltoid muscle of the dominant arm at the investigator’s discretion (e.g., open wound near/on the proposed 
injection site, request of the volunteer, etc.). Immediately after injection, the subject will be observed closely for 
30 minutes. Complete vital signs will be recorded prior to administration, at 15 minutes and 30 minutes post-
injection. Injection site evaluations will be recorded at 15 minutes and 30 minutes post-injection. The volunteer 
will be instructed in the evaluation of these local reactions; study personnel will observe and instruct while the 
volunteer takes his/her own temperature at Visit 1 (as guide for subsequent evaluations. Volunteer diary card for 
immunization reactions will be dispensed and instructions for its completion will be given. 
 
If there are no clinically meaningful abnormalities and the volunteer has no complaints which are considered cause 
for concern by the Principal Investigators or his designee, he/she may leave the clinic with instructions to 
immediately call a designated staff member should any complications arise. If there are any local or systemic 
reactions present, the volunteer will be asked to return to the clinic the following day for a follow-up visit. 
 
Treatment of AEs will be at the discretion of the Investigator and the clinic staff. Medication (epinephrine and 
Benadryl) and equipment for treatment of emergencies will be available during injection and for 30 minutes 
immediately following to allow a rapid response to any acute reactions. At all stages of the administration, aseptic 
procedures must be followed. It is important to use a separate sterile syringe for each individual study participant to 
prevent transmission of infectious agents. Once taken out of the refrigerator, prepare as soon as products have reach 
room temperature, and once reconstituted, use as soon as possible, but within 1 hour. Discard reconstituted unused 
vaccine. 
 
After reconstitution and preparation, inspect the vaccine for particulate matter and discoloration. If either of these 
conditions exist, the vaccine should not be administered and another syringe/replacement dose should be selected. 
The staff in charge of product preparation will affix an opaque cover on each syringe. 

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9.6. 
Study Drug Accountability 
 
The IHV Research pharmacy will be responsible for study drug accountability. The Research Pharmacist will utilize 
the University of Maryland Medical Center Policy 06-05, Investigational Drug Accountability to ensure complete 
and accurate records of investigational drug accountability.  (See Appendix 3) 
 
9.7. 
Study Drug Handling and Disposal 
 
All vaccine products will be prepared by an investigational pharmacist who will provide the product to research 
study personnel in a blinded fashion in a syringe pre-packaged and prepared with vaccine antigen and diluent, vaccine 
antigen and adjuvant, or placebo (diluent) and diluent mixed together. All materials for this study must be stored 
under recommended storage conditions in an area free of environmental extremes with controlled limited access. 
The FLSC will be kept at +2C to +8Celsius; and brought out to room temperature no earlier than one hour prior 
to administration of vaccine.  The placebo (preservative free normal saline) will be stored as per package insert. 

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10. 
CLINICAL SAMPLE COLLECTION 
 
10.1. 
Blood Sample Collection 
 
Blood sample collection will occur as outlined in Table 4 and in Section 6.1.1. Blood volumes for these assessments 
will be as outlined in Table 5. 
 
10.2. 
Urine Sample Collection 
 
Urine sample collection will occur as outlined in Table 4 and in Section 6.1.1. 
 
10.3. 
Sample Analysis 
 
All safety laboratory assessments will be analyzed by the University of Maryland Medical Center Clinical Laboratory 
as noted in Section 15.2 
 
All immunogenicity laboratory assessments will be analyzed at one of the laboratories outlined in Section 15.2 and 
per description in Section 12.2 and Section 15.3. 

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11. 
ASSESSMENT OF SAFETY 
 
Although no safety concerns have been identified with this vaccine product in animal studies to date, there is a 
theoretical risk of the development of anti-CD4 antibodies. Antibodies against CD4 have been shown to occur in 
HIV infected individuals and their significance is not known. However, the presence of these antibodies has not 
been demonstrated to be deleterious in these individuals. Therefore, we do not believe that this vaccine poses a risk 
to the individuals enrolling in the trial. In order to ensure volunteer safety, we are monitoring CD4 cell count 
frequently throughout the trial. Any individual who experiences any of the criteria noted in Section 7.3.1 will be 
withdrawn from the study. 
 
11.1. 
Safety Parameters 
 
The safety parameters to be utilized in this study are listed below. The schedule for their assessment is listed in 
Table 4 and Section 6.1.1. 
 
1. Local and systemic vaccine reactogenicity. 
 
2. Laboratory Safety Evaluation 
 
3. Medical History and Physical Examination 
 
11.1.1. 
Demographic/Medical History 
 
A complete medical history will be conducted on all volunteers prior to enrollment. The medical history will include 
a review of body systems, determination of any current symptoms or conditions, and documentation of any 
concurrent medications and other treatments that might preclude the volunteer from participation in the study. It 
will also include a review of the volunteer’s prior medical record. A complete physical examination will consist of 
an exam including evaluations of the following: general appearance, skin, HEENT, extremities, heart, lungs, lymph 
nodes, and abdomen; additional examination based on history and symptoms. A directed physical examination will 
be performed at interim visits as noted in the protocol and Table 4 Schedule of Assessments and will include 
examinations of the injection site(s) and lymph nodes with special attention to the axillary lymph nodes. In addition, 
physical manifestations of any previously noted condition or adverse experience will be evaluated. 
 
11.1.2. 
Vital Signs 
 
Vital signs will be taken at the study visits as outlined in Section 6.1.1. 
 
11.1.3. 
Weight and Height 
 
Weight and height will be taken at the study visits as outlined in Section 6.1.1. 
 
11.1.4. 
Physical Examination 
 
A complete physical examination will be conducted on all volunteers prior to enrollment. A complete physical 
examination will consist of evaluations of the following: general appearance, skin, HEENT, extremities, heart, lungs, 
lymph nodes, and abdomen; additional examination based on history and symptoms. A directed physical 
examination will be performed at interim visits as noted in the protocol (Section 6.1.1 and Table 4) and will include 
examinations of the injection site(s) and lymph nodes with special attention to the axillary lymph nodes. In addition, 
physical manifestations of any previously noted condition or adverse experience will be evaluated. 
 
11.1.5. 
Laboratory Assessments 
 
All abnormal laboratory values will be scored utilizing the ACTG toxicity grading system (see Appendix 2) where 
applicable or other appropriate criteria.  Hematology and clinical laboratory evaluations will be performed by the 

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UMMS clinical laboratory facility.  The following safety tests will be performed as outlined in the Schedule of 
Assessments (Table 4). 
 
 Hematology: CBC, including differential, platelets 
 
 Clinical Chemistries: serum electrolytes, liver function tests, renal function tests, PT/PTT 
 
 Urinalysis: routine and microscopic, pregnancy test on women 
 
 CD4 + T cell count 
 
 HIV viral load by Roche-Amplicor ultra-sensitive RNA PCR 
 
11.1.5.1. Hematology 
 
CBC, including differential, platelets.  The schedule is as outlined in Section 6.1.1 and Table 4 . 
 
11.1.5.2. Blood Chemistry 
 
Serum electrolytes, liver function tests, renal function tests, PT/PTT will be performed as outlined in Section 6.1.1 
and Table 4. 
 
11.1.5.3. Urinalysis 
 
Urinalysis will be performed as outlined in Section 6.1.1 and Table 4. 
 
11.1.5.4. Virus Serology 
 
Serologies for HIV, Hepatitis B and Hepatitis C will be performed as outlined in Section 6.1.1 and Table 4. 
 
11.1.5.5. Pregnancy Screen 
 
Serum pregnancy test will be performed at the screening visit. Subsequently urine pregnancy tests will be performed 
prior to each immunization and at the end of the study. It will also be performed if there is concern for pregnancy 
in a volunteer during the study. 
 
11.1.5.6. Assessment of Vaccine Reactogenicity 
 
The safety evaluation will include an evaluation of both local and systemic reactions to the candidate 
immunotherapeutic vaccines. Assessment of local reactogenicity will include erythema, induration, swelling, itching, 
pain and tenderness, skin discoloration, skin breakdown, and presence of subcutaneous nodules at the site of 
injection. Assessment of systemic reactions will include assessment of fever, chills, nausea, vomiting, arthralgia, 
myalgia, malaise, urticaria, wheezing, dizziness, headache. Each volunteer will complete a self-administered 
questionnaire/diary daily for 7 days after each immunization to assess reactogenicity. In addition, follow up 
telephone contact or clinic visit will be conducted by research nurse 24 to 48 hours following each immunization to 
record reactogenicity/adverse events. The study personnel will also conduct a careful assessment of possible adverse 
experiences at each clinic visit (See Table 4). Both the volunteer diary and the elicited adverse experiences will be 
used to determine the occurrence of adverse events. Any discrepancies between these sources will be resolved by 
careful review of the data with the volunteer. All adverse events will be recorded in the CRFs as noted in 
Section 11.4. 

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11.2. 
Adverse and Serious Adverse Events 
 
11.2.1. 
Definition of Adverse Events 
 
11.2.1.1. Adverse Event (AE) 
 
An adverse event is defined as any unfavorable or unintended change in body structure (signs), body function 
(symptoms) or laboratory result associated temporally with the use of study treatment, whether or not considered 
related to the study treatment.  As defined by 21 CFR 312.32 (a), an unexpected adverse drug experience is: 
 
“An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not 
required or available, is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure 
as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.” 
 
All AEs that occur after any volunteer has signed consent or within 84 days following the cessation of immunizations 
and while being followed on the study protocol, whether or not they are related to the study, must be recorded on 
forms provided by the Institute of Human Virology. 
 
11.2.1.2. Serious Adverse Event (SAE) 
 
A serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), 
and at any dose of the investigational product, comparator or placebo, that fulfills one or more of the following: 
 
 Results in death 
 
 It is immediately life-threatening (i.e., the volunteer was, in the opinion of the Investigator, at 
immediate risk of death from the event as it occurred). 
 
 It requires in-patient hospitalization or prolongation of existing hospitalization 
 
 It results in persistent or significant disability or incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
 
 Results in a congenital abnormality or birth defect 
 
 Is an important and significant medical event that, based upon appropriate medical judgment, may 
jeopardize the patient or volunteer and may require medical or surgical intervention to prevent one of 
the other outcomes defining serious. 
 
 
 
All SAEs that occur after any volunteer has signed consent or within 84 days following the cessation of treatment, 
and while on study protocol, whether or not they are related to the study, must be recorded on forms provided by the 
Institute of Human Virology. 
 
Any serious adverse event (including death) due to any cause must be reported immediately to the principal 
investigator and the sponsor. 

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11.2.1.3. Other Adverse Event (OAE) 
 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Clinical Study Team Physician 
during the evaluation of safety data for the Clinical Study Report. Significant adverse events of particular clinical 
importance, other than SAEs and those AEs leading to discontinuation of the volunteer from the study, will be 
classified as OAEs.  For each OAE, a narrative may be written and included in the Clinical Study Report. 
 
11.3. 
Relationship to Study Drug 
 
An Investigator who is qualified in medicine must make the determination of relationship to the investigational 
product for each AE. The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. The relationship of an adverse event 
to the study medication will be determined by the investigator based on the following criteria. 
 
1. Definitely Related: 
 
a. It follows a reasonable temporal sequence from vaccine administration 
b. It follows a known pattern of response to the vaccine 
c. Adverse event is most likely explained by vaccination than by other mechanisms. (It cannot be reasonably 
explained by the known characteristics of the volunteer's clinical state, environmental or toxic factors, or 
other modes of therapy administered to the volunteer) 
d. It appears on re-challenge with the vaccine or there is a local reaction at the injection site. 
 
2. Probably Related: 
 
a. It follows a reasonable temporal sequence from vaccine administration 
b. It follows a known pattern of response to the vaccine 
c. Adverse event is more likely explained by vaccination than by other mechanisms. ( It cannot be 
reasonably explained by the known characteristics of the volunteer's clinical state, environmental or toxic 
factors, or other modes of therapy administered to the volunteer) 
 
3. Possibly Related: 
 
a. It follows a reasonable temporal sequence from vaccine administration. 
b. It follows a known pattern of response to the vaccine 
c. Adverse event is explained equally well by causes other than vaccination. (It may have been produced by 
the volunteer's clinical state, environmental or toxic factors, or other modes of therapy administration to 
the volunteer) 
 
4. Not Related: 
 
a. It is clearly and incontrovertibly due to causes other than vaccination (e.g. disease, environment, etc.) 
b. It does not follow a reasonable temporal sequence from vaccine administration. 
c. It does not meet any of the criteria for vaccine relationship as listed under remotely related, possibly 
related or probably related. 
 
If the relationship between the AE/SAE and the investigational product is determined to be “possible” or “probable” 
the event will be considered to be related to the investigational product for the purposes of expedited regulatory 
reporting. 
 
11.4. 
Recording Adverse Events 
 
Adverse events spontaneously reported by the volunteer and/or in response to an open question from the study 
personnel or revealed by observation will be recorded during the study at the investigational site. However, abnormal 
values that constitute an SAE or lead to discontinuation of administration of study drug must be reported and recorded 

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as an AE. Information about AEs will be collected from signing of consent until the end of the study. Serious 
Adverse Event information will be collected from signing of consent until 24 weeks following the last dose of study 
drug. The AE term should be reported in standard medical terminology when possible. For each AE, the investigator 
will evaluate and report the onset (date and time), resolution (date and time), intensity, causality (as defined in 
Section 11.3), action taken, serious outcome (if applicable), and whether or not it caused the patient to discontinue 
the study. 
 
All adverse events occurring during the trial must be evaluated by the investigator and graded according to the 
adverse experience grading table (Appendix 2). 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity whereas seriousness 
is defined by the criteria under Section 11.2.1.2.  An AE of severe intensity may not be considered serious. 
 
Should a pregnancy occur, it must be reported and recorded on the Institute of Human Virology’s pregnancy form. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational product may have 
interfered with the effectiveness of a contraceptive medication. However, it is a criterion for stopping immunizations 
in a volunteer as noted in Section 6.1.1.6 and Section 7.3.1.1. 
 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented even if the patient was discontinued from the study. 
 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported 
and handled as SAEs.  Elective abortions without complications should not be handled as AEs. 
 
11.5. 
Reporting Adverse Events 
 
11.5.1. 
Adverse Events 
 
All adverse events, including both observed and volunteered problems, complaints, signs or symptoms, and any 
death occurring while on study are to be recorded (whether or not the event is related to vaccine administration). 
The duration and intensity of the event as well as whether or not the event might be associated with the study 
medication or other causes will be evaluated. 
 
The severity of each adverse event will be graded according to the common toxicity criteria of the AIDS Clinical 
Trials Group (ACTG) as listed in Appendix 2. When intensity changes occur more frequently than once a day, the 
maximum severity for the event should be listed. If the intensity category changes over a number of days, then these 
changes should be recorded separately, having distinct onset and stop dates for each grade. 
 
If the investigator has evidence that the adverse event is not caused by the vaccine, and after consultation with the 
study Principal Investigator, then the study vaccine may be continued. All adverse events, irrespective of causality, 
must be recorded in the CRF. All changes in study regimen must be accurately recorded on the study drug pages of 
the CRF. All adverse events occurring during the trial must be evaluated by the investigator and graded according 
to the adverse experience grading table (Appendix 2). Any serious adverse event (including death) due to any 
cause must be reported immediately to the principal investigator and the sponsor. The decision to remove a 
patient for an adverse event, whether laboratory or clinical, will depend on the severity of the event and its relation 
to the vaccine and study requirements and therefore, will require judgment. The guiding principal will be to insure 
the safety of participants and integrity of the study. It is expected that all vaccine related grade 4 events will require 
discontinuation as will most grade 3 events. Vaccines will be discontinued for any Grade event or at the discretion 
of the investigator or wish of the volunteer. If a volunteer is withdrawn due to an adverse event follow-up will be 
conducted as outlined in Section 6.1.1.7. 

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11.5.2. 
Serious Adverse Events 
 
All SAEs (related and unrelated) will be recorded while on study protocol.  Any SAEs considered possibly or 
probably related to the investigational product and discovered by the Investigator at any time after the study should 
be reported. All SAEs must be reported to the Institute of Human Virology through the Medical Monitor within 
one business day of the first awareness of the event. The Investigator must complete, sign and date the SAE pages, 
verify the accuracy of the information recorded on the SAE pages with the corresponding source documents, and 
send a copy by fax to the Institute of Human Virology.  If a volunteer is withdrawn due to a serious adverse event, 
follow-up will be conducted as outlined in Section 6.1.1.7. 
 
Additional follow-up information, if required or available, should all be faxed to the Institute of Human Virology 
within one business day of receipt and this should be completed on a follow-up SAE form and placed with the 
original SAE information and kept with the appropriate section of the CRF and/or study file. 
 
The Institute of Human Virology is responsible for notifying the relevant regulatory authorities of certain events. 
It is the Principal Investigator’s responsibility to notify the IRB of all SAEs that occur at his or her site. 
Investigators will also be notified of all unexpected, serious, drug-related events (7/15 Day Safety Reports) that 
occur during the clinical trial. 
 
11.6. 
Data Safety Monitoring Board 
 
The Clinical Research Unit is experienced in establishing DSMBs in single-site protocols in the participation in 
single and multi-site clinical trials.  Adverse Event Reporting requirements of the IRB, FDA, the NIH 
Biotechnology Activities, and the industry/private sponsor will be followed. For this trial, IHV has established a 
DSMB.  The DSMB plan will be approved by the IRB prior to implementation. 
 
 
 
The Data Safety Monitoring Board (DSMB) will review this trial for safety beginning with the enrollment of the 
first volunteer into the study. The Board will meet prior to advancement to the next higher dose group as outlined 
in the protocol to insure that there are no safety concerns. It will also meet approximately every 3 months but can 
be called together on an ad-hoc basis if a particular patient event calls for immediate attention. At the regularly 
scheduled (3 month) meetings and the advancement to the higher dose group meetings, the board will review the 
following: 
 
 All Adverse Events 
 
 Update on all Serious / Study Related Events 
 
 All safety related amendments 
 
 Protocol deviations / exceptions 
 
 Laboratory tests, enrollment numbers, clinical summaries 
 
 Require changes in Standard Operational Procedures for Adverse Events Reporting and Chart Audit as 
necessary. 
 
All reviews will be of blinded data. However, the DSMB will have access to the envelopes with the treatment 
assignment of the volunteers to unblind the data should this be needed to ensure the safety of study participants. The 
DSMB may recommend or mandate changes to the study, and has the power to halt the study if it feels that a 
volunteer’s safety is compromised. The DSMB will provide the Principal Investigator, with a written report detailing 
its review of the study.  The investigator(s) will have the opportunity to respond to the DSMB’s report. 

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Board members will be notified of all internal serious study related, drug related, and/or device related Adverse 
Events in this study within 48 hours of occurrence via email. Each board member should respond via e-mail, or fax 
within 48 hours. 
 
A DSMB member who is a physician will be called upon via fax, e-mail, or phone call to discuss any 
deviations/exceptions a PI may be thinking of requesting prior to approaching the sponsor. This will help to 
determine if the deviation/exception is necessary and will not compromise the safety of the patient. 
 
The IHV DSMB will have at least 4 members not including the Medical Monitor. The DSMB will actively monitor 
the trial. The members of the Board will not be directly involved with the execution of this study, have conflicts of 
interest with the conduct of this study, or with study personnel. The Board will be composed of at least the following 
members: 
 
1. A Statistician 
 
2. At least two physician-investigators 
 
DSMB includes the following members: John Bartlett MD from Johns Hopkins SOM  who will also serve as 
committee Chair; Alan Cross MD from the University of Maryland SOM; Philip Mackowiak MD from the 
University of Maryland SOM; Kirsten Lyke MD (Medical Monitor) from the University of Maryland SOM; and 
Lawrence Moulton PhD from Johns Hopkins SOM (statistician). 

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12. 
Assessment of Immunogenicity 
 
12.1. 
Endpoint Evaluations of Immunogenicity 
 
12.1.1. 
Immunogenicity Endpoint 
 
The primary evaluation of immunogenicity will consist of the generation of antibodies to FLSC as determined by 
antibody titration using FLSC as the detection antigen. A positive vaccine response will be defined as a 4-fold 
increase in antibody directed against native FLSC protein by ELISA. In addition geometric mean antibodies titers 
will be assessed and compared among groups. 
 
12.1.2. 
Secondary Immunogenicity Endpoints 
 
The secondary evaluation of immunogenicity will include the generations of antibodies to gp120 and human CD4, 
components of FLSC, determined by antibody titration using gp120 and human CD4 as the detection antigen. 
 
12.1.3. 
Exploratory/Developmental Immunogenicity Endpoints 
 
1. Antigen-specific CD4+ T cell responses measured by peptide stimulated intracellular cytokine production 
coupled with surface markers to identify CD4+ T cell subsets, particularly those of the T-follicular helper 
cell lineage. 
 
2. Assess the presence of neutralizing antibodies; 
 
3. Antibody-Dependent Cellular Cytotoxicity activity; 
 
4. To assess and compare the induction of T-helper and cytotoxic T-lymphocyte activity by ELISPOT and 
intracellular cytokine staining; 
 
5. Additional developmental assays might be performed on de-identified specimens for antigen-specific B cell 
responses based on emerging literature 
 
12.2. 
Immunogenicity Assays 
 
12.2.1. 
Endpoint Assay 
 
ELISA based assay using FLSC protein will be used. A positive vaccine response will be defined as a 4-fold increase 
in antibody directed against native FLSC protein by ELISA. 
 
The human serum samples collected before and after immunization will be analyzed, after a 1 hour heating step at 
60°C, for the presence of anti-FLSCI antibodies (total IgG) by the ELISA technique. To determine whether the 
development of anti-FLSC antibodies is really linked to a specific immune stimulation following vaccination and 
not to a general immune activation, all sera will be also tested against an irrelevant HIV antigen, p24, that is not 
cross-reactive with FLSC. In this case, the titers against p24 should remain constant. The results will be expressed 
as half-maximal antibody titers in arbitrary units (log). 
 
The ELISA assays will be conducted as follows: 6 to 12 serial three-fold dilutions of the serum samples, starting at 
1/10, will be tested in 96-well ELISA plates pre-coated with the antigen of interest (ie FLSC or p24). The presence 
of specific antibodies will be revealed by addition of an anti-human total IgG peroxidase-conjugate, followed of a 
chromogenic hydrogen peroxide-specific substrate. Finally, each well will be read by an automatic plate reader at an 
optical density (OD) of 450-650 nm. 

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The background will be given by the blanks (ie 6 to 12 wells with all the reagents except sera) which OD values 
should not exceed 0.2 in average. The OD values from all samples will be subtracted from this mean blank OD. One 
negative control, a serum from an HIV-negative volunteer, will be present on each ELISA plate. Its OD value, 
subtracted from the mean blank OD, should not exceed 0.2 at the lowest dilution (1/100). 
 
Two anti-FLSC (or anti-p24) human sera will be on on each ELISA plate: one, with a predetermined antibody titer 
(see below*), will serve as the standard: ie all sample titers will be calculated from the regression curve of this 
standard ( OD = f(inverse dilution) ) using the SoftMaxPro software (Molecular Devices). The second positive serum 
will be used as the positive control: its mean titer (m) and the corresponding standard deviation (sd), will have to be 
calculated from the standard after several independent experiments. The assay will be considered as valid if the titer 
of this positive control measured on the ELISA plate is included in the titer range: m + 3 sd (log). 
 
*The titer of the standard will predetermined in several independent experiments: it will represent the average of the 
values obtained after all these experiments, each value being the inverse serum dilution giving an OD of around 1 
(subtracted from the mean blank OD). 
 
The person responsible for the ELISA assays will be Dr. Timothy Fouts, at Profectus BioSciences. 
 
12.2.2. 
Secondary Endpoint Assay 
 
ELISA based assay using gp120 and soluble human CD4 will be carried out as described in Section 12.2.1. 
 
12.2.3. 
Developmental Assays 
 
1. Antigen-specific CD4+ T cell responses will be measured by peptide stimulated intracellular cytokine 
production coupled with surface markers to identify CD4+ T cell subsets, particularly those of the T-follicular 
helper cell lineage. These responses will be assessed by culturing 3×106 PBMC in 1 mL of R10 medium 
containing brefeldin A (10 ug/mL) in the absence or presence of FLSC peptide pools (15mers overlapping 
by 11 residues), or 1 ug/mL SEB (Sigma) for 6 hours. Cells will be surface stained with titrated amounts of 
anti-CD3, anti-CD4, anti-CD27, anti-CD45RO, anti-CCR7, anti-CXCR5, anti-CD150, anti-CCR6, anti-PD- 
1 and anti-CD19 antibodies. The surface-stained cells will be permeabilized (Cytofix/Cytoperm kit; BD 
Biosciences) and stained with anti-IFN-γ, anti-IL-2, anti-IL-17a, anti-IL-21 and anti-CD154 antibodies. 
Events will be collected on a FACSFortessa equipped with four lasers and a high-throughput module. 
Electronic compensation will employ antibody capture beads (BD Biosciences) and the data analyzed using 
FlowJo, Version 10.6. 
 
2. Assess the presence of neutralizing antibodies by TZM-bl cells (Seaman, Janes et al. 2010) and A3R5 assays 
(Sarzotti-Kelsoe, Daniell et al. 2014). 
 
3. Antibody-dependent Cellular Cytotoxicity activity (ADCC); 
 
4. To assess and compare the induction of T-helper and cytotoxic T-lymphocyte activity by ELISPOT and 
intracellular cytokine staining; 
 
5. Additional developmental assays might be performed on de-identified specimens for antigen-specific B cell 
responses based on emerging literature 
 
12.2.4. 
Assay Timepoints 
 
The scheduled assay timepoints are detailed in Table 4. 

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12.2.5. 
Data Analysis 
 
Immunogenicity parameters will be compared using response and non-response as well as mean medium and 
geometric mean titers between vaccine recipients and placebo recipients (i.e. Arms 1 and 2 compared to Arm 3) as 
determined by Student’s T test and chi-square analyses. Immunogenicity parameters will be compared between 
FLSC in Arms 1, 2, and 3 as well as between the placebo recipients (Arms 1 to 3 and 2 to 3). Exploratory analyses 
will be performed (e.g., examination of frequency distributions, modality of distributions, kurtosis and skewness, 
etc.) for all variables collected before subjecting the values to statistical analysis. Cross-sectional parametric and 
non-parametric analyses will be conducted on variables exhibiting normal and non-normal distributions, 
respectively, to examine differences and trends among treatment categories. 
 
The dose selected will be that which provides the optimal CD4i epitope immunogenicity and antiviral activity and 
safety profile. Based on our results in macaques, we believe that the FLSC will be safe even when administered at 
the highest dose of 300 μg. Titers will be evaluated for normality (Kolmogorov-Smirnov test) then compared via a 
parametric test such as one-way analysis of variance (ANOVA). If the data fails the normality test we will use the 
Kruskal-Wallis test (3-group comparison) and Wilcoxon rank-sum test (2-group comparison) to compare groups. A 
p value < 0.05 will indicate that one of the vaccination regimens elicits significantly higher response in that measure 
versus the others. 

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13. 
STATISTICS 
 
13.1. 
Determination of Sample Size 
 
The sample size was set to 60 (15 active vaccine recipients in each group and 5 placebo recipients in each group) to 
allow adequate identification of potential toxicities and document safety. The study design was developed as a 
compromise between the costs of vaccine manufacturing and regulatory clearance and the need to detect safety. 
Within each group: The study is planned with 15 experimental volunteers and 5 control volunteers. With expectation 
that significant adverse event in the control volunteers to be very small (<0.1%), we will be able to detect a minimal 
SAE rate of 73.5% among experimental volunteers with power of 0.8. The Type I error probability associated with 
this test of the null hypothesis that the SAE rates for experimental and control subjects are equal is 0.05. We used 
Fisher’s exact test to evaluate this null hypothesis. Pooled across groups: The study is planned with 45 experimental 
volunteers and 15 control volunteers. With expectation that significant adverse event in the control volunteers to be 
very small (<0.1%), we will be able to detect a minimal SAE rate of 36.8% among experimental volunteers with 
power of 0.8. The Type I error probability associated with this test of the null hypothesis that the SAE rates for 
experimental and control volunteers are equal is 0.05.  We used Fisher’s exact test to evaluate this null hypothesis. 
 
13.2. 
Statistical Methods 
 
Each safety parameter assessed will be compared between vaccine recipients and placebo recipients as determined 
by Student’s T test and chi-square analyses. In addition safety parameters with be compared between vaccine dose 
groups as well as to placebo recipients. In addition each volunteer will serve as their own control for the occurrence 
of toxicity. Adverse reaction as defined in Appendix 1 and 3 will be reported independent of a statistical association. 
 
Immunogenicity parameters will be compared using response and non-response as well as mean medium and 
geometric mean titers between vaccine recipients and placebo recipients as determined by Student’s T test and chi- 
square analyses. Immunogenicity parameters will be compared between vaccine dose groups as well as between 
each to placebo recipients. Exploratory analyses will be performed (e.g., examination of frequency distributions, 
modality of distributions, kurtosis and skewness, etc.) for all variables collected before subjecting the values to 
statistical analysis. Cross-sectional parametric and non-parametric analyses will be conducted on variables exhibiting 
normal and non-normal distributions, respectively, to examine differences and trends among treatment categories. 
 
13.3. 
Volunteer Population 
Sixty (60) volunteers.  Volunteers that do not complete the study may be replaced at the discretion of the principal 
investigator.  Volunteers will be recruited from the healthy population in the Baltimore community and the 
metropolitan Baltimore/Washington area. 
 
13.3.1. 
Population analyzed 
 
13.3.1.1. Definitions of Populations 
 
Included patients: volunteers performing at least V0 (screening) visit. 
Randomized patients: volunteers assigned a randomization number 
 
 
Injected patients:  volunteers administered at least one dose of product 

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13.3.1.2. Full Analysis Set 
 
As the sample size was small, immunogenicity data will be analyzed on the population of injected volunteers in an 
"intent to treat" analysis. This population will be identified as the Full analysis set. 
 
Volunteers’ data will be analyzed in the treatment group allocated by randomization. 
No per protocol analysis will be performed. 
A complete description of protocol violations will be performed in order to investigate the possible impact of 
protocol violations on the immunogenicity evaluation. 
 
Volunteers included and not injected (i.e., not in the full analysis set) will not be taken into account. 
 
13.3.1.3. Safety Analysis Sets 
 
The safety data will be analyzed for all volunteers who receive at least one injection (= Full analysis set). Only 
safety information collected after at least one injection will be taken into account. Adverse events which occur 
between V0 and the first injection will be listed. 
In case of randomization error, a volunteer will be analyzed according to the treatment he/she actually received. 
For safety evaluation “after any injection” all the volunteers injected and evaluated at least once will be considered 
as assessable. In case of withdrawal, it may lead to an underestimation of the occurrence rate. 
 
Exploratory analyses will be performed (e.g., examination of frequency distributions, modality of distributions, 
kurtosis and skewness, etc.) for all variables collected before subjecting the values to statistical analysis. 
 
13.3.1.4. Immunogenicity Analysis Sets 
 
The immunogenicity data will be analyzed for all volunteers who receive at least one injection (= Full analysis set). 
Only safety information collected after at least one injection will be taken into account. 
In case of randomization error, a volunteer will be analyzed according to the treatment he/she actually received. 
Exploratory analyses will be performed (e.g., examination of frequency distributions, modality of distributions, 
kurtosis and skewness, etc.) for all variables collected before subjecting the values to statistical analysis. 
 
13.4. 
Primary Criterion Analysis 
 
The primary reactogenicity (safety) endpoints are occurrence of severe systemic and severe local reactions. 
Separate assessments of systemic and local reactions will be performed. Each safety parameter assessed will be 
compared between vaccine recipients and placebo recipients as determined by Fisher exact test with a Type I error 
of no greater than 5%. 
 
 
 
13.5. 
Secondary Criterion Analysis 
 
Immunogenicity parameters will be compared using response and non-response as well as mean medium and 
geometric mean of titers between vaccine recipients and placebo recipients as determined by Wilcoxon matched 
pairs test or the Sign test and the Fisher exact test. Immunogenicity parameters will be compared between dose 
groups of the FLSC vaccine as well as between each to placebo recipients. Exploratory analyses will be performed 
(e.g., examination of frequency distributions, modality of distributions, kurtosis and skewness, etc.) for all variables 
collected before subjecting the values to statistical analysis. 

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13.6. 
Level of significance 
 
Level of significance is not pertinent to this trial as it is a Phase 1 safety and immunogenicity trial. 
 
13.7. 
Criteria for Termination of the Trial 
 
The Institute of Human Virology and the Principal Investigator reserve the right to discontinue this study for 
administrative reasons at any time. The trial may also be discontinued if there is insufficient product to continue or 
if it is determined that the study medication may not be safe for further administration to volunteers. See 
Section 6.4.1 , Section 6.5 and Section 7.3. 
 
13.8. 
Procedures for Missing or Spurious Data 
 
Missing or spurious data will be reviewed by appropriate study personnel and the IHV monitors. These personnel 
will attempt to determine the cause of the missing or spurious data and to clarify the data. Any information that is 
not obtained as specified in the protocol should be indicated by the designation ND for not done or NA for not 
applicable. An explanation should be noted on the case report form as to why the required information was not 
obtained. If illegible or uncertain entries require clarification, the clarification may be printed above the original 
entry, initialed and dated. 
 
13.9. 
Changes in Statistical Methods 
 
Any deviation from the original statistical plan will only be done after consultation with a statistician and approval 
of the sponsor. This is not expected to occur except if it is determined that the original statistical plan is not sufficient 
or appropriate for the data analyzed. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
14.1. 
Study Monitoring 
 
Before an investigational site can enter a patient into the study, a representative of Institute of Human Virology will 
visit the investigational study site to: 
 
 Determine the adequacy of the facilities 
 
 Discuss with the investigator(s) and other personnel their responsibilities with regard to protocol 
adherence, and the responsibilities of the Institute of Human Virology or its representatives. This will be 
documented in a Clinical Study Agreement between the Institute of Human Virology and the investigator. 
 
During the study, a monitor from the Institute of Human Virology or representative will have regular contacts with 
the investigational site, for the following: 
 
 Provide information and support to the investigator(s) 
 
 Confirm that facilities remain acceptable 
 
 Confirm that the investigational team is adhering to the protocol, that data are being accurately recorded 
in the case report forms, and that investigational product accountability checks are being performed 
 
 Perform source data verification. This includes a comparison of the data in the case report forms with 
the patient’s medical records at the hospital or practice, and other records relevant to the study. This will 
require direct access to all original records for each patient (e.g. clinic charts). 
 
 Record and report any protocol deviations not previously sent to Institute of Human Virology. 
 
 Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs have been 
forwarded to Institute of Human Virology and those SAEs that met criteria for reporting have been 
forwarded to the IRB. 
 
The monitor will be available between visits if the investigator(s) or other staff needs information or advice. 
 
14.2. 
Audits and Inspections 
 
Authorized representatives of the Institute of Human Virology, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, including source 
data verification.  The purpose of an Institute of Human Virology audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice guidelines of the International Conference on Harmonization, and any applicable regulatory requirements. 
The investigator should contact Institute of Human Virology immediately if contacted by a regulatory agency 
about an inspection. 
 
14.3. 
Institutional Review Board (IRB) 
 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, and all materials 
approved by the IRB for this study including the patient consent form and recruitment materials must be 
maintained by the Investigator and made available for inspection. 

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15. 
Quality Control and Quality Assurance 
 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, the Institute of 
Human Virology may conduct a quality assurance audit.  Please see Section 14.2 for more details regarding the 
audit process. 
 
15.1. 
Study Monitoring 
 
The study will be monitored by the Sponsor or its representatives in compliance with government regulations and 
according to good clinical practices and standard operating procedures. Regular telephone contacts and site visits 
will be made throughout the course of the study.  These individuals will have access, both during the trial and after 
trial completion, to review and audit all records (including original volunteer records, drug accountability and 
storage, and general study documentation and execution) necessary to ensure integrity of the data, and will 
periodically review progress of the study with the principal investigator. Every attempt will be made to follow the 
protocol and to obtain and record all data requested for each volunteer at the specified times.  However, ethical 
reasons may warrant the failure to obtain and record certain data, or to record data at the times specified.  If this 
becomes necessary, the reasons for such must be clearly documented on the case report form. 
 
Monitoring visits will be made on a frequent basis with advanced notification of the study center by the sponsor or 
its representatives.  Study center personnel will be informed of the study documents/records which will be 
reviewed at each visit.  It is expected that monitoring visits will be made approximately every 4 to 12 weeks 
dependent upon the rapidity of enrollment. 
 
15.2. 
Laboratory 
 
All safety laboratories will be performed at the University of Maryland Medical Center Clinical laboratories, a 
CLIA certified laboratory. 
 
All immunology laboratory studies are planned to occur at the IHV Immunology Laboratory, Profectus 
Biosciences or one or more of the Bill and Melinda Gates Core Laboratories which currently include the Vaccine 
Research Center, NIH; the Duke Human Vaccine Center, Durham, North Carolina; Harvard’s Ragon Institute, 
Cambridge, MA, or Dartmouth University, Hanover,NH. 
 
15.3. 
Handling of Biologic Samples 
 
The transmission of retroviruses may occur through contact with contaminated needles and blood or blood 
products.  Consequently universal blood and body fluid precautions should be employed by all personnel involved 
in drawing of blood and handling of specimens in clinic and laboratory locations. For samples that have to be 
shipped to other sites, specific regulations regarding intersFLSCe/international shipment apply and these 
procedures must be adhered to.  It is the responsibility of the investigator to ensure that all study specimens are 
appropriately handled. 
 
1. Virology Evaluations:  For HIV PCR and other research virology assays, plasma and cells must be 
collected and processed within 6 hours, and either stored at < –135 Cfor PBMC and < –70C for serum 
or used by the laboratory investigator in an appropriate time frame. 
 
2. 2) Immunology Evaluations:  All clinical and research immunological studies must be performed on 
samples collected and processed within a 6 hour period and stored at <–135 Cfor PBMC and <–70C for 
serum or provided to the appropriate laboratory 

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16. 
Ethics 
 
16.1. 
Ethics Review 
 
The final study protocol, including the final version of the Informed Consent Form, must be approved or given a 
favorable opinion in writing by an IRB which is constituted and operates in accordance with Part 56 of Title 21 of 
the Code of Federal Regulations. The investigator must submit written approval to the Institute of Human Virology 
before he or she can enroll any patient/subject into the study. 
 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or IEC must approve all advertising used to recruit patients 
for the study. The protocol must be re-approved by the IRB or IEC upon receipt of amendments and annually, as 
local regulations require. 
 
The Principal Investigator is also responsible for providing the IRB with reports of any reportable serious adverse 
drug reactions from any other study conducted with the investigational product. Institute of Human Virology will 
provide this information to the Principal Investigator. 
 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB or IEC according to 
local regulations and guidelines. 

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17. 
Ethical Conduct of the Study 
 
The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki 
and are consistent with ICH/Good Clinical Practice, applicable regulatory requirements and the Institute of Human 
Virology’s policy on Bioethics. 
 
Investigator Responsibilities 
 
The execution responsibility of this protocol rests with the Principal Investigator. The Principal Investigator is 
responsible for the submission of the AEs, and an assessment of the causal relationship with the treatment. AEs will 
be recorded using an adverse experience grading system adapted from the ACTG and AVEG tables; all AEs must 
be recorded in the case report forms with details of the duration and grade of each episode, and the action taken for 
each event. A serious AE is considered one that results in death, a life threatening adverse drug experience, inpatient 
hospitalization, a persistent disability/incapacity, or a congenital abnormality/birth defect. All serious adverse 
experiences, including death, on study or within 30 days of withdrawal, must be recorded on a serious adverse events 
(SAE) form and sent to the study sponsor. 
 
Protocol Modification 
 
It is essential to the success of the study that the Investigator adhere to both the spirit and the letter of the protocol. 
Except in the event of a medical emergency or where necessary to protect the safety, rights or welfare of the study 
volunteer(s), any changes to the protocol will require the prior written approval of the sponsor, the IHV. In the case 
of a minor deviation from protocol, a letter from the Sponsor will suffice. Changes to the protocol affecting study 
objectives, study design, volunteer population, study procedures or significant administrative aspects will require 
that the protocol be formally amended. Protocol amendments will be made only after having been agreed to by the 
investigators and IHV. All formal amendments must be approved by the Institutional Review Board (IRB) prior to 
implementation. 
 
17.1. 
Written Informed Consent 
 
Volunteer 
 
The volunteer will be informed of the nature of the study agent and its intended purpose; study procedures and 
associated risks will be explained as well as possible adverse experiences. Written informed consent shall then be 
obtained from each volunteer, in accordance with FDA regulations set forth in Part 50 of Title 21 of the Code of 
Federal Regulations, prior to entering the volunteer into the trial or prior to performing any unusual or non routine 
procedure that involves risk to the volunteer. The investigator shall provide a copy of the current IRB-approved 
informed consent to the volunteer and a signed copy shall be maintained in the volunteer’s record file. The informed 
consent will be written in accordance with US Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a] and 21 CFR 50.25[b]). 
 
Investigator 
 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Patients must also be notified that they 
are free to discontinue from the study at any time. The patient should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
 
The patient’s signed and dated informed consent must be obtained before conducting any study procedures. 
 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy of the signed 
Informed Consent Form must be given to the patient. 

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18. 
DATA HANDLING AND RECORDKEEPING 
 
18.1. 
Inspection of Records 
 
Institute of Human Virology will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the drug storage area, 
study drug stocks, drug accountability records, volunteer charts and study source documents, and other records 
relative to study conduct. In addition, representatives of the Food and Drug Administration (FDA) and the 
Institutional Review Board (IRB) shall have access to the source data and documents when requested. During any 
document reviews, volunteer anonymity will be maintained with strict adherence to professional standards of 
confidentiality. 
 
18.2. 
Retention of Records 
 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 years after the last 
marketing application approval, or if not approved 2 years following the discontinuance of the test article for 
investigation. If it becomes necessary for Institute of Human Virology or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 
 
18.3. 
Data Recording 
Source documents of all data will be maintained in the volunteer’s research clinical record. In addition Case 
Reports Forms (CRF) will be created and maintained for each volunteer utilizing REDCap(Research Electronic 
Data Capture) software. All study data will be recorded on the Case Report Forms (CRFs). REDCap tracks all data 
corrections made by authorized users, providing audit trails for monitoring or query. 
 
Any information that is not obtained as specified in the protocol should be indicated by the designation ND for not 
done or NA for not applicable. An explanation should be noted on the case report form as to why the required 
information was not obtained. 
 
18.4. 
Data Control Methods 
 
In order to assure adequate control and provide study data which are consistent and of the highest quality, the 
following measures will be employed: 
 
 Each clinical procedure (e.g. physical examination) for a particular volunteer will be conducted by the 
same person, if possible, throughout the volunteer's study participation; 
 
 Data automatically generated will be acceptable only after review by the appropriate specialist; for 
example, computer-generated EKG interpretation must be signed off by a cardiologist. 
 
 
Adverse Events will be both volunteered by the volunteer and specially elicited by questioning. 
Careful unbiased monitoring of volunteers for development of adverse experiences will be 
essential throughout the study.  Volunteers will be questioned at every clinical visit in order to 
detect toxicity, however mild.  Volunteer interviews must be conducted in a non-leading way 
(e.g. "How have you been feeling since your last clinic visit; have you noticed anything out of 
the ordinary?").  Questions may be specific to symptoms previously reported in order to follow 
ongoing complaints. 

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19. 
PUBLICATION POLICY 
 
All personnel involved in the study shall not disclose or use for any purpose any data, records, and other information 
related to the study until approved by Principal Investigator. The data shall be confidential until publication. Any 
publication or presentation related to the trial must be approved by the Institute of Human Virology before 
submission of the manuscript. 

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20. 
LIST OF REFERENCES 
 
 
 
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mucosal simian-human immunodeficiency virus infection." Nat Med 6(2): 200-206. 
 
Barouch, D. H., J. Liu, et al. (2012). "Vaccine protection against acquisition of neutralization-resistant SIV 
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Barouch, D. H., K. E. Stephenson, et al. (2013). "Protective efficacy of a global HIV-1 mosaic vaccine against 
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Chen, B., E. M. Vogan, et al. (2005). "Structure of an unliganded simian immunodeficiency virus gp120 core." 
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DeVico, A., T. Fouts, et al. (2007). "Antibodies to CD4-induced sites in HIV gp120 correlate with the control of 
SHIV challenge in macaques vaccinated with subunit immunogens." Proc Natl Acad Sci U S A 104(44): 
17477-17482. 
 
Ferrari, G., J. Pollara, et al. "A HIV-1 gp120 Envelope Human Monoclonal Antibody that Recognizes a C1 
Conformational Epitope Mediates Potent ADCC Activity and Defines a Common ADCC Epitope in Human 
HIV-1 Serum." J Virol. 
 
Ferrari, G., J. Pollara, et al. (2011). "An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 
conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and 
defines a common ADCC epitope in human HIV-1 serum." J Virol 85(14): 7029-7036. 
 
Florese, R. H., T. Demberg, et al. (2009). "Contribution of nonneutralizing vaccine-elicited antibody activities to 
improved protective efficacy in rhesus macaques immunized with tat/env compared with multigenic 
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Forthal, D. N., G. Landucci, et al. (2001). "Antibody from patients with acute human immunodeficiency virus (HIV) 
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Fouts, T. R., K. Bagley, et al. (2015). "Balance of cellular and humoral immunity determines the level of protection 
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Fouts, T. R., R. Tuskan, et al. (2000). "Expression and characterization of a single-chain polypeptide analogue of the 
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Fung, M. S. C., C. R. Y. Sun, et al. (1992). "Identification and characterization of a neutralization site within the 
second variable region of human immunodeficiency virus type 1 gp120." J. Virol. 66: 848-856. 
 
Gomez-Roman, V. R., L. J. Patterson, et al. (2005). "Vaccine-elicited antibodies mediate antibody-dependent cellular 
cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with 
SIVmac251." J Immunol 174(4): 2185-2189. 
 
Guan, Y., M. Pazgier, et al. (2013). "Diverse specificity and effector function among human antibodies to HIV-1 
envelope glycoprotein epitopes exposed by CD4 binding." Proceedings of the National Academy of Sciences 
of the United States of America 110(1): E69-78. 

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Hahn, B. H., M. A. Gonda, et al. (1985). "Genomic diversity of the acquired immune deficiency syndrome virus 
HTLV-III: different viruses exhibit greatest divergence in their envelope genes." Proc Natl Acad Sci U S A 
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Hartley, O., P. J. Klasse, et al. (2005). "V3: HIV's switch-hitter." AIDS Res Hum Retroviruses 21(2): 171-189. 
Haynes, B. F., P. B. Gilbert, et al. (2012). "Immune-correlates analysis of an HIV-1 vaccine efficacy trial." N Engl 
J Med 366(14): 1275-1286. 
 
Hessell, A. J., L. Hangartner, et al. (2007). "Fc receptor but not complement binding is important in antibody 
protection against HIV." Nature 449(7158): 101-104. 
 
Hessell, A. J., E. G. Rakasz, et al. (2009). "Broadly neutralizing human anti-HIV antibody 2G12 is effective in 
protection against mucosal SHIV challenge even at low serum neutralizing titers." PLoS Pathog 5(5): 
e1000433. 
 
Hidajat, R., P. Xiao, et al. (2009). "Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody 
activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 
challenge of rhesus macaques." J Virol 83(2): 791-801. 
 
Kramski, M., M. S. Parsons, et al. (2013). "HIV-specific antibody immunity mediated through NK cells and 
monocytes." Curr HIV Res 11(5): 388-406. 
 
Kwong, P. D., M. L. Doyle, et al. (2002). "HIV-1 evades antibody-mediated neutralization through conformational 
masking of receptor-binding sites." Nature 420(6916): 678-682. 
 
Kwong, P. D., R. Wyatt, et al. (1998). "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 
receptor and a neutralizing human antibody." Nature 393: 648-659. 
 
Larche, M., D. S. Robinson, et al. (2003). "The role of T lymphocytes in the pathogenesis of asthma." J Allergy Clin 
Immunol 111(3): 450-463; quiz 464. 
 
Leonard, C. K., M. W. Spellman, et al. (1990). "Assignment of intrachain disulfide bonds and characterization of 
potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein 
(gp120) expressed in Chinese hamster ovary cells." J Biol Chem 265(18): 10373-10382. 
 
Lewis, G. K. (2013). "Qualitative and quantitative variables that affect the potency of Fc- mediated effector function 
in vitro and in vivo: considerations for passive immunization using non-neutralizing antibodies." Curr HIV 
Res 11(5): 354-364. 
 
Mascola, J. R., M. G. Lewis, et al. (1999). "Protection of macaques against pathogenic simian/human 
immunodefiency virus 89.6PD by passive transfer of neutralizing antibodies." J Virol 73: 4009-4018. 
 
Mason, U., J. Aldrich, et al. (2002). "CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized 
monoclonal anti-CD4 treatment of active rheumatoid arthritis." J Rheumatol 29(2): 220-229. 
 
Mourad, G. J., F. I. Preffer, et al. (1998). "Humanized IgG1 and IgG4 anti-CD4 monoclonal antibodies: effects on 
lymphocytes in the blood, lymph nodes, and renal allografts in cynomolgus monkeys." Transplantation 65(5): 
632-641. 
 
Myszka, D. G., R. W. Sweet, et al. (2000). "Energetics of the HIV gp120-CD4 binding reaction." Proc Natl Acad 
Sci U S A 97(16): 9026-9031. 
 
Pollara, J., M. Bonsignori, et al. (2013). "Epitope specificity of human immunodeficiency virus-1 antibody 
dependent cellular cytotoxicity [ADCC] responses." Curr HIV Res 11(5): 378-387. 
 
Putney, S. D., T. J. Matthews, et al. (1986). "HTLV-III/LAV-neutralizing antibodies to an E. coli-produced fragment 
of the virus envelope." Science 234(4782): 1392-1395. 

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Reimann, K. A., R. Khunkhun, et al. (2002). "A humanized, nondepleting anti-CD4 antibody that blocks virus entry 
inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus." AIDS 
Res Hum Retroviruses 18(11): 747-755. 
 
Rerks-Ngarm, S., P. Pitisuttithum, et al. (2009). "Vaccination with ALVAC and AIDSVAX to prevent HIV-1 
infection in Thailand." N Engl J Med 361(23): 2209-2220. 
 
Rerks-Ngarm, S., P. Pitisuttithum, et al. (2009). "Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 
Infection in Thailand." N Engl J Med 20: 20. 
 
Robb, M. L., S. Rerks-Ngarm, et al. (2012). "Risk behaviour and time as covariates for efficacy of the HIV vaccine 
regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial 
RV 144." Lancet Infect Dis. 
 
Rusche, J. R., K. Javaherian, et al. (1988). "Antibodies that inhibit fusion of human immunodeficiency virus-infected 
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Saag, M. S., B. H. Hahn, et al. (1988). "Extensive variation of human immunodeficiency virus type-1 in vivo." 
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Sarzotti-Kelsoe, M., X. Daniell, et al. (2014). "Optimization and validation of a neutralizing antibody assay for HIV- 
1 in A3R5 cells." J Immunol Methods 409: 147-160. 
 
Sattentau, Q. J. (1996). "Neutralization of HIV-1 by antibody." Curr. Opin. Immunol. 8: 540-545. 
 
Seaman, M. S., H. Janes, et al. (2010). "Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for 
assessment of neutralizing antibodies." J Virol 84(3): 1439-1452. 
 
Sun, Y., M. Asmal, et al. "Antibody-Dependent Cell-Mediated Cytotoxicity in Simian Immunodeficiency Virus- 
Infected Rhesus Monkeys." J Virol. 
 
Tomaras, G. D., G. Ferrari, et al. (2013). "Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 
envelope blocks binding and effector function of IgG." Proc Natl Acad Sci U S A 110(22): 9019-9024. 
 
Truneh, A., R. L. Frescatore, et al. (1990). "Humoral response of cynomolgus macaques to human soluble CD4: 
antibody reactivity restricted xeno-human determinants." Cell. Immunol. 131: 98-108. 
 
Vargas-Inchaustegui, D. A. and M. Robert-Guroff (2013). "Fc receptor-mediated immune responses: new tools but 
increased complexity in HIV prevention." Curr HIV Res 11(5): 407-420. 
 
Watanabe, M., Z. W. Chen, et al. (1991). "Soluble human CD4 elicits an antibody response in rhesus monkeys that 
inhibits simian immunodeficiency viurs replication." Proc. Natl. Acad. Sci. U. S. A. 88: 120-124. 
 
Watanabe, M., C. G. Levine, et al. (1991). "Immunization of simian immunodeficiency virus-infected rhesus 
monkeys with soluble human CD4 elicits an antiviral response." Proc. Natl. Acad. Sci. U. S. A. 88: 4616- 
4620. 
 
Watanabe, M. J., j. E. Boyson, et al. (1992). "Chimpanzees immunized with recombinant soluble CD4 develop anti- 
self CD4 antibody responses with anti-human immunodeficiency virus activity." Proc. Natl. Acad. Sci. U. S. 
A. 89: 5103-5107. 
 
Wei, X., J. M. Decker, et al. (2003). "Antibody neutralization and escape by HIV-1." Nature 422: 307-312. 
 
Wilflingseder, D., Z. Banki, et al. (2007). "IgG opsonization of HIV impedes provirus formation in and infection of 
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Wyatt, R., P. D. Kwong, et al. (1998). "The antigenic structure of the HIV gp120 envelope glycoprotein." Nature 
393(6686): 705-711. 
 
Xiao, P., J. Zhao, et al. (2010). "Multiple vaccine-elicited nonneutralizing antienvelope antibody activities contribute 
to protective efficacy by reducing both acute and chronic viremia following simian/human immunodeficiency 
virus SHIV89.6P challenge in rhesus macaques." J Virol 84(14): 7161-7173. 

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21. 
APPENDICES 

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YES/NO 
ONSET 
DURATION
 
(m/d/y)
(hours)
 
APPENDIX 1. DETAILED REACTOGENICITY FORM 
 
(Note these are the items which will be on the diary card given to each volunteer after each immunization to record 
any events occurring in the first 7 days following each immunization.) 
 
PATIENT NAME:   
 
 
STUDY NUMBER: 
STUDY DAY:  
 
  
NURSE:  
 
DATE:   
 
PLEASE ENTER ANY SYMPTOMS YOU MAY HAVE WITHIN 48 HOURS AFTER YOUR VACCINE INJECTION IN THE COLUMN BESIDE IT. MAIL IT IN 
THE ENVELOPE PROVIDED (CIRCLE Y OR N) 
 
SYMPTOM 
YES/NO 
ONSET 
DURATION
 
 
(m/d/y) 
(hours)
FEVER 
Y 
N 
CHILLS 
Y 
N 
NAUSEA 
Y 
N 
VOMITING 
Y 
N 
JOINT PAINS (arthralgia) 
Y 
N 
MUSCLE ACHES (myalgia) 
Y 
N 
FATIGUE (malaise) 
Y 
N 
HIVES OR RASH (urticaria) 
Y 
N 
WHEEZING 
Y 
N 
HEADACHES 
Y 
N 
ITCHING 
Y 
N 
PAIN 
Y 
N 
DIARRHEA 
Y 
N 
OTHER 
Y 
N 
 
*PLEASE CALL YOUR PROTOCOL NURSE/PHYSICIAN IF YOU SHOULD HAVE ANY OF THE SIGNS AT THE INJECTION SITE ON THIS LIST (CIRCLE Y 
OR N). 
SYMPTOM 
 
REDNESS (erythema) 
Y 
N 
ROUGHNESS (induration) 
Y 
N 
SWELLING 
Y 
N 
NODULE (subcutaneous) 
Y 
N 
TENDERNESS 
Y 
N 
SKIN BREAKDOWN 
Y 
N 
SWOLLEN OR TENDER LYMPH NODES 
UNDER YOUR ARM 
 
Y  
N 
INABILITY TO MOVE OR USE ARM 
Y 
N 
OTHER 
Y 
N 
 
 
Reviewed by 
(Protocol Nurse) 
 
 
Reviewed by 
(Study MD) 

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APPENDIX 2. TABLE FOR GRADING SEVERITY OF ADULT ADVERSE 
EXPERIENCES 
 
(Adapted from the ACTG and AVEG tables) 
ABBREVIATIONS:   Abbreviations utilized in the Table: 
 
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal 
Rx  = Therapy 
Req = Required 
Mod = Moderate 
IV  = Intravenous 
ADL = Activities of Daily Living 
Dec = Decreased 
 
 
 
ESTIMATING SEVERITY GRADE 
 
For abnormalities NOT found elsewhere on the Table, use the scale below to estimate grade of severity: 
 
GRADE 1 
 
GRADE 2 
Mild 
Moderate 
Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Mild to moderate limitation in activity - some assistance may be needed; no 
or minimal medical intervention/therapy required 
 
GRADE 3 
 
Severe 
 
Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
 
GRADE 4 
 
Life- threatening 
 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered a grade 4 
adverse experience.  Clinical events considered to be serious or life-threatening include, but are not limited to: 
 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse petechiae, 
paralysis, acute psychosis 
 
MISCELLANEOUS 
 
> 
When two values are used to define the criteria for each parameter, the lowest values will occur first. 
 
> 
Parameters are generally grouped by body system. 
 
> 
Some protocols may have additional protocol specific grading criteria. 

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PARAMETER 
 
GRADE 1 
 MILD 
 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
 
GRADE 4 
POTENTIALLY LIFE
 
 
 
 
THREATENING 
HEMATOLOGY 
 
 
 
 
 
Hemoglobin 
 
8.0 g/dL - 
 
7.0 g/dL - 
6.5 g/dL - 
 
<6.5 g/dL 
 
9.4 g/dL 
7.9 g/dL
6.9 g/dL
 
 
Absolute Neutrophil 
 
1000 - 1500/mm3 
 
750 - 999/mm3 
500 - 749/mm3 
 
<500/mm3 
Count 
 
 
 
 
 
Platelets 
 
75,000 - 
99,000/mm3 
 
50,000 - 
74,999/mm3 
20,000 - 
49,999/mm3 
 
<20,000/mm3 
 
Prothrombin Time (PT) 
 
>1.0 - 1.25 x 
 
>1.25 - 1.5 x 
>1.5 - 3.0 x 
 
>3 x 
 
ULN 
ULN
ULN
ULN
 
PTT 
 
>1.0 - 1.66 x ULN 
 
>1.66 - 2.33 x 
>2.33 - 3.0 x 
 
>3.0 x 
 
ULN 
ULN
ULN
ULN
 
Methemoglobin 
 
5.0 - 10.0% 
 
10.1 - 15.0% 
15.1 - 20.0% 
 
>20% 
CHEMISTRIES 
 
 
 
 
 
SODIUM 
 
 
 
 
Hyponatremia 
130 - 135 meq/L 
123 - 129 meq/L
116 - 122 meq/L 
<116 meq/L
 
Hypernatremia 
 
146 - 150 meq/L 
 
151 - 157 meq/L 
158 - 165 meq/L 
 
>165 meq/L 
 
POTASSIUM 
 
 
 
 
Hypokalemia 
3.0 - 3.4 meq/L 
2.5 - 2.9 meq/L
2.0 - 2.4 meq/L 
<2.0 meq/L
 
Hyperkalemia 
 
5.6 - 6.0 meq/L 
 
6.1 - 6.5 meq/L 
6.6 - 7.0 meq/L 
 
>7.0 meq/L 
 
PHOSPHATE 
Hypophosphatemia 
2.0 - 2.4 mg/dL 
1.5 - 1.9 mg/dL 
1.0 - 1.4 mg/dL 
<1.0 mg/dL 
 
CALCIUM - (corrected for albumin) 
Hypocalcemia 
7.8 - 8.4 mg/dL 
7.0 - 7.7 mg/dL 
6.1 - 6.9 mg/dL 
<6.1 mg/dL 
Hypercalcemia 
10.6 - 11.5 mg/dL 
11.6 - 12.5 mg/dL 
12.6 - 13.5 mg/dL 
>13.5 mg/dL 
MAGNESIUM 
Hypomagnesemia 
1.2 - 1.4 meq/L 
0.9 - 1.1 meq/L 
0.6 - 0.8 meq/L 
<0.6 meq/L 
 
BILIRUBIN 
Hyperbilirubinemia 
>1.0 - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 - 5 x ULN 
>5 x ULN 

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PARAMETER 
 
GRADE 1 
 MILD 
 
GRADE 2 
 MODERATE   
GRADE 3 
SEVERE   
 
GRADE 4 
 POTENTIALLY LIFE 
 
GLUCOSE 
 
 
 
THREATENING
Hypoglycemia 
55 - 64 mg/dL 
40 - 54 mg/dL
30 - 39 mg/dL 
<30 mg/dL
 
Hyperglycemia 
(nonfasting and 
no prior diabetes) 
 
116 - 160 mg/dL 
 
161 - 250 mg/dL 
251 - 500 mg/dL 
 
>500 mg/dL 
 
Triglycerides 
 
------ 
 
400 - 750 mg/dL 
751 - 1200 mg/dL 
 
>1200 mg/dL 
 
 
Creatinine 
>1.0 - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
 
URIC ACID 
 
 
 
 
 
Hyperuricemia 
 
7.5 - 10.0 mg/dL 
 
10.1 - 12.0 mg/dL 
12.1 - 15.0 mg/dL 
 
>15.0 mg/dL 
 
LIVER TRANSAMINASE (LFTs) 
 
AST (SGOT) 
 
1.25 - 2.5 x ULN 
 
>2.5 - 5.0 x ULN 
>5.0 - 10.0 x ULN 
 
>10.0 x ULN 
 
ALT (SGPT) 
 
1.25 - 2.5 x ULN 
 
>2.5 - 5.0 x ULN 
>5.0 - 10.0 x ULN 
 
>10.0 x ULN 
 
GGT 
 
1.25 - 2.5 x ULN 
 
>2.5 - 5.0 x ULN 
>5.0 - 10.0 x ULN 
 
>10.0 x ULN 
 
Alk Phos 
 
1.25 - 2.5 x ULN 
 
>2.5 - 5.0 x ULN 
>5.0 - 10.0 x ULN 
 
>10.0 x ULN 
 
PANCREATIC ENZYMES 
 
Amylase 
 
>1.0 - 1.5 x ULN 
 
>1.5 - 2.0 x ULN 
>2.0 - 5.0 x ULN 
 
>5.0 x ULN 
 
Pancreatic amylase 
 
>1.0 - 1.5 x ULN 
 
>1.5 - 2.0 x ULN 
>2.0 - 5.0 x ULN 
 
>5.0 x ULN 
 
Lipase 
 
>1.0 - 1.5 x ULN 
 
>1.5 - 2.0 x ULN 
>2.0 - 5.0 x ULN 
 
>5.0 x ULN 
CARDIOVASCULAR  
 
 
 
 
Cardiac Arrhythmia 
 
----- 
 
Asymptomatic; 
transient 
dysrhythmia, 
no Rx req 
Recurrent/persistent 
dysrhythmia; 
symptomatic 
Rx req 
 
Unstable 
dysrhythmia, 
hospitalization and 
Rx req 

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PARAMETER 
 
GRADE 1 
MILD 
GRADE 2 
MODERATE
GRADE 3 
SEVERE
 
GRADE 4 
POTENTIALLY LIFE
 
 
 
 
THREATENING 
 
Hypotension 
 
Transient orthostatic 
hypotension, no Rx 
(with heart rate 
increased by 
>20 beats/min 
correctable with 
OR decreased by 
<10 mm Hg 
systolic BP) 
Symptoms 
(OR BP 
decreased 
by <20 mm Hg 
systolic) 
 
oral fluid Rx 
IV fluid req, no 
hospitalization req 
 
Hospitalization 
req 
 
Hypertension 
 
Transient, increase 
>20 mm/Hg; 
no Rx 
Recurrent; chronic 
increase, 
>20 mm/Hg, 
Rx req 
Acute Rx req; 
outpatient 
hospitalization 
possible 
 
Hospitalization 
req 
 
Pericarditis 
 
Minimal effusion 
Mild/mod 
asymptomatic 
effusion, no Rx 
Symptomatic 
effusion, pain, 
EKG changes 
 
Tamponade OR 
pericardio 
centesis OR 
surgery req 
 
Hemorrhage, blood 
Loss 
 
------ 
Mildly 
symptomatic, 
no Rx required 
Gross blood loss 
OR 1-2 units 
transfused 
 
Massive blood 
loss OR >2 units 
transfused 
GASTROINTESTINAL 
 
Nausea 
Mild OR transient; 
reasonable intake 
maintained 
Mod discomfort 
OR intake 
decreased for
Severe discomfort 
OR minimal intake 
for >3 days
 
Hospitalization 
req 
 
 
<3 days 
 
 
 
Vomiting 
Mild OR transient; 
2-3 episodes per day 
OR mild vomiting 
lasting <1 week 
Mod OR persistent; 
4-5 episodes per day; 
OR vomiting lasting
>1 week 
Severe vomiting 
of all food/fluids 
in 24 hrs OR 
orthostatic 
hypotension 
OR IV Rx req 
 
Hypotensive 
shock OR 
hospitalization 
req for 
IV Rx req 
 
Diarrhea 
Mild OR transient; 
3-4 loose stools per 
day OR mild 
diarrhea 
lasting <1 week 
Mod OR persistent; 
5-7 loose stools per 
day OR diarrhea 
lasting >1 week 
Bloody diarrhea; 
OR orthostatic 
hypotension 
OR >7 loose 
stools/day 
OR IV Rx required 
 
Hypotensive 
shock OR 
hospitalization 
req 

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PARAMETER 
 
GRADE 1 
 
GRADE 2
GRADE 3
 
GRADE 4
 
MILD 
MODERATE
SEVERE
POTENTIALLY
LIFE THREATENING 
 
Oral Discomfort/ 
Dysphagia 
Mild discomfort, 
no difficulty 
swallowing 
Difficulty 
swallowing but 
able to eat and 
drink 
Unable to swallow 
solids 
Unable to drink 
fluids; IV fluids 
req 
 
Constipation 
 
Mild 
Moderate 
(abdominal pain 
for 78 hours with 
impaction, require 
output prescription 
Severe 
(Requiring 
disimpaction 
or hospital 
treatment) 
 
Distention with 
vomiting(OR 
obstipation) 
 
RESPIRATORY 
 
 
 
 
 
Cough (for 
aerosol studies) 
 
Transient; no Rx 
Treatment 
associated 
cough; inhaled 
bronchodilator 
Uncontrolled 
cough;systemic 
Rx req 
 
------ 
 
Bronchospasm Acute 
 
Transient; no Rx; 
FEV1 70% - <80% 
(or peak flow) 
Rx req; normalizes 
with bronchodilator; 
FEV1 50%-<70% 
(or peak flow) 
No normalization 
with bronchodilator; 
FEV1 25% - <50% 
(or peak flow), 
retractions 
 
Cyanosis; 
FEV1 <25% 
(or peak flow) 
OR intubated 
 
Dyspnea 
 
Dyspnea on 
exertion 
Dyspnea with 
normal activity 
Dyspnea at rest 
 
Dyspnea requiring 
O2 therapy 
NEUROLOGIC 
 
Neuro-cerebellar 
Slight 
Intention tremor 
Ataxia requiring 
Unable to stand 
incoordination OR 
OR dysmetria OR 
assistance to walk 
dysdiadochokinesia 
slurred speech OR 
or arm 
nystagmus 
incoordination 
interfering with 
ADLs 
 
Neuro-psych/mood 
------ 
------ 
Severe mood 
Acute psychosis 
changes requiring 
req 
 
medical 
hospitalization 
 
 
intervention 
(suicidal 
gesture/attempts) 

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PARAMETER 
 
GRADE 1 
 
GRADE 2
GRADE 3
 
GRADE 4
 
MILD 
MODERATE
SEVERE
POTENTIALLY
LIFE THREATENING 
 
Paresthesia 
(burning, 
tingling, etc) 
Mild discomfort; 
no Rx req 
Mod discomfort; 
non-narcotic 
analgesia req 
Severe 
discomfort;OR 
narcotic analgesia 
with symptomatic 
req  with 
symptomatic 
improvement 
Incapacitating; 
OR not responsive 
to narcotic 
 
analgesia 
 
Neuro-motor 
 
Mild weakness in 
muscle of feet but 
able to walk and/or 
mild increase or 
decrease in reflexes 
Mod weakness in 
feet(unable to 
walk on heels 
and/or toes), mild 
weakness in 
hands, still able to 
do most hand 
tasks and/or loss 
of previously 
present reflex or 
development of 
hyperreflexia 
and/or unable to 
do deep knee 
bends due to 
weakness 
Marked distal 
weakness (unable 
to dorsiflex toes 
or foot drop), and 
mod proximal 
weakness e.g., in 
hands interfering 
with ADLs and/or 
req assistance to 
walk and/or unable 
to rise from chair 
unassisted 
 
Confined to bed 
or wheel chair 
because of 
 
Neuro-sensory 
 
Mild impairment 
(dec sensation, e.g., 
vibratory, pinprick, 
hot/cold in great toes) 
in focal area or 
symmetrical distri- 
bution 
Mod impairment 
(mod  dec sensation, 
e.g., vibratory, 
pinprick, hot/cold 
to ankles) and/or 
joint position or 
mild impairment 
Severe impairment 
(dec or loss of 
sensation to knees 
or wrists) or loss 
of sensation of at 
least mod degree 
in multiple 
 
Sensory loss 
involves limbs 
and trunk. 
that is not 
different body areas 
symmetrical 
(i.e., upper and lower 
extremities) 
 
MUSCULOSKELETAL 
 
Arthralgia/Arthritis 
Arthralgia 
Arthralgia with 
Frank arthritis 
------
 
 
joint effusion or
with or without 
 
 
 
moderate
effusion OR
 
 
 
impairment of
resulting in
 
 
 
activity
severe impair-ment of 
 
 
 
activity
 

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PARAMETER 
 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
GRADE 4 
SEVERE 
POTENTIALLY 
 
 
 
LIFE THREATENING
 
Myalgia 
 
Myalgia without 
limitation of 
activity 
Muscle 
tenderness at 
other than 
injection site or 
with moderate 
impairment of 
activity 
Frank 
----- 
myonecrosis OR 
with severe 
impairment of 
activity 
URINALYSIS 
 
 
 
 
Proteinuria 
 
 
 
 
Spot urine 
 
1+ 
2 - 3+ 
4+ 
Nephrotic 
Syndrome 
 
24 hour urine 
 
200 mg-1 g 
loss/day OR 
<0.3% OR <3 g/l 
>1 - 2 g 
loss/day OR 
0.3 - 1.0% OR 
3 - 10 g/l 
>2 - 3.5 g 
Nephrotic 
loss/day OR 
syndrome OR 
>1.0% OR 
>3.5 g loss/day 
>10 g/l 
 
Gross Hematuria 
 
Microscopic only 
Gross, no clots 
Gross plus clots 
Obstructive OR 
transfusion req 
MISCELLANEOUS  
 
 
 
Fever 
oral >12 hours 
 
37.7 - 38.5C OR 
100.0 - 101.5F 
38.6 - 39.5C OR 
101.6 - 102.9F 
39.6 - 40.5C OR 
>40.5C OR 
103 - 105F 
>105F 
 
Headache 
 
Mild; no Rx req 
Mod; OR 
non-narcotic 
analgesia Rx 
Severe; OR 
Intractable; OR 
responds to 
requiring repeated 
initial narcotic Rx 
narcotic Rx 
 
Allergic Reaction 
 
Pruritus without 
rash 
Localized urticaria 
Generalized 
Anaphylaxis 
urticaria 
angioedema 

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PARAMETER 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
 
LIFE 
MILD 
MODERATE
SEVERE
POTENTIALLY
LIFE 
THREATENING
 
Cutaneous/Rash/ 
Erythema, pruritus 
Diffuse 
Vesiculation OR 
ANY ONE: 
Dermatitis 
 
maculopapular
moist
mucous membrane
 
 
rash OR dry
desquamation 
involvement,
 
 
 
desquamation 
OR ulceration
 
suspected Stevens-
Johnson(TEN),
erythema
multiforme,
necrosis req surgery,
exfoliative
dermatitis
 
 
Local Reaction 
(2o parenteral Rx - 
Erythema 
Induration <10mm 
OR inflammation 
Induration >10mm 
OR ulceration 
Necrosis of skin
not vaccination or 
skin test) 
 
OR phlebitis
 
 
 
Fatigue 
 
Normal activity 
reduced <25% 
 
Normal activity 
reduced 25-50% 
Normal activity 
reduced >50%; 
cannot work 
 
Unable to care 
for self 
 
Eye 
 
----- 
 
Mild pain, visual 
changes, 
conjunctival 
erythema, 
abnormal slit lamp 
Loss of vision, 
clinically 
diagnosed uveitis, 
moderate to 
severe pain, 
glaucoma 
 
----- 

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APPENDIX 3. INVESTIGATIONAL DRUG ACCOUNTABILITY 
POLICY/PROCEDURE 
 
 
 
Section 06 
 
Policy No. 05 
 
PAGE 1 of 4 
 
 
 
 
 
 
 
 
UNIVERSITY OF MARYLAND MEDICAL 
CENTER 
 
 
 
DEPARTMENT OF PHARMACY SERVICES 
POLICY AND PROCEDURE MANUAL 
POLICY NO.  06-05 
 
 
 
Effective Date:  08/06 
Revision Date: 08/07 
 
 
 
P&P SECTION: Investigational Drug Services 
SUBJECT: Investigational Drug Accountability 
Policy Owner:  Assistant Director, 
 
Clinical Pharmacy Services 
 
 
 
 
 
Site Application: UMMC 
 
 
 
 
 
Distribution: Pharmacy Leadership 
 
APPROVALS: 
 
 
 
Director, Department of Pharmacy Services  
 

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1. PURPOSE 
 
The purpose of this policy is to ensure complete and accurate records of investigational drug 
accountability. 
 
2. SCOPE 
 
This policy applies to all pharmacists and technicians involved in preparation and dispensing of 
investigational drugs. The National Cancer Institute (NCI) accountability form is the preferred 
drug accountability record form (DARF) for all investigational studies, unless the sponsor 
requires different dispensing documentation.  The procedure defined below pertains to the NCI 
DARF. 
 
3. RESPONSIBILITY 
 
All pharmacists and technicians involved in preparation and dispensing of investigational drugs 
are responsible for maintaining accurate and complete records of drug accountability. 
 
4. POLICY 
 
Investigational drug accountability records will meet defined requirements for completeness and 
accuracy. 
 
5. PROCEDURES 
 
5.1 
A separate accountability log will be maintained for each drug in each protocol.  If there 
is more than one strength or dosage form for a drug for the same protocol, a separate DARF is 
required for each product (e.g. a drug with a 1 mg vial and a 5 mg vial requires a different DARF 
for the 1 mg vial and for the 5 mg vial). 
 
5.2 
The accountability log will be completed accurately. 
 
5.2.1 Each line will be completed for all spaces. 
 
5.2.2 Corrections will be performed by placing one line through the error, then initialing, and 
dating the error.  Erasures and “whiteouts” are not permitted. 
 
5.2.3 A black ball point pen will be used to record all entries on the logs. 
 
5.2.4 All agent transactions will be noted on the DARF (e.g. receipt of agent, broken vials, 
returns, transfer of agent). 
 
5.2.5 No clinical notes will be placed on the DARF. 
 
5.3 To begin a new DARF, complete the upper portion of the form as follows: 
 
Page Number - Record the page number consecutively on the forms for each drug used on the 
protocol. 
 
Control Record- Check this box if the record is being used to account for research drug stored 
at the control pharmacy. 

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Satellite Record – Check this box if the record is being used to account for research drug not at 
the control pharmacy or primary site. 
 
Name of Institution (the name of the location to which the drug is shipped from NCI) 
 
 
 
Protocol Number (NCI) (may add the institutional protocol number if necessary) 
 
Drug Name, Dose Form and Strength 
 
Protocol Title - May use abbreviations if necessary. 
 
Dispensing Area (the location where the drug is dispensed, e.g. infusion center pharmacy, 
satellite location, central pharmacy) 
 
Investigator (name of the investigator whose name the drug is ordered from NCI) 
 
Balance Forward- Enter zero if the current page is the first page or bring the balance forward 
from the previous page. 
 
5.4 Upon receiving a drug shipment, enter the following information on the DARF : 
Date (Date the drug is received including year) 
Patient’s Initials, Patient’s ID Number and Dose - Enter “Received from [name of the study 
sponsor]” 
 
Quantity Dispensed or Received (“ + “ and # of vials, ampoules, tablets, or kits indicating # to 
be added to balance) 
 
Balance (Balance total) 
 
Manufacturer and Lot Number - If the drug shipment contains more than one lot number, 
make separate entry for optimal record keeping. 
 
Recorder’s Initials 
 
5.5 When preparing drugs for dispensing, enter the following information on the DARF: 
Date (the date of dispensing/preparation including year) 
Patient’s Initials - Use the same initials as for the protocol registration. 
 
Patient’s I.D. Number (patient’s study number) 
 
Dose (actual dose administered) 
 
Quantity Dispensed (“-“ and # of vials, ampoules, tablets, or kits dispensed indicating the # to 
be subtracted from balance) 
 
Balance - Balance total should equal quantity on hand. 
 
Manufacturer and Lot Number - If there is more than one lot number being used, make 
separate entries for optimal record keeping. 
 
Recorder’s Initials 
 
5.6 When transferring investigational drugs to a satellite location, enter the following 
information on the DARF: 

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Date (the date of transfer including year) 
 
Patient’s Initials, Patient’s I.D. Number, and Dose (“transfer to [name of location]”) 
 
 
 
Quantity Dispensed and Received (“-“ and # of vials, ampoules, tablets or kits dispensed 
indicating the # to be subtracted from the balance; provide sufficient supply for at least one 
treatment; also document receipt of returned drug with “+” and the # received from the satellites 
indicating an addition to the balance) 
 
Balance - Balance total should equal quantity on hand. 
 
Manufacturer and Lot Number - If there is more than one lot number being used, make 
separate entries for optimal record keeping. 
 
Recorder’s Initials 
 
5.7 Upon receiving the drugs, the satellite should enter the following information on the DARF: 
Date (the date of transfer including year) 
Patient’s Initials, Patient’s I.D. Number, and Dose (“Received or transferred from Control 
Pharmacy”) 
 
Quantity Received (“+” and # received indicating # to be added to the balance) 
 
Balance (balance total) 
 
Manufacturer and Lot Number If there is more than one lot number being used, make separate 
entries for optimal record keeping. 
 
Recorder’s Initials 
 
5.8 To return drugs to NCI or the sponsor, complete the Return Drug List Form and enter the 
following information in the DARF: 
 
Date (the date of return including year) 
 
Patient’s Initials, Patient’s I.D. Number, and Dose – Enter “Returned to NCI or [name of 
sponsor]” 
 
Quantity Received (“-” and # returned indicating # to be subtracted from the balance) 
 
Balance (balance total) 
 
Manufacturer and Lot Number- If there is more than one lot number being used, make 
separate entries for optimal record keeping. 
 
Recorder’s Initials 
 
5.9 When transferring DCTB supplied study drugs to another DCTD approved protocol, enter 
the following on the DARF 
 
Date (the date of transfer including year) 
 
Patient’s Initials, Patient’s I.D. Number, and Dose (“transfer to [name of protocol]”) 
 
Quantity Dispensed and Received (“-“ and # of vials, ampoules, tablets or kits transferred) 

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Balance (balance total should equal quantity on hand) 
 
 
 
 
 
Manufacturer and Lot Number - If there is more than one lot number being used, make 
separate entries for optimal record keeping. 
 
Recorder’s Initials 
 
5.10 
When subject specific multi-dose investigational agent kit is dispensed, all 
transactions will be recorded following: 
Subject specific investigational agent kit may contain multi-dose investigational agents. 
Investigational drug service pharmacy must keep master and subject specific drug accountability 
logs for multi-dose investigational agent kit. 
 
Upon receipt of multi-dose subject specific kit from the sponsor, it will be logged in into a 
master drug accountability log as “Received from (sponsor’s name)”. 
 
When the multi-dose subject specific kit is dispensed to the specific study subject, entire 
assigned investigational drug kit will be logged out from the master drug accountability log on 
the date of the first treatment as “Transferred to (subject’s initials) drug accountability log”. 
 
The entire assigned multi-dose subject specific kit will be logged in into the subject specific drug 
accountability log on the date of the first treatment as “Received from master drug accountability 
log”.