A Randomized, Double-blinded, Placebo-controlled, Dose-escalation Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of Recombinant HIV Envelope Protein BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, in Healthy, HIV-1 Uninfected Adults

Study Overview
=================
Brief Summary
-----------------
This a phase 1 first-in-human clinical trial to evaluate the safety, tolerability, and immunogenicity of BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, in up to 60 healthy adult HIV-uninfected volunteers.

Detailed Description
-----------------
This a phase 1 first-in-human clinical trial to evaluate the safety, tolerability, and immunogenicity of BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, in up to 60 healthy adult HIV-uninfected volunteers. BG505 SOSIP.664 gp140 is a stable, soluble, cleaved HIV envelope trimer formulated in 0.55mL at 2mg/mL in 20 mM Tris, 100 mM NaCl, pH 7.5 and will be administered IM.

Official Title
-----------------
A Randomized, Double-blinded, Placebo-controlled, Dose-escalation Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of Recombinant HIV Envelope Protein BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, in Healthy, HIV-1 Uninfected Adults

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Biological: BG505 SOSIP.664 gp140, adjuvanted
* Biological: BG505 SOSIP.664 gp140, adjuvanted
* Biological: BG505 SOSIP.664 gp140, adjuvanted
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male and female, including transgender individuals, as assessed by a medical history, physical exam, and laboratory tests At least 18 years of age on the day of screening and has not reached his/her 51st birthday on the day of first vaccination Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study In the opinion of the Principal Investigator or designee and based on Assessment of Informed Consent Understanding results, has understood the information provided and potential impact and/or risks linked to vaccination and participation in the trial; written informed consent will be obtained from the volunteer before any study-related procedures are performed Willing to undergo HIV testing, risk reduction counselling and receive HIV test results All volunteers born female engaging in sexual activity that could lead to pregnancy must commit to use an effective method of contraception for 4 months following investigational product administration All volunteers born female, who are not heterosexually active at screening, must agree to utilize an effective method of contraception if they become heterosexually active All volunteers born female must be willing to undergo urine pregnancy tests at time points indicated in the Schedule of Procedures (Appendix A and B) All sexually active volunteers born male, regardless of reproductive potential, must be willing to use an effective method of contraception (such as consistent condom use) from the day of first vaccination until at least 4 months after the last vaccination to avoid exposure of partners to investigational product in ejaculate and to prevent conception with female partners Willing to forgo donations of blood, or any other tissues during the study and, for those who test HIV-positive due to vaccine-induced antibodies, until the anti-HIV antibody titers become undetectable Exclusion Criteria: Confirmed HIV-1 or HIV-2 infection Any clinically relevant abnormality on history or examination including history of immunodeficiency or autoimmune disease; use of corticosteroids (the use of topical, nasal, or inhaled steroids is permitted), immunosuppressive, anticancer, anti-tuberculosis or other medications considered significant by the investigator within the previous 6 months. The following exceptions are permitted and will not exclude study participation: use of corticosteroid nasal spray for rhinitis, topical corticosteroids for an acute uncomplicated dermatitis; or a short course (duration of 10 days or less, or a single injection) of corticosteroid for a non-chronic condition (based on investigator clinical judgment) at least 2 weeks prior to enrolment in this study Any clinically significant acute or chronic medical condition that is considered progressive or in the opinion of the investigator makes the volunteer unsuitable for participation in the study Reported risky behavior for HIV infection within 12 months prior to vaccination If female, pregnant or planning a pregnancy during the period of enrolment until 4 months after the last study vaccination; or lactating Bleeding disorder that was diagnosed by a physician (e.g., factor deficiency, coagulopathy or platelet disorder that requires special precautions.) (Note: A volunteer who states that he or she has easy bruising or bleeding, but does not have a formal diagnosis and has IM injections and blood draws without any adverse experience, is eligible) Infectious disease: chronic hepatitis B infection (HbsAg-positive), current hepatitis C infection (for US sites: HCV Ab positive and HCV RNA positive, for African site: HCV Ab positive only) treatment for chronic hepatitis C infection in the past year, or active syphilis (positive RPR confirmed by TPHA); active tuberculosis (for African site only) History of splenectomy Any of the following abnormal laboratory parameters listed below: Hematology Absolute Neutrophil Count (ANC) - all volunteers: ≤1,000/mm3 Absolute Lymphocyte Count (ALC) - all volunteers: ≤650/mm3 Hemoglobin - African volunteers: <9.5 g/dl in females; <11.0 g/dl in males Hemoglobin - US volunteers: <10.5 g/dl in females; <11.0 g/dl in males Platelets - African volunteers: <100,000 cells/mm3 Platelets - US volunteers: <125,000 cells/mm3 Chemistry Creatinine >1.1 x upper limit of normal (ULN) ALT >1.25 x ULN AST >1.25 x ULN Urinalysis Clinically significant abnormal dipstick confirmed by microscopy: Protein = 1+ or more Blood = 2+ or more (not due to menses) Receipt of live attenuated vaccine within the previous 30 days or planned receipt within 30 days after vaccination with Investigational Product; or receipt of other vaccine within the previous 14 days or planned receipt within 14 days after vaccination with Investigational Product. (Exception is live attenuated influenza vaccine within 14 days) Receipt of blood transfusion or blood-derived products within the previous 3 months Participation in another clinical trial of an Investigational Product currently, within the previous 3 months or expected participation during this study; Concurrent participation in an observational study not requiring any blood or tissue sample collection is not an exclusion Prior receipt of another investigational HIV vaccine candidate or HIV monoclonal antibody (Note: receipt of placebo in a previous HIV vaccine trial will not exclude a volunteer from participation if documentation is available and the Medical Monitor gives approval) History of severe local or systemic reactogenicity to vaccines (e.g., anaphylaxis, respiratory difficulties, angioedema, injection site necrosis or ulceration) Psychiatric condition that compromises safety of the volunteer and precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years prior to screening, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years Seizure disorder: A participant who has had a seizure in the last 3 years prior to screening is excluded. (Not excluded: a participant with a history of seizures who has neither required medications nor had a seizure for 3 years) A history of malignancy in the past 5 years (prior to screening) or ongoing malignancy (A history of a completely excised malignancy that is considered cured is not an exclusion) Active, serious infections requiring parenteral antibiotic, antiviral or antifungal therapy within 30 days prior to enrolment Body mass index (BMI) ≥35 Body weight <110 pounds (55 kg); for US sites only If, in the opinion of the Principal Investigator, it is not in the best interest of the volunteer to participate in the trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1<br>HIV-Uninfected participants | Biological: BG505 SOSIP.664 gp140, adjuvanted<br>* Dosage of 30ug, Intramuscular administration<br>Biological: Placebo<br>* Tris-NaCl Diluent<br>|
| Placebo Comparator: Group 2<br>HIV-Uninfected participants | Biological: BG505 SOSIP.664 gp140, adjuvanted<br>* Dosage of 100ug, Intramuscular administration<br>Biological: Placebo<br>* Tris-NaCl Diluent<br>|
| Placebo Comparator: Group 3<br>HIV-Uninfected participants | Biological: BG505 SOSIP.664 gp140, adjuvanted<br>* Dosage of 300ug, Intramuscular administration<br>Biological: Placebo<br>* Tris-NaCl Diluent<br>|
| Placebo Comparator: Group 4<br>HIV-Uninfected participants | Biological: BG505 SOSIP.664 gp140, adjuvanted<br>* Dosage of 30ug, Intramuscular administration<br>Biological: Placebo<br>* Tris-NaCl Diluent<br>|
| Placebo Comparator: Group 5<br>HIV-Uninfected participants | Biological: BG505 SOSIP.664 gp140, adjuvanted<br>* Dosage of 100ug, Intramuscular administration<br>Biological: Placebo<br>* Tris-NaCl Diluent<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of volunteers with moderate or greater reactogenicity (i.e., solicited adverse events) during a 7-day follow-up period after each vaccination | To evaluate the safety and tolerability of the study regimens based on the frequency of local and systemic reactogenicity events as assessed using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v2.1). | 7 days post-vaccination | 
| Proportion of volunteers with moderate or greater and/or vaccine related unsolicited adverse events (AEs), including safety laboratory (biochemical, haematological) parameters, from the day of each vaccination up to 28 days post each vaccination | To evaluate the safety and tolerability of the study regimens based on the proportion of volunteers with moderate or greater unsolicited adverse events including safety laboratory as assessed using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v2.1). | 28 days post-vaccination | 
| Proportion of volunteers with vaccine-related serious adverse events (SAEs) throughout the study period | To evaluate the safety and tolerability of the study regimens based on the proportion of volunteers with vaccine-related serious adverse events including safety laboratory as assessed using the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v2.1). | 18 months | 
| Proportion of volunteers in each group with potential immune-mediated diseases (pIMD) from the day of injection throughout the study period | To evaluate the proportion of volunteers in each group with potential immune-mediated diseases (pIMDs) based on a defined list of pIMDs in the study protocol. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess immune responses elicited by the different BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, doses: | Proportion of volunteers with neutralizing antibodies against autologous BG505 SOSIP.664 gp140 Vaccine, Adjuvanted | 20 months | 
| To assess immune responses elicited by the different BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, doses: | Proportion of volunteers with and magnitude of trimer binding antibodies to BG505 SOSIP.664 gp140 Vaccine, Adjuvanted | 20 months | 
| To assess immune responses elicited by the different BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, doses: | Proportion of volunteers with neutralizing antibodies against additional viral strains (e.g., Tier 1a/b, Tier 2) | 20 months | 
| To assess immune responses elicited by the different BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, doses: | Proportion of volunteers with and magnitude of binding antibodies to HIV Env | 20 months | 
| To assess immune responses elicited by the different BG505 SOSIP.664 gp140 Vaccine, Adjuvanted, doses: | Proportion of volunteers with HIV Env specific B and T-cell responses | 20 months |