A Phase I Study of Safety and Immunogenicity of the WRAIR HIV-1 Vaccine

Study Overview
=================
Brief Summary
-----------------
To evaluate the safety of LFn-p24 administered at three different doses with Alhydrogel given intramuscularly To evaluate immune responses to LFn-p24 with Alhydrogel at three different doses given intramuscularly

Detailed Description
-----------------
The study seeks to enroll healthy, vaccine naïve volunteers, 18 through 45 years old. Recruitment consists of using flyers, newspaper advertising, radio, and direct mailing at local military installations, targeting the general population of the greater Washington D.C. area. The study's primary objective is the safety and tolerability of Lfn-p24 given IM. Volunteers will be screened (visit 1) and enrolled within 2 to 12 weeks prior to the first vaccination. Study volunteers will receive a briefing from the Principal Investigator (PI) or a sub investigator. The briefing is followed by an opportunity for questions from the volunteers. The PI or designee will then review the consent form with potential volunteers (visit 1) and answer any questions. After review, an Informed Consent will be signed and a Test of Understanding will be completed by all volunteers, prior to enrollment in the study. A second pre-screening visit (visit 2) will occur 3 - 30 days prior to the first vaccination (visit 3) to confirm eligibility for vaccination. During this visit each volunteer will have an opportunity to ask questions about the study. On the day of vaccination (visits 3, 6, and 10), volunteers will be observed for 30 minutes following injection for acute adverse experiences and will be contacted the day following injection for a brief adverse reaction interview. In addition, volunteers will complete diaries for 7 days following each vaccination and will be evaluated by a clinical investigator if significant symptoms are reported. Adverse effects and laboratory abnormalities will be tabulated. Routine measurements of hematology, serum chemistry, and urinalysis laboratory tests will be performed in subsequent safety and general follow up visits.renee LFn-p24 with Alhydrogel adjuvant will be delivered IM in the deltoid muscle at the intervals shown below. Groups will be enrolled in staggered fashion beginning with the lowest dose group. The subsequent groups receiving higher doses will then be enrolled by the investigator if the second injection of the immediate lower dose is shown to be safe and well tolerated (< grade II toxicity), after the 2 week post vaccination follow-up visit. IMMUNIZATION SCHEDULE Group I Subjects *6 0:150µg LFn-p24 Alhydrogel;4th Week:150µg LFn-p24 Alhydrogel; 16th Week:150µg LFn-p24 Alhydrogel; Group II Subjects *6 0:300µg LFn-p24 Alhydrogel; 4th Week: 300µg LFn-p24 Alhydrogel; 16th Week: 300µg LFn-p24 Alhydrogel; Group III Subjects *6 0: 450µg LFn-p24 Alhydrogel; 4th Week: 450µg LFn-p24 Alhydrogel; 16th Week: 450µg LFn-p24 Alhydrogel *Six subjects per group includes 4 vaccines and 2 placebos.

Official Title
-----------------
RV 151: A Phase I Study of Safety and Immunogenicity of the WRAIR HIV-1 Vaccine LFn-p24 Administered by the Intramuscular (IM) Route in Healthy Adults, WRAIR #984, HSRRB Log # A-11905.

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

Intervention / Treatment
-----------------
* Biological: HIV LFn-p24


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Citizens of the U.S.A. who are not at high-risk for HIV infection. Age: 18 through 45 years of age. For women, negative serum pregnancy test will be required within two days prior to any injection, as well as verbal assurance that adequate contraceptive measures are applied. Good health as determined by medical history, physical examination, and clinical judgment. Clinical laboratory values at screening within the following ranges: Hematocrit: Women: > 34%: Men >38% (Mild anemia in any potential trial volunteer who is otherwise healthy attributable by appropriate laboratory studies to thalassemia minor will not be cause for exclusion) White blood cell count: 3,000 to 12,000 cells/mm3 Platelets: 125,000 to 550,000 per mm3 Chemistry Panel: Expanded chemistry panel within institutional normal ranges or accompanied by site physician approval. Urine dipstick for protein and blood: negative or trace. If either is ≥ 1+, obtain complete urinalysis (UA). If microscopic UA confirms evidence of hematuria or proteinuria ≥ 1+, the volunteer is ineligible unless menstruating, then a repeat UA is required. Negative serology for HIV infection (ELISA test). Availability for at least 52 weeks Successful completion of the Test of Understanding, Commitment for Trial Participation and signature of the approved Trial Consent Form. Exclusion Criteria: Acknowledge engaging in highest-risk behavior within 48 weeks of study entry: (i.e., active injecting drug use or having sexual intercourse with a known HIV-1 infected partner). Have active tuberculosis or other systemic infectious process by review of systems and physical examination. Have a history of immunodeficiency, chronic illness requiring continuous or frequent medical intervention, autoimmune disease, or use of immunosuppressive medications. Have evidence of psychiatric, medical and/or substance abuse problems during the past 48 weeks that the investigator believes would adversely affect the volunteer's ability to participate in the trial. Have occupational or other responsibilities that would prevent completion of participation in the study. Have received any live, attenuated vaccine within 60 days of study entry. NOTE: Medically indicated subunit or killed vaccines (e.g., Hepatitis A or Hepatitis B) are not exclusionary but should be given at least 2 weeks before or after HIV immunization to avoid potential confusion of adverse reactions. Acute or chronic Hepatitis caused by viral or other etiology. Have used experimental therapeutic agents within 30 days of study entry. Have received blood products or immunoglobulins in the past 12 weeks. Have a history of anaphylaxis or other serious adverse reactions to vaccines. Have previously received an HIV and/or anthrax vaccine. Currently enrolled in other vaccine trials. Are pregnant or lactating. NOTE: Women of child-bearing potential must be using effective contraception from the date of enrollment into the protocol. Have an immediate type hypersensitivity reaction to aminoglyocides, e.g., kanamycin (used to prepare the LFn-p24 vaccine). Are study site employees who are involved in the protocol and may have direct access to the immunogenicity results. Are receiving ongoing therapy with immunosuppressive therapy such as systemic corticosteroids or cancer chemotherapy. Are active duty military or reserves.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - LFn-p24 ISOug with Alhydrogel<br>HIV LFn-p24 is a combination of an Anthrax derived polypeptide Lethal factor (LFn), from which the toxin domain has been removed, and the HIV-1 gag p24 protein has been fused to LFn. Lfn-p24 is formulated in liquid form, and vialed. Product is administered IM, 1ml. Six subjects (4 vaccines and 2 placebos). Placebo recipients will receive a saline preparation in similar volume given IM. Immunizations given at 0, 4 and 16 weeks | Biological: HIV LFn-p24<br>* HIV LFn-p24 is a combination of an Anthrax derived polypeptide Lethal factor (LFn), from which the toxin domain has been removed, and the HIV-1 gag p24 protein has been fused to LFn. Lfn-p24 is formulated in liquid form, and vialed at 200 µg/ml and 600 µglml. The product will be administered IM in doses ranging from 150µg to 450µg with Alhydrogel.<br>|
| Experimental: Group 2 - LFn-p24 300ug with Alhydrogel<br>HIV LFn-p24 is a combination of an Anthrax derived polypeptide Lethal factor (LFn), from which the toxin domain has been removed, and the HIV-1 gag p24 protein has been fused to LFn. Lfn-p24 is formulated in liquid form, and vialed. Product is administered IM, 1ml. Six subjects (4 vaccines and 2 placebos). Placebo recipients will receive a saline preparation in similar volume given IM. Immunizations given at 0, 4 and 16 weeks | Biological: HIV LFn-p24<br>* HIV LFn-p24 is a combination of an Anthrax derived polypeptide Lethal factor (LFn), from which the toxin domain has been removed, and the HIV-1 gag p24 protein has been fused to LFn. Lfn-p24 is formulated in liquid form, and vialed at 200 µg/ml and 600 µglml. The product will be administered IM in doses ranging from 150µg to 450µg with Alhydrogel.<br>|
| Experimental: Group 3 - LFn-p24 450ug with Alhydrogel<br>HIV LFn-p24 is a combination of an Anthrax derived polypeptide Lethal factor (LFn), from which the toxin domain has been removed, and the HIV-1 gag p24 protein has been fused to LFn. Lfn-p24 is formulated in liquid form, and vialed. Product is administered IM, 1ml. Six subjects (4 vaccines and 2 placebos). Placebo recipients will receive a saline preparation in similar volume given IM. Immunizations given at 0, 4 and 16 weeks | Biological: HIV LFn-p24<br>* HIV LFn-p24 is a combination of an Anthrax derived polypeptide Lethal factor (LFn), from which the toxin domain has been removed, and the HIV-1 gag p24 protein has been fused to LFn. Lfn-p24 is formulated in liquid form, and vialed at 200 µg/ml and 600 µglml. The product will be administered IM in doses ranging from 150µg to 450µg with Alhydrogel.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral: Responders to ELISA and Western Blot antibodies to HIV-1 subtype B gag p24 | An HIV-I enzyme linked immunosorbent assay (ELISA) assay will be performed as designated throughout the course of the protocol during Visits 1 through 15. If the ELISA is reactive it will be repeated and an FDA- approved HIV Western blot will be performed. If the Western blot is positive, HIV molecular diagnostics (Roche Amplicor) will be performed | Days 0, 14, 42, 70, 126, 182, 252 and 364 | 
| Cellular: Cytotoxic T-lymphocyte (CTL) responses against subtype B gag antigen target expressed in Epstein Barr Virus (EBV) transformed autologous B cell lines. | Cytotoxic T-lymphocyte (CTL) responses against subtype B gag antigen target expressed in Epstein Barr Virus (EBV) transformed autologous B cell lines. Bulk CTL is currently defined to be positive if the HIV-1 antigen expressing targets relative to control have a specific lysis 10%. CD8+ CTL occurs when lytic activity decreases by 50% after removal of CD8 cells, while removal of CD4 cells maintains specific lysis at 5%. An analogous rule is applied for CD4+ CTL | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 
| IFN-y ELISPOT assay against HIV-gag antigen. | IFN-y ELISPOT assay using a panel of B clade gag peptides. A positive responder will be defined in accordance with other HIV Vaccine Trial Network (HVTN) definitions. For example a positive response may be defined by a significant difference between the number of IFN-g spot forming cell s (SFC)/million peripheral blood mononuclear cells (PBMC) in the presence of HIV gag antigen and no antigen. Other arbitrary definitions may be used. | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 
| IFN- ICS assay against HIV-gag antigen. | For the IFN-gamma intracellular cytokine staining (ICS) assay we will use a panel of B clade gag peptides or other appropriate gag antigens. A positive responder will be defined in accordance with the HIV Vaccine Trial Network (HVTN) definitions or other definitions as appropriate. For example a positive response may be defined as a two-fold difference between the percentage of CD3+CD8+IFN-y+ or CD3+CD4+IFN-y+ T cells in the presence of HIV gag antigen compared with no antigen | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 
| Lymphocyte proliferative responses to HIV-1 subtype B gag | Lymphocyte proliferative responses to HIV- I subtype B gag p24. The data are expressed as a Lymphocyte Stimulation Index (LSI)= (PBMC cpm + antigen/ mitogen) I (PBMC cpm+ medium)] to define antigen specificity. Individuals are arbitrarily designated as responders non-responders if their LSI is greater than or equal to 5. | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Humoral- Binding antibodies to LFn | Expression profile surveillance of 8000 fully annotated genes in peripheral blood mononuclear cells using the Affymetrix Human Focus GeneChip to assess sentinel genes and associated cellular processes that might be correlated with protection by the vaccine. | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 
| Neutralizing antibodies to LFn | Expression profile surveillance of 8000 fully annotated genes in peripheral blood mononuclear cells using the Affymetrix Human Focus GeneChip to assess sentinel genes and associated cellular processes that might be correlated with protection by the vaccine. | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 
| Cellular: Lymphoproliferation to LFn | Expression profile surveillance of 8000 fully annotated genes in peripheral blood mononuclear cells using the Affymetrix Human Focus GeneChip to assess sentinel genes and associated cellular processes that might be correlated with protection by the vaccine. | Days 3, 14, 42, 70, 126, 182, 252, and 364 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, Lfn-p24, Anthrax, IM, HIV-1, HIV Preventive Vaccine