Therapeutic Vaccine for HIV

The advent of combination antiretroviral therapy (cART) has dramatically improved the
clinical outcome in human immunodeficiency virus (HIV)-infected individuals through sustained
reduction in viral replication. However, it has become clear that cART alone cannot eradicate
HIV in infected individuals, likely in part due to the persistence of viral reservoirs in
peripheral blood and various tissue compartments. Consequently, a major thrust of HIV
research over the past several years has been to develop therapeutic strategies that can
eliminate persistent viral reservoirs and boost host immunity to control viral replication
upon discontinuation of cART. Therapeutic HIV vaccination is one approach that could
potentially achieve these goals through vaccine-induced improvement in HIV-specific immune
responses and/or by direct reactivation of HIV-specific CD4+ memory T cells that harbor
latent HIV. An effective therapeutic vaccine could augment immunologic control of HIV
infection and potentially obviate the need for chronic cART.

The current study is an exploratory randomized, 2-arm (1:1), double-blind, placebo-controlled
trial evaluating the safety and efficacy of an HIV-1 multiantigen plasmid DNA (HIV-MAG pDNA)
vaccine prime in combination with an interleukin-12 plasmid DNA (IL-12 pDNA) adjuvant
delivered by in vivo electroporation followed by a recombinant vesicular stomatitis virus
vector containing the HIV-1 gag gene (rVSV HIV gag) booster vaccine in subjects on cART who
started therapy during acute or early HIV infection.

Subjects will be randomized to receive placebo or the HIV-MAG pDNA (3000 g) vaccine prime and
IL-12 pDNA adjuvant (1000 g) at week 0, 4, 12, and 36, and the rVSV HIV gag booster vaccine
(1x107 plaque-forming units) at week 24 and 48. The HIV-MAG pDNA vaccine prime and IL-12 pDNA
adjuvant will be administered as 2 IM injections, 1 into each deltoid, with electroporation
using the Ichor TDS device, while the rVSV HIV gag booster vaccine will be administered as 2
conventional IM injections, 1 into each deltoid. After the week 56 visit, all subjects will
undergo an analytical treatment interruption to determine if the vaccination strategy results
in an improved immune control of viral replication, as evidenced by a blunted or absent
rebound in HIV plasma viremia. All subjects will be followed through week 96 for safety and
efficacy parameters.

The study population includes HIV-infected adults who began cART during acute or early
infection. Subjects must be receiving an effective cART regimen, with a CD4 cell count of
>450 cells/mm3 at screening, and they must have documented viral suppression below the limit
of detection for greater than1 year. The rationale for testing the study vaccine regimen in
this subject population is because these individuals may have a relatively preserved immune
function, which could be augmented by therapeutic vaccination.

- INCLUSION CRITERIA:

1. Age, 18-65 years.

2. Institution of cART within 12 weeks of being diagnosed with acute or early HIV-1
infection.

Acute HIV-1 infection is defined as:

1. Detectable plasma HIV-1 RNA levels of greater than 2000 copies/mL with a
negative result from an HIV-1 EIA, or

2. Positive result from an HIV-1 EIA with a negative or indeterminate result
from an HIV-1 western blot that subsequently evolves to a confirmed positive
result, or

3. Negative result from an HIV-1 EIA within the past 4 months and HIV-1 RNA
levels of greater than 400,000 copies/mL, in the setting of a potential
exposure to HIV-1.

Early HIV-1 Infection is defined as:

1. Negative result from an HIV-1 EIA within 6 months prior to a positive result
from an HIV-1 EIA and an HIV-1 western blot.

2. Negative result from a rapid HIV-1 test within 1 month prior to a positive
result from an HIV-1 EIA and an HIV-1 western blot.

3. Presence of low level of HIV antibodies as determined by having a positive
EIA or a positive Western blot with a non-reactive detuned EIA according to
a serologic testing algorithm for recent infection.

3. CD4+ cell count greater than 450 cells/mm3 at screening.

4. Documentation of continuous cART treatment with suppression of plasma viral level
below the limit of detection for greater than 1 year. Subjects with a single blip
(i.e., detectable viral levels on cART) prior to randomization may be included
provided they satisfy the following criteria:

1. The blips are less than 400 copies/mL, and

2. Succeeding viral levels return to levels below the limit of detection on
subsequent testing.

5. Willingness to undergo ATI.

6. Laboratory values within pre-defined limits at screening:

- Absolute neutrophil count greater than 1,000/mm3.

- Hemoglobin levels greater than 10.0 g/dL for men and greater than 9.0 g/dL
for women.

- Platelet count greater than 100,000/mm3.

- Prothrombin time (PT) and partial thromboplastin time (PTT) less than 1.5
upper limit of normal (ULN).

- Estimated or a measured creatinine clearance rate of greater than 60 mL/min
as determined by the NIH Clinical Center laboratory.

- AST and ALT levels of less than 2.5 x ULN.

7. Willingness to have samples stored for future research.

8. Women of childbearing potential must have a negative pregnancy test result.

- They must agree to use an adequate form of contraception:

- Hormonal contraception.

- Male or female condoms with or without a spermicidal

- Diaphragm or cervical cap with a spermicidal.

- Intrauterine device.

EXCLUSION CRITERIA:

1. Allergy to amide-type local anesthetics (bupivacaine (Marcaine), lidocaine
(Xylocaine), Mepivacaine (Polocaine/Carbocaine), etidocaine (Duranest), prilocaine
(Citanest, EMLA cream).

2. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen
(HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced by a positive test
for HCV RNA. Subjects with a positive test for HCV antibody and a negative test for
HCV RNA are eligible.

3. Changes in cART regimen due to virologic breakthrough.

4. HIV immunotherapy or vaccine(s) received within 1 year prior to screening.

5. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza,
pneumococcal polysaccharide) received within 4 weeks prior to study entry.

6. Interruption of cART for greater than 3 months since its initiation. 8. Any active
malignancy that may require systemic chemotherapy or radiation therapy.

7. Pregnancy or planned pregnancy during the study period or breastfeeding.

8. Any active malignancy that may require systemic chemotherapy or radiationtherapy.

9. Immunosuppressive medications received within 6 months before the first study
vaccination (Not excluded: (1) corticosteroid nasal spray for allergic rhinitis; (2)
topical corticosteroids for mild, uncomplicated dermatitis; or (3) oral/parenteral
corticosteroids administered for non-chronic conditions not expected to recur (length
of therapy less than or equal to10 days, with completion in greater than or equal to
30 days prior to enrollment).

10. Evidence of hepatic decompensation in subjects with cirrhosis: history of ascites,
hepatic encephalopathy, or bleeding esophageal varices, or screening laboratory
results with any of the following:

1. International normalized ratio of greater than or equal to1.5 x ULN.

2. Serum albumin less than 3.2 g/dL.

3. Serum total bilirubin greater than 1.8 x ULN, unless history of Gilbert's disease
or deemed related to treatment with atazanavir.

11. History or other clinical evidence of:

1. Significant or unstable cardiac disease (e.g., angina, congestive heart failure,
recent myocardial infarction, significant arrhythmia).

2. Severe illness, malignancy, immunodeficiency other than HIV, or any other
conditions that, in the opinion of the investigator, would make the subject
unsuitable for the study.

3. AIDS-defining condition.

12. Known allergy or sensitivity to the components of the investigational therapy.

13. History of significant cardiac arrhythmia (e.g., supraventricular tachycardia,
ventricular tachycardia, and atrial fibrillation/flutter).

14. Active drug or alcohol use or any dependence other pattern of behaivor that, in the
opinion of the investigator, would interfere with adherence to study requirements.

15. Any active systemic inflammatory or autoimmune disease or condition.

16. Presence of implanted electronic medical device (e.g., pacemaker, implantable cardiac
defibrillator) or surgical/traumatic metal implant in the upper limb and/or upper
torso.

17. Neurological or neuropsychiatric disorder that may interfere with the assessment of
safety (e.g., frequent recurring headaches, for example, a pattern of greater than 1
headache/month affecting activities of daily living/work, frequent or
severe/complicated migraines, cluster headaches); or history of encephalitis,
narcolepsy, stroke with sequelae, moderate/severe major depressive disorder,
moderate/severe bipolar disorder, seizure disorder.

18. Deltoid skinfold measurements (by caliper) of greater than 40 mm.

19. Body mass index greater than 40.