Safety, Tolerability and Immune Response to LC002, an Experimental Therapeutic Vaccine, in Adults Receiving HAART

The use of highly active antiretroviral therapy (HAART) has dramatically improved the rates
of survival, morbidity, and mortality among HIV-infected people throughout the world.
However, the costs, long-term toxicity, and problems with adherence associated with HAART
regimens make such treatment plans less than optimal for individuals seeking treatment for
HIV infection. Also, because viral reservoirs cannot be eradicated, HIV-infected people must
usually be on HAART indefinitely in order to keep their infection under control. While the
mechanism is still unclear, the immune system weakens as HIV disease progresses. A
therapeutic HIV vaccine given to HIV infected people may help to promote better immune
responses. LC002 is a novel HIV therapeutic vaccine containing a DNA plasmid that codes for
most of HIV-1's proteins. LC002 is a unique vaccine in that it is given through topical
administration; this allows for Langerhans cells (immune cells located under the surface of
the skin) to pick up the vaccine and deliver it to the lymph nodes, causing an immune
reaction. This study evaluated the safety, tolerability, and immunogenicity of LC002 in
HIV-infected adults currently receiving HAART.

There were three cohorts in this study which were enrolled sequentially. Participants in a
given cohort were randomly assigned to receive either LC002 (6 participants) or placebo (2
participants).

- In Cohort 1, participants received three separate low-dose vaccinations of LC002 (Arm A:
0.1 mg DNA/participant, 0.8 ml total, administered over two skin sites of 80 cm^2 each,
0.4 ml/site) or 3 separate vaccinations of placebo (Arm B: 0.8 ml total, administered
over two skin sites of 80 cm^2 each, 0.4 ml/site). Vaccinations were given over two skin
sites on the left and right upper back. Participants received vaccinations at weeks 1,
7, and 13.

- In Cohort 2, participants received three separate high-dose vaccinations of LC002 (Arm
C: 0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites of 80 cm^2
each, 0.8 ml/site) or three separate vaccinations of placebo (Arm D: 3.2 ml total,
administered over four skin sites of 80 cm^2 each, 0.8 ml/site). Vaccinations were given
over four skin sites on the left and right upper back and left and right upper ventral
thigh. Participants received vaccinations at weeks 1, 7, and 13.

- In Cohort 3, participants received six separate high-dose vaccinations of LC002 (Arm E:
0.4 mg DNA/participant, 3.2 ml total, administered over four skin sites of 80 cm^2 each,
0.8 ml/site) or six vaccinations of placebo (Arm F: 3.2 ml total, administered over four
skin sites of 80 cm^2 each, 0.8 ml/site). Vaccinations were given over four skin sites
on the left and right upper back and left and right upper ventral thigh. Participants
received vaccinations at study entry and weeks 1, 6, 7, 12, and 13.

The decision to open the next cohort was made when all participants in the current cohort
have remained on study for >=14 days after the second vaccination or prematurely discontinued
from study or had a primary safety endpoint (see primary outcome measure definition). Dose
escalation required no primary safety endpoint and on-study follow-up for >=6 participants in
the previous cohort(s).

Prior to receiving the vaccine, the chosen vaccine administration site on the back or thigh
was disinfected and exfoliated. A skin patch was applied to the site, and the vaccine
solution was placed on the skin underneath the patch with a needleless syringe. Participants
were allowed to remove the skin patch 3 hours post vaccination. For the first and second
vaccinations, participants were required to remain at the clinic for 3 hours post-vaccination
so study staff can assess for side effects. If no side effects occurred after the first two
vaccinations, participants were required to stay at the clinic for only 30 minutes after
receiving later vaccinations.

At the start of the study, participants were asked to keep a diary and record daily any side
effects or skin irritation they may have experienced following vaccination. Participants were
required to bring their diaries with them to their next clinic visit. Two days after
vaccination, participants were followed-up by phone and were asked about any side effects
they may have experienced. Participants who experienced side effects were asked to return to
the clinic for examination. There were 13 study visits; they occurred at study entry and
Weeks 1, 3, 6, 7, 9, 12, 13, 15, 17, 24, 37, and 61. Study visits included medication
history, a physical exam, and collection of diaries. Blood and urine collection occurred at
selected visits. HAART was not be provided by the study.

Inclusion Criteria:

- HIV-1-infected

- On a stable HAART regimen without changes or interruptions for more than 4 consecutive
days for at least 12 weeks prior to study entry. Patients must be currently taking
regimens containing drugs of at least two different classes.

- Two readings of plasma HIV-1 viral load of less than 50 copies/ml within 30 days prior
to study entry. More information on this criterion can be found in the protocol.

- CD4 count greater than 350 cells/mm^3 within 12 weeks prior to study entry

- Lowest CD4 count greater than 250 cells/mm^3 at any time prior to study entry

- Willing to use acceptable forms of contraception

- Karnofsky performance score 90 or higher obtained within 30 days prior to study entry

Exclusion Criteria:

- HIV-1 viral load greater than 500 copies/ml within the 24 weeks prior to study entry

- History of or current active skin disease (e.g., atopic dermatitis, psoriasis) or any
chronic autoimmune disease (e.g., Graves' disease). Participants with minor, localized
skin conditions that, in the opinion of the investigator, do not represent a safety
concern, are not excluded.

- Treatment with topical corticosteroids at the proposed vaccination sites (Cohort 1:
left and right upper back; Cohorts 2 and 3: left and right upper back and left and
right upper ventral thigh) within 2 weeks of study entry

- Excessive exposure to the sun (e.g., sunbathing, tanning bed) within 2 weeks prior to
study entry

- Laser hair removal within 2 weeks prior to study entry

- Use of any local skin treatments (e.g., topical/chemical hair removal, ointments,
possible irritants) to the targeted vaccination sites within 7 days prior to study
entry

- History of diabetes or bleeding disorders

- Previous CDC Category C event. More information on this criterion can be found in the
protocol.

- Use of immunomodulating therapy, including cyclosporine, IgG-containing products,
interleukins, interferons, or systemic glucocorticosteroids (including those inhaled)
within 6 months prior to study entry

- Exposure to an experimental HIV vaccine within 6 months prior to study entry

- Any vaccine within 30 days prior to study entry

- Investigational products within 12 weeks prior to study entry

- Allergy or sensitivity to study vaccine products, adhesives, or polyester

- Current drug or alcohol use or dependence that, in the opinion of the investigator,
would interfere with the study

- Serious illness requiring systemic treatment and/or hospitalization. Participants who
complete therapy or are clinically stable on therapy for at least 14 days prior to
study entry are not excluded.

- Positive hepatitis B surface antigen or positive anti-hepatitis C antibody at
screening

- History of treatment with HAART during primary infection

- History of lymph node irradiation

- Pregnant or breastfeeding

- Certain abnormal laboratory results. More information on this criterion can be found
in the protocol