Evaluating the Safety and Immune Response to an HIV Vaccine in Healthy, HIV-Uninfected Adults Who Have Participated in Previous HIV Vaccine Clinical Trials and in Adults Who Have Not Participated in Previous HIV Vaccine Clinical Trials

Previous clinical trials have shown that people who receive a second vaccine for certain
conditions after having received a prior vaccine may have a better antibody response to the
second vaccine than people who receive the vaccine for the first time. This is known as
"priming" and it may occur in people receiving a second vaccine even if the first vaccine
was received several years previously. This study will enroll healthy, HIV-uninfected adults
who have participated in a previous HIV vaccine clinical trial and received HIV-1 subtype B
envelope subunit vaccines with MF59 adjuvant, and healthy, HIV-uninfected adults who have
not participated in a previous HIV vaccine clinical trial and therefore have not previously
received any HIV vaccines. Participants in this study will receive a total of two
injections, each 6 months apart, of the HIV-1 Sub Cgp140 vaccine with MF59 adjuvant.
Researchers will evaluate the safety and immune response to the study vaccine and determine
if people who participated in a previous HIV vaccine clinical trial demonstrate an improved
antibody response to the study vaccine versus people who have never received an HIV vaccine.

This study will enroll two groups of participants. Group 1 will include healthy,
HIV-uninfected adults who have participated in a previous HIV vaccine clinical trial. Group
2 will include healthy, HIV-uninfected adults who have not participated in an HIV vaccine
clinical trial. All participants will receive the study vaccine injected into their upper
arm at baseline and Month 6.

At the baseline study visit, all participants will undergo a physical examination, a medical
and medication history review, and blood collection. Female participants will also take a
pregnancy test. Participants will complete questionnaires and receive counseling on HIV risk
reduction and pregnancy prevention. Saliva samples will be obtained from all participants
and rectal fluids, semen samples, and cervical secretions will be obtained from some
participants. After receiving the vaccine, participants will remain in the clinic for at
least 30 minutes for observation and monitoring of side effects. For 3 days after the
vaccination, participants will record any side effects in a symptom log.

Participants in Group 1 will attend study visits 1 and 2 weeks after the first vaccination
study visit, at Month 6 for the second vaccination, 1 and 2 weeks after the Month 6 study
visit, and at Months 9 and 12. Participants in Group 2 will attend study visits 1 and 3 days
and 1 and 2 weeks after the first vaccination study visit, at Month 6 for the second
vaccination, 1 and 3 days and 1 and 2 weeks after the Month 6 study visit, and at Months 9
and 12. Follow-up study visits will include select study procedures. Blood collected during
study visits may be saved for future testing. Study researchers will contact participants at
Month 18 for follow-up health monitoring.

In July 2013, an extension to the study was announced. Current study participants will be
screened to see if they are eligible to participate in the study extension. Participants who
are eligible will receive one additional injection of the study vaccine, at a visit
approximately 14 to 20 months after their second (Month 6) vaccination. Additional study
visits will occur 2 weeks, and 3 and 6 months after receiving the third vaccination. Select
visits will include a physical examination, blood collection, saliva collection, pregnancy
test for female participants, HIV testing and risk reduction counseling, and interviews and
questionnaires. Study researchers will contact participants 1 year after the third
vaccination for follow-up health monitoring.

Inclusion Criteria:

- Access to a participating HVTN Clinical Research Site (CRS) and willing to be
followed for the planned duration of the study

- Able and willing to provide informed consent

- Assessment of understanding: must demonstrate understanding of this study and the
Step Study results; completes a questionnaire prior to first vaccination with verbal
demonstration of understanding of all questionnaire items answered incorrectly

- Willing to receive HIV test results

- Willing to discuss HIV infection risks, amenable to HIV risk reduction counseling,
and committed to maintaining behavior consistent with low risk of HIV exposure
through the last required study clinic visit

- Assessed by the clinic staff as being at low risk for HIV infection

- Agrees not to enroll in another study of an investigational research agent prior to
completion of last required study clinic visit

- In good general health as shown by medical history, physical exam, and screening
laboratory tests

- For Group 1: Prior receipt of an HIV-1 subtype B envelope subunit vaccine (gp120,
gp140) with MF59 adjuvant. More information on this criterion can be found in the
protocol.

- Hemoglobin greater than or equal to 11.0 g/dL for participants who were born female,
greater than or equal to 13.0 g/dL for participants who were born male

- White blood cell (WBC) count equal to 3,300 to 12,000 cells/mm^3

- Total lymphocyte count greater than or equal to 800 cells/mm^3

- Remaining differential either within institutional normal range or with site
physician approval

- Platelets equal to 125,000 to 550,000/mm^3

- Chemistry panel: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
less than 1.25 times the upper limit of normal; creatinine less than or equal to the
institutional upper limits of normal

- Negative HIV-1 and -2 blood test: Group 1 (primed) participants must have a negative
test result for HIV infection following the HVTN Lab Program's in-study HIV testing
algorithm. Group 2 (unprimed) participants must have a negative test result for
HIV-infection following the CRS's routine HIV screening procedures with an
FDA-approved blood test.

- Negative Hepatitis B surface antigen (HBsAg)

- Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase
chain reaction (PCR) if the anti-HCV is positive

- Normal urine: Negative urine glucose, negative or trace urine protein, and negative
or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a microscopic
urinalysis within institutional normal range)

- Participants who were born female: negative serum or urine beta human chorionic
gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of
initial vaccination

- Participants who were born female must agree to consistently use effective
contraception from at least 21 days prior to enrollment through the last required
protocol clinic visit for sexual activity that could lead to pregnancy, or not be of
reproductive potential, or be sexually abstinent. More information on this criterion
can be found in the protocol.

- Participants who were born female must also agree not to seek pregnancy through
alternative methods, such as artificial insemination or in vitro fertilization, until
after the last required study clinic visit

- Participants who were born female and agree to cervical fluid collection must report
having a normal Pap smear or atypical squamous cells of undetermined significance
(ASCUS) with no evidence of high risk HPV within 3 years prior to enrollment in order
to participate in cervical mucosal sampling. This is not a requirement for study
entry.

Inclusion Criteria for Study Extension:

Prior to participation in the study extension, participants will be rescreened for
eligibility. The participant must have received the two earlier vaccinations in the study.

Participants must demonstrate understanding of the study extension and complete a
questionnaire prior to receiving the third vaccination; however, understanding of the Step
study results will not be specifically reassessed.

Study extension participants must have a negative test result for HIV infection following
the HVTN Lab Program's in-study HIV testing algorithm, within 21 days prior to receipt of
the third vaccination.

All inclusion criteria listed above for the study still apply EXCEPT the following
criteria:

- Age of 18 to 55 years

- Assessment of understanding

- Prior receipt of an HIV-1 subtype B envelope subunit vaccine (gp120, gp140) with MF59
adjuvant (Group 1 participants)

- Negative hepatitis B surface antigen (HBsAg), and negative anti-hepatitis C virus
antibodies (anti-HCV), or negative HCV polymerase chain reaction (PCR) if the
anti-HCV is positive. Repeat testing is not necessary for syphilis and hepatitis B
and C, which will be excluded based on updated participant medical history.

- Normal Pap smear or atypical squamous cells of undetermined significance (ASCUS)
criteria with no evidence of high risk HPV within 3 years prior to enrollment in
order to participate in cervical mucosal sampling.

Exclusion Criteria:

- History of newly acquired syphilis, gonorrhea, non-gonococcal urethritis, herpes
simplex virus type 2 (HSV2), chlamydia, pelvic inflammatory disease (PID),
trichomonas, mucopurulent cervicitis, epididymitis, proctitis, lymphogranuloma
venereum, chancroid, or hepatitis B within the 12 months prior to study entry

- Untreated or incompletely treated syphilis infection

- For Group 2 only: HIV vaccine(s) received in a prior HIV vaccine trial. For potential
participants who have received control/placebo in an HIV vaccine trial, the HVTN 088
Protocol Safety Review Team (PSRT) will determine eligibility on a case-by-case
basis.

- Non-HIV experimental vaccine(s) or adjuvant(s) other than MF59 received within the 5
years prior to study entry in a prior vaccine trial. Exceptions may be made for
vaccines/adjuvants that have subsequently undergone licensure by the FDA. For
potential participants who have received an experimental vaccine(s)/adjuvant(s)
greater than 5 years before study entry, eligibility for enrollment will be
determined by the PSRT on a case-by-case basis. For potential participants who have
received control/placebo in an experimental vaccine trial, the HVTN 088 PSRT will
determine eligibility on a case-by-case basis.

- Live attenuated vaccines other than influenza vaccine received within 30 days before
first vaccination or scheduled within 14 days after injection (e.g., measles, mumps,
and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever)

- Influenza vaccine or any vaccines that are not live attenuated vaccines (e.g.,
pneumococcal, tetanus, hepatitis A or B) and were received within 14 days prior to
any vaccination

- Allergy treatment with antigen injections within 30 days before first vaccination or
that are scheduled within 14 days after first vaccination

- Immunosuppressive medications received within 168 days before first vaccination. (Not
excluded: [1] corticosteroid nasal spray for allergic rhinitis; [2] topical
corticosteroids for mild, uncomplicated dermatitis; or [3] oral/parenteral
corticosteroids given for non-chronic conditions not expected to recur [length of
therapy 10 days or less with completion at least 30 days prior to study entry].)

- Blood products received within 120 days before first vaccination

- Immunoglobulin received within 60 days before first vaccination

- Investigational research agents received within 30 days before first vaccination

- Intent to participate in another study of an investigational research agent during
the planned duration of the study

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Clinically significant medical condition, physical examination findings, clinically
significant abnormal laboratory results, or past medical history with clinically
significant implications for current health. More information on this criterion can
be found in the protocol.

- Any medical, psychiatric, occupational, or other condition that, in the judgment of
the investigator, would interfere with, or serve as a contraindication to, study
adherence, assessment of safety or reactogenicity, or a participant's ability to give
informed consent

- Serious adverse reactions to vaccines, including anaphylaxis and related symptoms
such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not
excluded: a participant who had a nonanaphylactic adverse reaction to pertussis
vaccine as a child.)

- Autoimmune disease

- Immunodeficiency

- Asthma other than mild, well-controlled asthma. More information on this criterion
can be found in the protocol.

- Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not
excluded: history of isolated gestational diabetes.)

- Thyroidectomy, or thyroid disease requiring medication during the 12 months before
study entry

- History of hereditary angioedema, acquired angioedema, or idiopathic forms of
angioedema

- Hypertension: If a person has been diagnosed with hypertension during screening or
previously, exclude for hypertension that is not well controlled. If a person has NOT
been diagnosed with hypertension during screening or previously, exclude for systolic
blood pressure greater than or equal to 150 mm Hg at study entry or diastolic blood
pressure greater than or equal to 100 mm Hg at study entry. More information on this
criterion can be found in the protocol.

- Body mass index (BMI) greater than or equal to 40; or BMI greater than or equal to 35
with two or more of the following: age greater than 45, systolic blood pressure
greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg, current
smoker, or known hyperlipidemia

- Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy,
platelet disorder requiring special precautions)

- Cancer (Not excluded: a participant with a surgical excision and subsequent
observation period that in the investigator's estimation has a reasonable assurance
of sustained cure or is unlikely to recur during the period of the study.)

- Seizure disorder (Not excluded: a participant with a history of seizures who has not
required medications or had a seizure within the 3 years prior to study entry.)

- Asplenia: any condition resulting in the absence of a functional spleen

- Psychiatric condition that precludes compliance with the study. Specifically excluded
are people with psychoses within the 3 years prior to study entry, ongoing risk for
suicide, or history of suicide attempt or gesture within the 3 years prior to study
entry.

- Pregnant or breastfeeding

Exclusion Criteria for Optional Mucosal Sampling:

- Any medical, psychiatric, or social condition, or occupational or other
responsibility that, in the judgment of the investigator, would interfere with, or
serve as a contraindication to the planned procedure

Exclusion Criteria for Study Extension:

Prior to participation in the study extension, participants will be rescreened for
eligibility. The participant must have received the two earlier vaccinations in the study.
All exclusion criteria listed above for the study still apply EXCEPT the following
criteria:

- HIV vaccine(s) received in a prior HIV vaccine trial (Group 2 participants)

- BMI greater than or equal to 40; or BMI greater than or equal to 35 with two or more
of the following: age greater than 45, systolic blood pressure greater than 140 mm
Hg, diastolic blood pressure greater than 90 mm Hg, current smoker, or known
hyperlipidemia