Evaluating the Safety and Immune Response to Three Different Prime-Boost HIV Vaccine Regimens in Healthy, HIV-Uninfected Adults

The purpose of this study is to evaluate the safety, tolerability, and immune response to
three different HIV-1 prime-boost vaccine regimens in healthy, HIV-1-uninfected adults. The
regimens will differ by the type of HIV-1 envelope insert (Nat-B env, CON-S env, or Mosaic
env) contained in both the DNA prime vaccine and the NYVAC boost vaccine.

The study will enroll 180 healthy, HIV-1-uninfected adults in two stages (Part A and Part
B). After Part A of the study is fully enrolled, study researchers will evaluate study
immunogenicity data to determine whether to enroll participants into Part B. The study
design and vaccination schedule for both parts of the study will be the same.

Participants will be randomly assigned to one of three groups and receive either one of the
experimental vaccine regimens or a placebo vaccine regimen. Participants will receive four
total injections: on Day 0 and Day 28 (DNA vaccine or placebo) and on Day 84 and Day 168
(NYVAC vaccine or placebo). Group 1 participants will receive DNA Nat-B env and NYVAC Nat-B
env vaccines, Group 2 participants will receive DNA CON-S env and NYVAC CON-S env vaccines,
and Group 3 participants will receive DNA Mosaic env and NYVAC Mosaic env vaccines.

Total study duration will be either 3 years after enrollment (for participants in the United
States) or 5 years after enrollment (for participants in Switzerland). For all participants,
study visits will occur on Days 0, 14, 28, 42, 84, 98, 168, 175, 182, 273, 357, and 364.
After the last study visit, participants will be contacted annually by phone or e-mail for a
total of 3 (U.S. participants) or 5 (Switzerland participants) years to answer questions
about their health.

At screening, participants will give a medical history; undergo a complete physical exam,
blood collection, urine collection, and an electrocardiogram (ECG); and receive risk
reduction counseling. At most follow-up visits, participants will undergo an abbreviated
physical exam, blood collection, urine collection, and receive risk reduction counseling.
Participants will have additional ECGs on Days 98 and 182. At all visits, female
participants who were born female will be assessed for pregnancy prevention, and at select
visits, will undergo a pregnancy test.

Inclusion Criteria:

- Access to a participating HIV Vaccine Trials Network (HVTN) clinical research site
(CRS) and willingness to be followed for the planned duration of the study

- Ability and willingness to provide informed consent

- Assessment of understanding: participant demonstrates understanding of this study;
completes a questionnaire prior to first vaccination with verbal demonstration of
understanding of all questionnaire items answered incorrectly

- Willing to be contacted annually after completion of scheduled clinic visits for a
total of 3 years for U.S. participants (5 years for participants in Switzerland)
following initial study injection

- Agrees not to enroll in another study of an investigational research agent

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

- Willingness to receive HIV test results

- Willingness 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 protocol clinic visit

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

- Hemoglobin greater than or equal to 12.5 g/dL for participants who were born female,
or greater than or equal to 13.5 g/dL for participants who were born male

- White blood cell 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: ALT, AST, and alkaline phosphatase less than 1.25 times the
institutional upper limit of normal (ULN); creatinine less than or equal to ULN

- Cardiac Troponin T or I (cTnT or cTnI) does not exceed the institutional ULN

- Negative HIV-1 and -2 blood test: U.S. participants must have a negative Food and
Drug Administration (FDA)-approved enzyme immunoassay. Non-U.S. sites may use locally
available assays that have been approved by HVTN Laboratory Operations.

- 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 with red blood cells levels 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

- Reproductive status: A participant who was born female must agree to consistently use
effective contraception for sexual activity that could lead to pregnancy from at
least 21 days prior to enrollment through the last required protocol clinic visit.
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 protocol clinic visit

Exclusion Criteria:

- Blood products received within 120 days before first vaccination

- Investigational research agents received within 30 days before first vaccination

- Body mass index (BMI) greater than or equal to 40; less than or equal to 18; or
greater than or equal to 35 with 2 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

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

- Pregnant or breastfeeding

- HIV vaccine(s) received in a prior HIV vaccine trial. For participants who have
received control/placebo in an HIV vaccine trial, the HVTN 099 Protocol Safety Review
Team (PSRT) will determine eligibility on a case-by-case basis and the identity of
the study control/placebo must be obtained.

- Non-HIV experimental vaccine(s) received within the last 5 years in a prior vaccine
trial. Exceptions may be made for vaccines that have subsequently undergone licensure
by the FDA. For volunteers who have received control/placebo in an experimental
vaccine trial, the HVTN 099 PSRT will determine eligibility on a case-by-case basis.
For volunteers who have received an experimental vaccine(s) greater than 5 years ago,
eligibility for enrollment will be determined by the HVTN 099 PSRT 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 and were
received within 14 days prior to first vaccination (e.g., tetanus, pneumococcal,
hepatitis A or B)

- 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; [2] inhaled corticosteroids; [3] topical
corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of
oral/parenteral corticosteroids at doses less than 2 mg/kg/day and length of therapy
less than 11 days with completion at least 30 days prior to enrollment.)

- 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.)

- Immunoglobulin received within 60 days before first vaccination

- Autoimmune disease

- Immunodeficiency

- Hypersensitivity to eggs and/or egg products

- Untreated or incompletely treated syphilis infection

- 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, protocol
adherence, assessment of safety or reactogenicity, or a volunteer's ability to give
informed consent

- Psychiatric condition that precludes compliance with the protocol. Specifically
excluded are persons with psychoses within the past 3 years, ongoing risk for
suicide, or history of suicide attempt or gesture within the past 3 years.

- Current anti-tuberculosis prophylaxis or therapy

- 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 last 12 months

- Hypertension: If a participant has been found to have elevated blood pressure or
hypertension during screening or previously, exclude for blood pressure that is not
well controlled (as defined in the protocol). If a person has NOT been found to have
elevated blood pressure or hypertension during screening or previously, exclude for
systolic blood pressure greater than or equal to 150 mm Hg at enrollment or diastolic
blood pressure greater than or equal to 100 mm Hg at enrollment. More information on
this criterion can be found in the protocol.

- History of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with
permanent sequelae, or clinically significant arrhythmia (including any arrhythmia
requiring medication, treatment, or clinical follow-up)

- Participants who have 2 or more of the following cardiac risk factors: participant
report of history of elevated blood cholesterol defined as fasting LDL greater than
160 mg/dL; first degree relative (e.g., mother, father, brother, or sister) who had
coronary artery disease before the age of 50 years; current smoker; or BMI greater
than or equal to 35

- ECG with clinically significant findings or features that would interfere with the
assessment of myo/pericarditis, as determined by the contract ECG Lab, cardiologist,
or study clinician. More information on this criterion can be found in the protocol.

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

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

- Malignancy (Not excluded: Participant who has had malignancy excised surgically and
who, in the investigator's estimation, has a reasonable assurance of sustained cure
or who is unlikely to experience recurrence of malignancy during the period of the
study)

- Seizure disorder: History of seizure(s) within past 3 years. Also exclude if
volunteer has used medications in order to prevent or treat seizure(s) at any time
within the past 3 years.

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