A Phase I Clinical Trial to Evaluate the Safety and Immunogenicity of a Booster Dose of a Recombinant Multiclade HIV-1 Adenoviral Vector Vaccine, VRC-HIVADV014-00-VP, in Uninfected Subjects Who Were Previously Immunized With VRC-HIVDNA009-00-VP in VRC 004
A Phase I Clinical Trial to Evaluate the Safety and Immunogenicity of a Booster Dose of a Recombinant Multiclade HIV-1 Adenoviral Vector Vaccine, VRC-HIVADV014-00-VP, in Uninfected Subjects Who Were Previously Immunized With VRC-HIVDNA009-00-VP in VRC 004
This study will test the safety and side effects of an experimental vaccine booster against HIV. A vaccine is a substance given to try to create immunity or resistance to a disease or infection. The vaccine used in this study is called VRC-HIVADV014-00-VP. It is made from an adenovirus (a common virus that causes upper respiratory infections) that contains DNA (genetic material) of three HIV proteins. Injected into a human, the viral DNA instructs the body to make small amounts of some HIV proteins. VRC-HIVADV014-00-VP will be given to people who previously received a vaccine called VRC-HIVDNA009-00-VP under NIH protocol 03-I-0022. Important: Study participants cannot catch an adenovirus infection or HIV or AIDS from the vaccine or any proteins made from it.
Healthy normal volunteers who participated in NIH protocol 03-I-0022 may be eligible for this study. They must have completed three injections of 4 mg or 8 mg of VRC-HIVDNA009-00-VP without experiencing a serious side effect that was possibly related to the vaccine. Candidates are screened with a medical history, clinical evaluation, blood and urine tests, and HIV and pregnancy counseling.
Participants receive one injection of VRC-HIVADV014-00-VP the day they enroll in the study (study day 0). They are observed for at least 30 minutes after immunization. At home, they record their temperature and any symptoms they may experience, including any effects at the injection site, for 5 days and call a study nurse 1 or 2 days after the injection. They immediately report any symptoms to the clinic staff and, if necessary, come to the clinic for an examination.
Participants have five additional clinic visits during the study, at weeks 2, 4, 6, 12 and 24, each lasting about 2 hours. At each visit, they are checked for health changes or problems and are asked about medications they are taking. Blood is drawn for immune function testing, HLA typing (a genetic test of immune system markers), and other genetic factors. A urine sample is collected at some visits. Additional laboratory tests may be requested between visits. Some participants may undergo apheresis at the week 4 visit to collect a large number of white blood cells for laboratory tests to see how the immune system responds to the study vaccine. For this procedure, blood is collected through a needle in an arm vein and flows through a catheter (plastic tube) into a machine that separates it into its components by centrifugation (spinning). The white cells are extracted and the rest of the blood is returned through another needle in the other arm. The procedure takes about 1 to 3 hours.
Participants are tested three or more times for HIV and are questioned about their sexual behavior and drug use. They complete a "social impact" questionnaire at week 24 that includes questions about any problems they may have experienced from their participation in the study regarding such things as insurance, health care, friends, family, employment, housing, education, or government agencies.
Study Design: This is a Phase I open-label study to examine safety, tolerability and immune response of a multiclade HIV adenoviral vector vaccine as a booster vaccination in uninfected adults. The hypothesis is that this vaccine will be safe as a booster vaccine and elicit immune responses to HIV. The primary objective is to evaluate the safety and tolerability of a VRC-HIVADV014-00-VP booster vaccination in uninfected subjects who previously received 3 injections of VRC-HIVDNA009-00-VP more than one year prior to the study vaccination. The secondary objectives include immunogenicity evaluations and adenovirus serotype 5 (Ad5) antibody titers, and social impacts. Exploratory evaluations include epitope mapping and other immunogenicity evaluations.
Product Description: VRC-HIVADV014-00-VP is a recombinant product composed of 4 adenoviral vectors (Ad) (in a 3:1:1:1 ratio) that encode the HIV-1 Gag/Pol polyprotein from clade B and HIV-1 Env glycoproteins from clades A, B, and C, respectively.
Subjects: Healthy adult volunteers who previously received three injections of VRC-HIVDNA009-00-VP at a dosage of 4 mg or 8 mg in the VRC 004 study (03-I-0022): subjects in these groups were between 20 and 39 years old at time of enrollment in VRC 004; those who participate in VRC 009 will be approximately 1-3 years older at the time of enrollment into VRC 009.
Study Plan: Up to thirty-two volunteers will receive one 1 mL injection of the study agent at a dosage of 1 x 10(10) PU IM in a deltoid muscle. Safety and immunogenicity will be evaluated by follow-up visits over the subsequent 24 weeks. The peripheral blood mononuclear cell (PBMC) sample for immunogenicity studies collected at Week 4 after vaccination will be obtained by apheresis if the subject is willing and eligible for apheresis and an apheresis appointment can be conveniently scheduled in the interval specified; otherwise PBMCs will be obtained from 80 mL blood collected by phlebotomy.
Study Duration: Subjects will be evaluated at 6 or more clinical visits for 24 weeks after the study injection.
Study Endpoints: The primary endpoint is safety of the vaccine administered at a dose of 1 x 10(10) particle units (PU) by intramuscular injection. Secondary endpoints are immunogenicity as indicated by HIV-specific antibody and cellular immune responses through Week 6, Ad5 antibody titer at Week 0 and Week 4 and social impact at Week 24. Exploratory analyses of immunogenicity at Weeks 12 and 24, Ad5 antibody titer at Week 24 and epitope mapping of the CD8+ and CD4+ T cell responses at Week 4.
A participant must meet all of the following criteria:
Completed three injections of 4 mg or 8 mg of study vaccine in VRC 004 (03-I-0022) without experiencing a serious adverse event (SAE) that was possibly, probably or definitely related to study vaccine.
Available for clinical follow-up for 24 weeks after enrollment.
Completion of an Assessment of Understanding prior to enrollment and able to verbalize understanding of all questions answered incorrectly.
Able and willing to complete the informed consent process.
Willing to receive HIV test results and willing to abide by NIH guidelines for partner notification of positive HIV results.
Willing to donate blood for sample storage to be used for future research.
Willing to discuss HIV infection risks and amenable to risk reduction counseling.
In good general health without clinically significant medical history and satisfactory completion of the screening process.
Laboratory Criteria within 28 days prior to enrollment:
Hemoglobin greater than or equal to 11.5 g/dL for women; greater than or equal to 13.5 g/dL for men.
WBC = 3,300-12,000 cells/mm(3).
Differential either within institutional normal range or accompanied by site physician approval.
Total lymphocyte count greater than or equal to 800 cells/mm(3).
Platelets = 125,000 - 550,000/mm(3).
ALT (SGPT) less than or equal to 1.25 x upper limit of normal.
Serum creatinine less than or equal to 1 x upper limit of normal (less than or equal to 1.3 mg/dL for females; less than or equal to 1.4 mg/dL for males).
Normal urinalysis defined as negative glucose, negative or trace protein, and no clinically significant blood in the urine.
Negative HIV PCR.
Negative Hepatitis B surface antigen.
Negative anti-HCV.
Female-Specific Criteria:
Negative beta-HCG pregnancy test (urine) on day of study enrollment for women presumed to be of reproductive potential.
A female participant must meet one of the following criteria:
No reproductive potential because of menopause [one year without menses] or because of a hysterectomy, bilateral oophorectomy, or tubal ligation,
or
Participant agrees to be heterosexually inactive at least 21 days prior to enrollment and through Week 24 of the study,
or
Participant agrees to consistently practice contraception at least 21 days prior to enrollment and through Week 24 of the study by one of the following methods:
EXCLUSION CRITERIA:
A volunteer will be excluded if one or more of the following conditions apply:
Women:
Breast-feeding or planning to become pregnant during the 24 weeks of study participation.
Volunteer has received any of the following substances:
Immunosuppressive or cytotoxic medications or inhaled corticosteroids within the past six months (with the exception of corticosteroid nasal spray for allergic rhinitis or topical corticosteroids for an acute uncomplicated dermatitis).
Blood products within 120 days prior to HIV screening.
Immunoglobulin within 60 days prior to HIV screening.
Live attenuated vaccines within 30 days prior to initial study vaccine administration.
Investigational research agents within 30 days prior to study vaccine administration.
Medically indicated subunit or killed vaccines, e.g. influenza, pneumococcal, or allergy treatment with antigen injections, within 14 days of study vaccine administration.
Current anti-TB prophylaxis or therapy.
Volunteer has a history of any of the following clinically significant conditions:
Serious adverse reactions to vaccines such as anaphylaxis, hives, respiratory difficulty, angioedema, or abdominal pain.
Autoimmune disease or immunodeficiency.
Asthma that is unstable or required emergent care, urgent care, hospitalization or intubation during the past two years or that requires the use of oral or intravenous corticosteroids.
Diabetes mellitus (type I or II), with the exception of gestational diabetes.
History of thyroidectomy or thyroid disease that required medication within the past 12 months.
Serious angioedema episodes within the previous 3 years or requiring medication in the previous two years.
Hypertension that is not well-controlled by medication or is more than 145/95 at enrollment.
Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws.
Syphilis infection that is active or a positive serology due to a syphilis infection treated less than six months ago.
Malignancy that is active or treated malignancy for which there is not reasonable assurance of sustained cure or malignancy that is likely to recur during the period of the study.
Seizure disorder other than: 1) febrile seizures under the age of two, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) a singular seizure not requiring treatment within the last 3 years.
Asplenia or any condition resulting in the absence or removal of the spleen.
Psychiatric condition that precludes compliance with the protocol; past or present psychoses; past or present bipolar disorder requiring therapy that has not been well controlled on medication for the past two years; disorder requiring lithium; or suicidal ideation occurring within five years prior to enrollment.
Any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent.