Phase I Study of West Nile Virus Vaccine
Phase I Study of West Nile Virus Vaccine
This study will test the safety of an experimental vaccine for preventing West Nile virus
 infection. The virus is spread mainly by mosquito bites. Symptoms can include high fever,
 headache, neck stiffness, stupor, muscle weakness, vision loss, numbness and paralysis.
 Rarely, infection leads to permanent nerve damage and possibly death. The vaccine used in the
 study is made from DNA that codes for West Nile virus proteins. Injected into a muscle, the
 DNA instructs the body to make a small amount of West Nile virus protein. This study will see
 if the body creates resistance or immunity to these proteins. Participants cannot get West
 Nile virus from the vaccine.

 Healthy normal volunteers between 18 and 65 years of age may be eligible for this study.
 Candidates are screened with a medical history, physical examination, and blood and urine
 tests for various infections and other medical problems. Women who are able to become
 pregnant are given a pregnancy test. Women who are pregnant or breastfeeding may not
 participate. Anyone who has received a vaccination for Yellow Fever or Japanese Encephalitis
 virus in the past may not participate in this research study.

 Participants will receive three injections of the experimental vaccine, the first on the
 first study day (Day 0), the second on Day 28, and the third on Day 56. The injections are
 given with a device called Biojector® (Registered Trademark) 2000 that delivers the vaccine
 through the skin into the muscle without the use of a needle. On the day of each injection,
 subjects are given a diary card to take home for recording their temperature and any symptoms
 or side effects for 5 days. They return to the clinic 2 weeks after each injection, bringing
 the completed card with them at that time. In addition to the injections, subjects have the
 following tests and procedures during clinic visits:

 -  Medical history and, if needed, physical examination: Day 0 and weeks 2, 4, 6, 8, 10,
 12, 24 and 32

 -  Vital signs and weight: Day 0 and weeks 2, 4, 6, 8, 10, 12, 24 and 32

 -  Lymph node exam: Day 0 and weeks 2, 4, 6, 8, 10, and 12

 -  Blood samples: Day 0 and weeks 2, 4, 6, 8, 10, 12, 24 and 32

 -  Pregnancy test (for women): Day 0 and weeks 4, 8 and 32

 -  Urine sample: Day 0 and weeks 2, 4, 6, 8, and 10

 The blood and urine tests are for health checks. Some blood samples are also used to study
 the immune response to the vaccine and for gene testing.
Study Design: This is a Phase I open-label study to evaluate safety, tolerability, and
 immunogenicity of a recombinant DNA vaccine, VRC-WNVDNA020-00-VP. The hypothesis is that this
 regimen will be safe for human administration and elicit a higher titer of neutralizing
 antibody response than a prior WNV DNA vaccine. The primary objectives are to evaluate the
 safety and tolerability in humans of the investigational vaccine in healthy young adults and
 in healthy older adults. Secondary and exploratory objectives are related to the
 immunogenicity of the study vaccine.

 Product Description: VRC-WNVDNA020-00-VP is composed of a single closed-circular DNA plasmid
 that encodes the WNV viral protein precursor transmembrane (prM) and envelope (E) with a
 CMV/R promoter. Vaccine vials will be supplied at 4 mg/mL. Each DNA vaccination will be 1 mL
 of vaccine administered intramuscularly (IM) in the deltoid muscle using the Biojector 2000
 Needle-Free Injection Management System (Biojector).

 Subjects: A total of 30 healthy adults will be enrolled in two groups: Group 1 will be
 comprised of 15 healthy adults 18 to 50 years old and Group 2 will be comprised of 15 healthy
 adults 51 to 65 years old.

 Study Plan: All subjects will receive 3 injections on the schedule shown in the schema. The
 protocol requires nine clinic visits and three telephone follow-up contacts.

 Study Duration: 32 weeks of clinical follow up for each participant. A long-term follow-up
 contact at Week 52 may include interim medical history and research blood draw; or subject
 may opt for the long-term contact to occur by telephone, e-mail or mail for the interim
 medical history only.

 Study Endpoints: The primary endpoint is safety and tolerability of the regimen. The
 secondary immunogenicity endpoints are WNV neutralizing antibody, WNV specific antibody as
 measured by ELISA, WNV-specific T cell responses measured by intracellular cytokine staining
 (ICS) assay and ELISPOT. Other immunogenicity assays through Week 32 may also be completed as
 exploratory evaluations, as well as from the Week 52 blood samples if collected.
-  INCLUSION CRITERIA:

 A participant must meet all of the following criteria:

 1. 18 to 65 years old.

 2. Available for clinical follow-up through Week 32 and contact (correspondence,
 telephone or e-mail) or clinical visit through Week 52 of the study.

 3. Able to provide proof of identity to the satisfaction of the study clinician
 completing the enrollment process.

 4. Complete an Assessment of Understanding prior to enrollment and verbalize
 understanding of all questions answered incorrectly.

 5. Able and willing to complete the informed consent process.

 6. Willing to receive HIV test results and willing to abide by NIH guidelines for partner
 notification of positive HIV results.

 7. Willing to donate blood for sample storage to be used for future research and genetic
 testing, including HLA analysis.

 8. In good general health without clinically significant medical history and has
 satisfactorily completed screening.

 9. Physical examination and laboratory results without clinically significant findings
 and a body mass index (BMI) less than 40 within the 28 days prior to enrollment.

 Laboratory Criteria within 28 days prior to enrollment:

 10. Hemoglobin greater than or equal to 11.5 g/dL for women; greater than or equal to 13.5
 g/dL for men.

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

 12. Absolute neutrophil count (ANC) within institutional normal range.

 13. Total lymphocyte count greater than or equal to 800 cells/mm(3).

 14. Platelets equal to 125,000 - 400,000/mm(3).

 15. Alanine aminotransferase (ALT; SGPT) less than or equal to 1.25 x upper limit of
 normal.

 16. 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).

 17. Normal urinalysis defined as negative glucose, negative or trace protein, and no
 clinically significant blood in the urine.

 18. Negative FDA-approved HIV blood test. [Note: Results of HIV ELISA will be documented,
 but a negative HIV PCR will be sufficient for eligibility screening of subjects with
 positive HIV ELISA that is due to prior participation in an HIV vaccine study.]

 19. Negative hepatitis B surface antigen.

 20. Negative anti-HCV and negative hepatitis C virus (HCV) PCR.

 Laboratory Criteria within 12 weeks (84 days) prior to enrollment:

 21. Negative flavivirus serology (in the Focus Technologies WNV antibody ELISA assay)
 within 84 days prior to enrollment and no history of prior vaccination against yellow
 fever or Japanese encephalitis virus; and no history of prior vaccination against West
 Nile virus with an investigational vaccine.

 Female-Specific Criteria:

 22. Negative beta-HCG pregnancy test (urine or serum) on day of enrollment for women
 presumed to be of reproductive potential.

 23. A female participant must meet any 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 32 of the study,

 or

 Participant agrees to consistently practice contraception at least 21 days prior to
 enrollment and through Week 32 of the study by one of the following methods:

 -  condoms, male or female, with or without a spermicide

 -  diaphragm or cervical cap with spermicide

 -  intrauterine device

 -  contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved
 contraceptive method

 -  male partner has previously undergone a vasectomy

 EXCLUSION CRITERIA:

 A volunteer will be excluded if one or more of the following conditions apply.

 Women:

 1. Breast-feeding or planning to become pregnant during the 32 weeks of study
 participation.

 Volunteer has received any of the following substances:

 2. Immunosuppressive medications, cytotoxic medications, inhaled corticosteroids, or
 long-acting beta-agonists within the past six months. (Note that use of corticosteroid
 nasal spray for allergic rhinitis, topical corticosteroids for an acute uncomplicated
 dermatitis, or short-acting beta-agonists in controlled asthmatics are not excluded).

 3. Blood products within 120 days prior to HIV screening.

 4. Immunoglobulin within 60 days prior to HIV screening.

 5. Investigational research agents within 30 days prior to initial study vaccine
 administration.

 6. Live attenuated vaccines within 30 days prior to initial study vaccine administration.

 7. Medically indicated subunit or killed vaccines, e.g. influenza, pneumococcal, or
 allergy treatment with antigen injections, within 14 days of study vaccine
 administration.

 8. Current anti-TB prophylaxis or therapy.

 Volunteer has a history of any of the following clinically significant conditions:

 9. Serious adverse reactions to vaccines such as anaphylaxis, hives, respiratory
 difficulty, angioedema, or abdominal pain.

 10. Autoimmune disease or immunodeficiency.

 11. 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.

 12. Diabetes mellitus (type I or II), with the exception of gestational diabetes.

 13. History of thyroidectomy or thyroid disease that required medication within the past
 12 months.

 14. Serious angioedema episodes within the previous 3 years or requiring medication in the
 previous two years.

 15. Hypertension that is not well controlled by medication or is more than 145/95 at
 enrollment.

 16. 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.

 17. 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.

 18. 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.

 19. Asplenia, functional asplenia or any condition resulting in the absence or removal of
 the spleen.

 20. Allergic reaction to aminoglycoside antibiotics.

 21. Psychiatric condition that precludes compliance with the protocol; past or present
 psychoses; past or present bipolar disorder; disorder requiring lithium; or within
 five years prior to enrollment, a history of suicide plan or attempt.

 22. 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.

 23. Active smoker within the past 5 years AND with 25 pack-years or greater smoking
 history.

 24. If age 51-65 years and with 3 or more of the 5 health risk factors noted below, the
 subject will be excluded:

 -  Current smoker (or quit smoking less than 28 days prior to enrollment)

 -  BMI greater than 35

 -  Fasting low density lipoprotein (LDL) greater than 159 mg/dL or fasting
 cholesterol greater than 239 mg/dL

 -  Systolic blood pressure greater than 140 mm Hg or diastolic blood pressure
 greater than 90 mm Hg

 -  Fasting blood glucose greater than 125 mg/dL

 Note: The fasting blood tests require 8 hours fast prior to the blood draw. The results
 used for eligibility screening must be from tests completed no more than 12 weeks (84 days)
 prior to day of enrollment. The individual criteria for BMI (inclusion item 9), blood
 pressure (exclusion item 15) and smoking history (exclusion item 23) must also be met.