VRC 308: An Open-Label Phase I Study of the Safety and Immunogenicity of an Investigational H1 DNA Influenza Vaccine, VRC-FLUDNA057-00-VP, in Healthy Adults 18-70 Years Old
VRC 308: An Open-Label Phase I Study of the Safety and Immunogenicity of an Investigational H1 DNA Influenza Vaccine, VRC-FLUDNA057-00-VP, in Healthy Adults 18-70 Years Old
Background:

 -  Vaccines are substances used to try to create resistance (or immunity) to a disease and
 to prevent an infection. Researchers are testing a new DNA vaccine designed for a new
 type of influenza, often referred to as swine flu. The DNA vaccine will instruct the
 body to make a particular kind of influenza protein that the immune system will be able
 to recognize.

 -  Researchers are interested in determining if the vaccine is safe and effective in
 humans, and would like to study the immune system's response to the vaccine. The vaccine
 will not give participants influenza; however, it may not be effective in preventing
 them from getting influenza at a later date.

 Objectives:

 -  To evaluate the safety and tolerability of the VRC-FLUDNA057-00-VP influenza vaccine as
 administered to healthy adults.

 -  To evaluate antibody responses to the new influenza vaccine.

 Eligibility:

 - Healthy adults between the ages of 18 and 70.

 Design:

 -  Participants will have seven planned clinic visits during this study (enrollment day and
 study weeks 1, 4, 8, 9, 12, and 32).

 -  All participants will receive three injections of the test vaccine, given as individual
 doses on day 0, day 28, and day 56 of the study. The vaccine will be given in the upper
 arm muscle.

 -  Injections will be given using a needleless system that delivers the vaccine through the
 skin by using the pressure of carbon dioxide to inject the vaccine through the skin and
 into the muscle. Participants will remain at the National Institutes of Health (NIH)
 Clinical Center for at least 30 minutes after the injection to be monitored for any
 reaction.

 -  Participants will be asked to keep a 7-day diary card after each injection to record
 their physical reactions to the vaccine.

 -  Participants will be asked to return to the NIH Clinical Center as requested by
 researchers for additional blood tests and other procedures, as required by the study.
STUDY DESIGN- This is an open-label Phase I study to evaluate the safety, tolerability, and
 immunogenicity of 3- injection vaccination regimen with an investigational plasmid DNA
 vaccine that encodes for H1 hemagglutinin (HA) of an H1N1 influenza virus. All study
 participants will be offered to receive an additional optional booster immunization with
 licensed inactivated monovalent H1N1 influenza vaccine.

 The hypothesis is that the DNA vaccine will be safe for human administration and will elicit
 an antibody response. The primary objectives are to evaluate the safety and tolerability of
 the VRC-FLUDNA057-00-VP DNA vaccine at a dosage of 4 mg administered in a 3-injection
 schedule. The secondary objectives are to evaluate antibody responses including induced
 antibody titer as measured by a hemagglutination inhibition (HAI) assay and to document the
 reactogenicity of the inactivated H1N1 influenza vaccine when administered to subjects
 previously vaccinated with the VRC-FLUDNA057-00-VP DNA vaccine.

 Exploratory objectives are related to further evaluation of the humoral and cellular immune
 responses, including the responses after each injection and after the boost with licensed
 H1N1 inactivated influenza vaccine.

 PRODUCT DESCRIPTIONS- The VRC-FLUDNA057-00-VP vaccine was developed and manufactured by VRC,
 NIAID and is composed of 1 closed-circular DNA plasmid with a CMV/R promoter that encodes for
 the H1 hemagglutinin from the Influenza A/California/04/2009 H1N1 virus, identified late in
 the 2008-2009 northern hemisphere (NH) influenza season that has been referred to as swine
 flu in news reports. Vaccine vials will be supplied at 4 mg/mL and each 4 mg dosage will
 require a 1 mL injection. Vaccinations with the H1 DNA vaccine will be administered
 intramuscularly (IM) in the deltoid muscle using the Biojector[R] 2000 Needle-Free Injection
 Management System (Biojector). Licensed inactivated monovalent H1N1 influenza vaccine will be
 obtained through the NIH Clinical Center (CC) pharmacy, for use as a booster injection, and
 administered with needle and syringe. The brand administered will depend upon what is
 available through the NIH CC.

 SUBJECTS- A total of 20 healthy adults in the 18-70 years age range will be enrolled;
 however, no more than 10 subjects will be in the 51-70 year old age range.

 STUDY PLAN- All subjects will receive 3 injections of the H1 DNA vaccine as shown in the
 schedule below. No more than 5 subjects may be enrolled in the first week of the study.
 Following the 5th enrollment, the remainder of subjects may be enrolled without restrictions
 on enrollment rate. All subjects that have no contraindications to the licensed - inactivated
 H1N1 influenza vaccine or to additional blood drawing will be offered the option to receive
 the licensed inactivated H1N1 influenza vaccine. The study includes 7 clinic visits and 3
 telephone contacts as well as 3 additional visits for subjects that opt to receive an
 inactivated influenza vaccine. Subjects who have received the inactivated H1N1 vaccine
 outside of the VRC Clinic after Study Week 12 may consent to contribute the additional
 research samples through completing the extra visits on the schedule for post boost
 evaluations. A target window for the inactivated H1N1 vaccine is shown in the schema below.
 However, given that all subjects will be at or beyond Study Week 12, the earliest mutually
 convenient date after the H1N1 vaccine supply and amended protocol become available is
 acceptable for administration of the optional injection. The added post-boost research sample
 collections will then be scheduled to occur relative to the date the H1N1 booster injection.

 Number of Subjects = 20

 VRC-FLUDNA057-00-VP 4 mg on Day 0; 4mg on Day 28 plus or minus 7; 4mg on Day 56 plus or minus
 7, at least 21 days between injections. Inactivated licensed H1N1 influenza vaccine
 (optional) Day 168 plus or minus 28 - 1 dose

 STUDY DURATION- Each participant will complete 32 weeks of clinical follow up.
-  INCLUSION CRITERIA:

 1. 18 to 70 years old.

 2. Available for clinical follow-up through Week 32.

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

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

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

 6. Willing to donate blood for sample storage to be used for future research.

 7. No evidence of previously undiagnosed clinically significant chronic diseases.

 8. Physical examination and laboratory results without clinically significant
 findings, no fever (greater than or equal to 100.4 degree F) in the 72 hours
 prior to enrollment, and a Body Mass Index (BMI) greater than or equal to 18 and
 < 42 within the 56 days prior to enrollment.

 Laboratory Criteria within 56 days prior to enrollment:

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

 10. White blood cells (WBC) = 3,300-12,000 cells/mm(3)

 11. Differential either within institutional normal range or accompanied by site
 physician approval as a differential that is consistent with healthy volunteer
 status

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

 13. Platelets = 125,000 - 500,000/mm(3)

 14. Alanine aminotransferase (ALT) less than or equal to 2.5 times upper limit of
 normal (ULN)

 15. Serum creatinine less than or equal to 1 times ULN (less than or equal to 1.3
 mg/dL for females; less than or equal to 1.4 mg/dL for males) and estimated
 glomerular filtration rate > 60 mL/min/1.73 m(2).

 16. Negative FDA-approved HIV blood test. [Note: Results of HIV enzyme-linked
 immunosorbent assay (ELISA) will be documented, but a negative HIV polymerase
 chain reaction (PCR) test result will be sufficient for eligibility screening of
 subjects with positive HIV ELISA that is due to prior participation in an HIV
 vaccine study].

 Female-Specific Criteria:

 17. Negative human chorionic gonadotropin (HCG) pregnancy test (urine or serum) for
 women presumed to be of reproductive potential on the day of enrollment.

 18. A female subject 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

 Agrees to be heterosexually inactive at least 21 days prior to enrollment and
 through Week 32 of the study,

 OR

 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:

 (Bullet) condoms, male or female, with or without a spermicide;

 (Bullet) diaphragm or cervical cap with spermicide;

 (Bullet) intrauterine device;

 (Bullet) contraceptive pills, patch, implant or any other FDA-approved
 contraceptive method;

 (Bullet) male partner has previously undergone a vasectomy.

 EXCLUSION CRITERIA

 Women Specific:

 1. Breast-feeding or planning to become pregnant during the first 32 weeks after
 enrollment in the study.

 Subject has received any of the following substances:

 2. Systemic immunosuppressive medications or cytotoxic medications within the 12
 weeks prior to enrollment. [With the exceptions that a short course (duration of
 10 days or less or a single injection) of corticosteroids for a self-limited
 condition at least 2 weeks prior to enrollment in this study will not exclude
 study participation.]

 3. Blood products within 112 days (16 weeks) prior to HIV screening

 4. Immunoglobulin within 56 days (8 weeks) prior to HIV screening

 5. Live attenuated vaccines within 28 days (4 weeks) prior to initial study vaccine
 administration

 6. Investigational research agents within 28 days (4 weeks) prior to initial study
 vaccine administration

 7. Medically indicated subunit or killed vaccines (e.g., pneumococcal, or allergy
 treatment with antigen injections) within 14 days (2 weeks) of initial study
 vaccine administration

 8. Current anti-TB prophylaxis or therapy

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

 9. Serious reactions to vaccines that preclude receipt of study vaccinations as
 determined by investigator.

 10. Hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic forms of
 angioedema.

 11. Asthma that is severe, unstable or required emergent care, urgent care,
 hospitalization or intubation during the past two years or that requires the use
 of oral, intravenous, or high dose inhaled corticosteroids.

 12. Diabetes mellitus type I.

 13. Thyroid disease that is not well-controlled.

 14. Generalized idiopathic urticaria within the last 1 year.

 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, 2) seizures secondary to alcohol
 withdrawal more than 3 years ago, or 3) seizures that have not required treatment
 within the last 3 years.

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

 20. Guillain-Barr Syndrome.

 21.Psychiatric condition that precludes compliance with the protocol; past or present
 psychoses; past or present bipolar disorder; disorder requiring lithium; or within 5
 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.