Experimental AD4-H5-VTN Vaccine in Healthy Volunteers

Background:

- Adenoviruses typically cause cold or pink eye symptoms. These viruses may be used in vaccines to help stimulate an immune system response. Researchers want to test an adenovirus vaccine called the AD4-H5-VTN to see if it produces a strong enough immune response. AD4-H5-VTN may then be used as part of vaccines to prevent diseases such as malaria or HIV. However, because the vaccine may cause cold symptoms, the people who receive the vaccine and members of their household must take part in the study.

Objectives:

- To test the safety and effectiveness of the AD4-H5-VTN vaccine.

Eligibility:

• Healthy volunteers between 18 and 45 years of age.
• Household members or intimate contacts of the volunteers between 18 and 65 years of age. People in households with young children or persons with immune system problems will not be allowed on this study.

Design:

• Participants will be screened with a physical exam and medical history. They will have blood and urine tests. They will also answer questions about their household and close contacts.
• Participants will receive the study vaccine in one of three forms: a pill, a nasal spray, or a throat spray given in the back of the mouth on the tonsils. Those who have the nasal or tonsil vaccine must stay in the hospital for 7 days after receiving it.
• Participants will keep diaries to record any symptoms or side effects of the vaccine.
• Followup study visits will be required weekly for the first month, and at 8 weeks, 6 months, and 1 year after taking the vaccine.
• Participants must not have vaccines (including seasonal flu vaccine) or allergy shots for 30 days before and after receiving the study vaccine....

This is a Phase 1 randomized, single center, dose-escalation study designed to evaluate the safety and immunogenicity of live, replication competent recombinant Adenovirus type 4-H5N1Influenza Vietnam 1194 Hemagglutinin (HA) (Ad4-H5-Vtn). Determining the optimal route and dose for this recombinant platform will greatly accelerate investigations of this vector as an influenza vaccine and an HIV vaccine platform.

Intranasal and tonsillar administration of the vaccine will be separately assessed. The oral enteric-coated capsule will also be assessed in 10 outpatients using similar blood sampling for comparison. The Ad4-H5-Vtn orally administered as enteric-coated capsules has already been evaluated in an ascending dose Phase 1 study, in dosages as high as 10(11) viral particles (vp).

The primary goal of this study is to evaluate safety of ascending dosages of the Ad4-H5-Vtn vaccine following intranasal and tonsillar administration. A dosage or dosages will be selected to further evaluate the humoral, cellular, and mucosal immune responses against both the vector and the inserted gene. The Ad4-H5-Vtn will be initiated at 10(3) vp. Once safety is established at the initial dose, a second round of testing will begin at the next ten-fold higher dose. The Ad4-H5-Vtn vaccine will be assessed in three participants at each dosage level. The maximum viral dose administered by the tonsillar route will be 10(8) vp.

In addition to clinical and laboratory monitoring of safety, the principal assessments will be shedding of the Ad4-H5-Vtn virus in rectal, cervicovaginal, throat, and nasal swabs, and assessment of the antibody (mucosal and systemic) response to the HA and to the Ad4 virus. Participants receiving the vaccination by the tonsillar route will remain in the NIH Special Clinical Studies Unit until they have 2 consecutive negative nasal washes or 7 days have elapsed since vaccination, whichever occurs first; they may remain on the unit longer if medically necessary. When safety has been confirmed in all three participants at a given dosage level, the next higher dose group is enrolled. If one grade 3 or greater toxicity (or pre-specified Grade 2 toxicity, see Section 3.4) attributable to the vaccine is observed, the group will be expanded at that dose. If a second attributable grade 3 or greater toxicity (or pre-specified Grade 2 toxicity, see Section 3.4) is observed, the dose will be reduced one level and the group will be expanded. Up to 25 Ad4-seronegative individuals will be enrolled at the maximum tolerated dose to fully evaluate safety and immunogenicity in the protocol.

All participants will be followed for 28 days following immunization, and again at 8 and 26 weeks to evaluate any long-term toxicity and persistence of immunity. Household and intimate contacts will also be enrolled and monitored for Adenovirus and HAI antibodies.

• Biological: Ad4-H5-VTN vaccination-tonsillar route
  N/A
• Biological: Ad4-H5-vaccination-oral route
  N/A

• Amara RR, Villinger F, Altman JD, Lydy SL, O'Neil SP, Staprans SI, Montefiori DC, Xu Y, Herndon JG, Wyatt LS, Candido MA, Kozyr NL, Earl PL, Smith JM, Ma HL, Grimm BD, Hulsey ML, Miller J, McClure HM, McNicholl JM, Moss B, Robinson HL. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science. 2001 Apr 6;292(5514):69-74.
• Baba TW, Jeong YS, Pennick D, Bronson R, Greene MF, Ruprecht RM. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science. 1995 Mar 24;267(5205):1820-5.
• Baba TW, Liska V, Khimani AH, Ray NB, Dailey PJ, Penninck D, Bronson R, Greene MF, McClure HM, Martin LN, Ruprecht RM. Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med. 1999 Feb;5(2):194-203. Erratum in: Nat Med 199 May;5(5):590.

• INCLUSION CRITERIA:

All participants (vaccinees, household contacts and intimate contacts) must meet all of the following criteria:

1. Age 18 to 49 years for vaccinees. Age 18 to 65 years for household and intimate contacts.
2. Negative FDA-approved HIV test
3. Able to provide proof of identity to the acceptance of the Principal Investigator or designee during enrollment.
4. Available and willing to participate in follow-up visits and tests for the duration of the study,
5. Willing to have samples stored for future research.

The following inclusion criteria apply to vaccinees and intimate contacts, but not to household contacts:

1. In good general health without clinically significant medical history.
2. Negative Beta-HCG pregnancy test for females presumed to be of reproductive potential.

3. A female must meet one of the following criteria:

   1. No reproductive potential because of menopause (one year without menses) or because of a hysterectomy, bilateral oophorectomy, or tubal ligation.

      or

   2. Participant agrees to be heterosexually inactive or consistently practice contraception at least 21 days prior to enrollment and 28 days following vaccination. Acceptable methods of contraception include the following:

      • condoms, male or female, with a spermicide
      • diaphragm or cervical cap with spermicide
      • contraceptive pills, Norplant, or Depo-Provera
      • male partner has previously undergone a vasectomy for which there is documentation.
      • intrauterine device
4. Male participants must agree to practice abstinence or effective birth control for at least 21 days prior to enrollment and during the first 28 days following vaccination

The following inclusion criteria apply only to vaccinees and not to household or intimate contacts:

1. Willing to receive HIV test results and abide by NIH guidelines for partner notification of positive HIV results.
2. Physical examination and laboratory results without clinically significant findings within the 8 weeks prior to enrollment.
3. Willing to avoid vaccination other than the study agent for 30 days prior to and 30 days after administration of the Ad4-H5-Vtn vaccine.

4. Safety Laboratory Criteria within 8 weeks prior to enrollment:

   Hematopoietic: -White blood cell count and Lymphocyte count plus or minus 25 percent the normal limits for the NIH Clinical Center -Platelet count of least 125,000/mm(3)

   • Hemoglobin > 11.2 g/dL for females and > 13.0 g/dL for males.
   • Renal: BUN < 23 mg/dL; creatinine within normal limits for the NIH Clinical Center
   • Hepatic: Serum total bilirubin less than or equal to 2 mg/dL
   • Metabolic: ALT < 2 times upper limit of normal range
   • Endocrine: Serum glucose within normal range
5. Additional Laboratoy Criteria:

Immunologic: No history of hypogammaglobulinemia

Serologic: Ad4 neutralizing antibody 480% inhibitory dilution < 1:100

The following inclusion criteria apply only to tonsillar vaccinees and not to oral vaccine recipients, household contacts, or intimate contacts:

1. Willing to be hospitalized at the Clinical Center under respiratory precautions for up to 7 days or longer if medically indicated.
2. Either no history of tonsillectomy, OR the presence of tonsils on physical exam.

EXCLUSION CRITERIA

A participant (vaccinees, household contacts, and intimate contacts) will be excluded if they have the following:

1. Any condition that, in the investigator's judgement, places the subject at undue risk by participating in the study.

The following exclusion criterion applies to vaccinees and intimate contacts, but not to household contacts:

1. History of any prior disease or therapy which would affect immune or pulmonary function.
2. Prior malignancy, except curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
3. History of radiation therapy or cytotoxic/cancer chemotherapy.
4. History of insulin-dependent diabetes mellitus.
5. Immunodeficiency or autoimmune disease.
6. Acute infection or a recent (within 6 months) history of chronic infection suggestive of immunodeficiency.
7. Taking any medication which may affect immune function, except participants may be taking low doses of nonprescription strength NSAIDS (including e.g. ibuprofen or aspirin) or acetaminophen.
8. Chronic respiratory disorders including asthma, emphysema, interstitial lung disease, pulmonary hypertension, recurrent pneumonia, or recent or ongoing respiratory tract infection. If a respiratory disorder is transient, defer immunization but do not exclude the participant.

9. Active Hepatitis B or C infection, as indicated by the presence of Hepatitis B antigen or Hepatitis C virus (i.e. Hepatitis B or C positive serology with the presence of virus antigen or DNA. Ongoing viral

   replication will be confirmed by a Hepatitis B antigen or Hepatitis C viral load).

10. Female of child-bearing potential who is breast-feeding or planning pregnancy during the 28 days following vaccination.

The following exclusion criteria apply only to vaccinees and not to household or intimate contacts:

1. 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 receipt of live virus vaccine, protocol adherence, or a participant's ability to give informed consent.
2. 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.

3. Participants that live in the same house or apartment with any of the following will be excluded:

   • An individual under 18 years of age
   • An immunocompromised or immunosuppressed individual
   • An individual with chronic respiratory disease
   • A woman who is currently pregnant or planning a pregnancy during the period of immunization
4. Healthcare worker who has direct contact with immunodeficient, unstable patients, or pediatric patients.

5. Receipt of any of the following:

   • Antiviral medications within 30 days prior to vaccination
   • Blood products within 120 days prior to HIV screening
   • Immunoglobulin within 60 days prior to HIV screening
   • Investigational research drugs or any other investigational agent that in the judgement of the PI might interact with the study vaccine within 30 days prior to initial study vaccine administration
   • Allergy treatment with antigen injections within 30 days of study vaccine administration
6. History of Guillain-Barr syndrome.
7. History of H5 influenza vaccination.