Experimental AD4-H5-VTN Vaccine in Healthy Volunteers
Experimental AD4-H5-VTN Vaccine in Healthy Volunteers
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.
 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. Tonsillar Participants
 will receive a booster dose of vaccine [SK1]at the 26-week visit and be seen for follow-up
 visits at Weeks 30 and 34. Household and intimate contacts will also be enrolled and
 monitored for Adenovirus and HAI antibodies.
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.

 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.
 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. All subjects will be
 offered to receive a booster vaccination with a recombinant hemagglutinin influenza H5
 vaccine after the 26-week visit and be seen for follow-up visits 4 and 8 weeks following
 booster immunization, with an additional telephone follow-up 6 months after boosting.
 Household and intimate contacts will also be enrolled and monitored for Adenovirus and HAI
 antibodies following Ad4-H5-Vtn administration only; household and intimate contacts will not
 be enrolled or monitored during the boost portion of the study.

 We will conduct an expansion H5N1 boost phase of this study, in which all vaccinees from the
 initial phase of the study will be offered re-enrollment to receive a booster vaccination
 with an FDA-approved H5N1 inactivated monovalent influenza vaccine. We will offer enrollment
 in the expansion phase to all participants who received the Ad4-H5-Vtn vaccine in the initial
 phase, regardless of whether they also received the recombinant hemagglutinin influenza H5
 vaccine boost. We will also enroll individuals who have never received an H5 influenza
 vaccine as controls. Participants will receive a single vaccination with the H5N1 vaccine and
 be seen for follow-up visits 4 and 8 weeks later for immunogenicity evaluations.
-  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. Vaccinees may be >49 years of age at the time of
 booster vaccination. 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.

 6. Negative <=-HCG pregnancy test for females presumed to be of reproductive potential.

 7. 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

 8. 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 +/- 25% the normal
 limits for the NIH Clinical Center

 -  Platelet count of least 125,000/mm3

 -  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 2 mg/dL

 -  Metabolic: ALT <2 times upper limit of normal range

 -  Endocrine: Serum glucose within normal range

 5. Additional Laboratory Criteria:

 -  Immunologic: No history of hypogammaglobulinemia

 -  Serologic: Ad4 neutralizing antibody 80% 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. Either no history of tonsillectomy OR the presence of tonsils on physical exam.

 INCLUSION CRITERIA FOR THE EXPANSION H5N1 BOOST PHASE:

 1. Age 18 to 64.

 2. Negative pregnancy test (women of childbearing potential).

 3. Group-specific inclusion criteria:

 -  For participants in the study group: prior receipt of the Ad4-H5-Vtn vaccine in
 the initial phase of this study.

 -  For participants in the control group: no prior receipt of an H5 vaccine product
 (by self-report).

 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. Participants caring for children <36 months of age. Potential vaccinees with any
 household or intimate contact who cares for children <36 months of age will also be
 excluded.

 6. 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

 7. History of Guillain-Barr(SqrRoot)(Copyright) syndrome.

 8. History of H5 influenza vaccination.

 EXCLUSION CRITERIA FOR THE EXPANSION H5N1 BOOST PHASE:

 1. History of systemic hypersensitivity reactions to egg proteins or life-threatening
 reactions to previous influenza vaccinations.

 2. History of Guillain-Barr(SqrRoot)(Copyright) syndrome.

 3. Acute infection or a recent (within 6 months) history of chronic infection suggestive
 of immunodeficiency.

 4. 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.

 5. Receipt of an approved vaccine, 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 H5N1 vaccine administration.

 6. 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 the H5N1 vaccine, protocol adherence, or a participant
 s ability to give informed consent.