Safety and Immunogenicity of a Live Attenuated H7N9 Influenza Virus Vaccine in Healthy Adults

Phase 1 Evaluation of the Safety and Immunogenicity of Live Influenza A Vaccine H7N9 (6-2) AA ca Recombinant (A/Anhui/1/2013 (H7N9) x A/Ann Arbor/6/60 ca), a Live Attenuated Virus Vaccine Candidate for Prevention of Influenza H7N9 Disease in the Event of a Pandemic

H7N9 avian influenza (AI) viruses have caused a recent outbreak of severe respiratory disease in humans in China. The purpose of this study is to evaluate the safety and immunogenicity of a live attenuated H7N9 A/Anhui/13 ca influenza virus vaccine in healthy adults. A single dose of inactivated subvirion H7N9 influenza vaccine will be administered 3 months later.

H7N9 AI viruses have recently caused a large outbreak of severe respiratory disease in humans in China. A vaccine for use in the event of an H7N9 AI pandemic is an important research priority. Previous studies have shown that when subjects who received a live bird flu vaccine received a subsequent "booster" dose of inactivated bird flu vaccine, a vigorous antibody response was detected. The inactivated vaccine served as a way to probe the immune response to the initial live vaccine. The purpose of this study is to evaluate the safety, infectivity, and immunogenicity of a live attenuated H7N9 A/Anhui/13 ca influenza virus vaccine in healthy adults, and to administer a booster dose of an inactivated subvirion H7N9 influenza vaccine 3 months later.

This study will enroll healthy adults who are willing to remain in an isolation unit in an inpatient clinic for several days during the study. They will be randomly assigned to receive either one dose (Group 1) or two doses (Group 2) of the live attenuated H7N9 A/Anhui/13 ca influenza virus vaccine, which will be delivered by a nasal spray device. Participants in both groups will receive one "booster" dose of inactivated subvirion H7N9 influenza vaccine 3 months later in an outpatient setting. All participants will be admitted to the inpatient clinic and will receive one dose of the live attenuated H7N9 A/Anhui/13 ca influenza virus vaccine 2 days after entering the clinic. Participants will remain in the inpatient clinic for approximately 9 days after receiving the vaccine. While in the clinic, participants will undergo medical history reviews, blood collections, urine collections, physical examinations, nasal wash procedures, and vital sign measurements.

Participants in Group 1 will attend a study visit at Day 28 and undergo a medical history review, blood collection, and a nasal wash. Participants in Group 2 will be readmitted to the inpatient clinic 2 days prior to receiving a second dose of the live attenuated H7N9 A/Anhui/13 ca influenza virus vaccine at Day 28. They will remain in the clinic for approximately 9 days after receiving the vaccine; while in the clinic, they will take part in the same study procedures as during the first inpatient visit.

All participants will attend a study visit at Day 56 and undergo a medical history review, blood collection, and a nasal wash. At Day 98, all participants will receive one "booster" dose of the inactivated subvirion H7N9 influenza vaccine, as outpatients. They will attend additional study visits on Days 101, 105, 112, 126, 154, and 180, which may include medical history reviews; physical examinations; and urine, blood, and nasal secretion collections.

Inclusion Criteria:

• Adult males and non-pregnant females between 18 years and 49 years of age, inclusive. Children will not be recruited or enrolled in this study because they are not in the apparent risk group, and for safety considerations and because of the need for isolation.
• General good health, without significant medical illness, physical examination findings, or significant laboratory abnormalities as determined by the investigator
• Agree to storage of blood specimens for future research
• Available for the duration of the trial
• Willingness to participate in the study as evidenced by signing the informed consent document
• Female participants of child-bearing potential must agree to use effective birth control methods for the duration of the study (for example, pharmacologic contraceptives including oral, parenteral, and transcutaneous delivery; condoms with spermicide; diaphragm with spermicide; intrauterine device; abstinence from heterosexual intercourse; surgical sterilization). All female participants will be considered being of child-bearing potential except those who have undergone hysterectomy and those in whom menopause occurred at least 1 year prior to the study.

Exclusion Criteria:

• Pregnancy, as determined by a positive human choriogonadotropin (beta-HCG) test

• Currently breastfeeding

• Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease by history, physical examination, and/or laboratory studies including urine testing. Alanine aminotransferase (ALT) levels greater than two times the upper normal limit will be exclusionary at baseline, prior to vaccination.

• Behavioral or cognitive impairment or psychiatric disease that in the opinion of the investigator affects the ability of the participant to understand and cooperate with the study protocol

• Previous enrollment in an H7 influenza vaccine trial or in any study of an avian influenza vaccine

• Seropositive to the H7N9 influenza A virus (serum HAI titer greater than 1:8)

• Positive urine drug toxicology test indicating narcotic use/dependency

• Have medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months

• Other condition that in the opinion of the investigator would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol

• History of anaphylaxis

• Allergy to oseltamivir as determined by participant report

• Current diagnosis of asthma or reactive airway disease (within the past 2 years)

• History of Guillain-Barré Syndrome

• Positive ELISA and confirmatory Western blot tests for human immunodeficiency virus-1 (HIV-1)

• Positive ELISA and confirmatory test (e.g., recombinant immunoblot assay) for hepatitis C virus (HCV)

• Positive hepatitis B virus surface antigen (HBsAg) by ELISA

• Known immunodeficiency syndrome

• Use of corticosteroids (excluding topical preparations) or immunosuppressive drugs within 30 days prior to vaccination

• Receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to study vaccination

• History of asplenia

• Receipt of blood or blood-derived products (including immunoglobulin) within 6 months prior to study vaccination

• Current smoker unwilling to stop smoking for the duration of the study:

  • A current smoker includes anyone stating they currently smoke any amount of a tobacco product.
  • The decision to exclude a potential participant is determined by medical history and a clinician's clinical judgment based on the physical examination.
  • After admission to the unit, nicotine patches will be provided to current smokers who request them for the inpatient portion of the study.

• Travel to the Southern Hemisphere within 14 days prior to study vaccination

• Travel on a cruise ship within 14 days prior to study vaccination

• Receipt of another investigational vaccine or drug within 30 days prior to study vaccination

• Allergy to eggs or egg products