Low Pathogenicity Avian H10N7 Influenza Virus in a Healthy Human Challenge Model

Study Description:

This is a dose-finding and pathogenicity study following human challenge with a low pathogenicity avian influenza A H10N7. Participants will be inoculated with 1 dose of challenge virus during the study and then followed for a minimum of 9 weeks after inoculation. Progressively increasing doses will be used according to a specific plan until either the maximum dose is reached or at least 60% of participants develop mild to moderate influenza disease (MMID).

Objectives:

Primary Objective:

• Determine the safe dose of A/Mallard/Ohio/99/1989 H10N7 human challenge virus that induces MMID in at least 60% of healthy volunteers or identify the rate of MMID at the maximum dose of 10^7 50% Tissue Culture Infective Dose (TCID50).

Secondary Objective:

• Evaluate clinical disease, identify clinical markers, and observe initiation of shedding, length of shedding, and pathogenesis in participants with low pathogenicity avian influenza A infection.

Exploratory Objective:

• Discover viral factors necessary for human infection/adaptation and evaluate host immune response, viral replication, viral fitness, and intrahost evolution.

Endpoints:

Primary Endpoint:

• Rate of MMID, defined as a positive US Food and Drug Administration (FDA) approved clinical test for influenza plus one or more influenza symptoms.

Secondary Endpoints:

• Daily and total score on FLU-PRO questionnaire in each participant
• Number and duration of symptoms and signs elicited by daily oral history and clinical exam
• Duration and quantity of shedding of influenza in nasal wash/SAM by quantitative real-time polymerase chain reaction (rtPCR).

Exploratory Endpoints:

• Levels and type of influenza infection induced gene expression determined by human gene expression analysis and high-throughput sequencing.
• Levels of mucosal and systemic antibodies after inoculation.
• Change in viral genotype from the inoculum of virus isolated from infected participants.

• INCLUSION CRITERIA:

An individual must meet all of the following criteria to be eligible for study participation:

• Greater than or equal to 18 and less than or equal to 50 years of age.
• Able to provide consent.
• Agrees to not use tobacco products, marijuana, or vaping products during participation in this study.
• Willing to remain in isolation for a minimum of 10 calendar days (or for the duration of viral shedding) and to comply with all study requirements.
• A male subject is eligible for the study if he meets one of the following criteria, beginning at least 4 weeks prior to enrollment and continuing until 10 weeks after administration of the human challenge virus and follow-up visit #4:

• Is infertile, including history of successful vasectomy.
• Agrees to practice abstinence.
• Agrees that, with heterosexual intercourse with a fertile female partner, he will use a condom with spermicide and his female partner (including those who have undergone bilateral tubal ligation) will use an acceptable form of contraception (see inclusion criterion 6c).
• A female participant is eligible for this study if she is not pregnant or breastfeeding and meets one of the following criteria, beginning at least 4 weeks prior to enrollment and continuing until 10 weeks after administration of the human challenge virus and follow-up visit #4:

• Is infertile, including postmenopausal status (as defined by no menses for greater than or equal to 1 year) or history of hysterectomy.
• Agrees to practice abstinence.
• Agrees that, with heterosexual intercourse with a fertile male partner, she will use an acceptable form of contraception and her male partner will use a condom with spermicide. Acceptable effective methods of female contraception include the following: bilateral tubal ligation, implant of levonorgestrel, injectable progestogen, intrauterine device, oral contraceptive pills, and diaphragm with spermicide.
• Willing to have samples stored for future research.
• Human immunodeficiency virus (HIV) uninfected with a negative test within 60 days of inoculation (Day 0).

Exclusion criteria

An individual meeting any of the following criteria will be excluded from study participation:

• Has self-reported or medically documented significant medical condition including but not limited to:

• Chronic pulmonary disease (e.g., asthma, emphysema).
• Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects).
• Chronic medical conditions requiring close medical follow-up or hospitalization during the past 5 years (e.g., insulin-dependent diabetes mellitus, renal dysfunction, hemoglobinopathies).
• Immunosuppression or ongoing malignancy.
• Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, seizures).
• Post-infectious or post-vaccine neurological sequelae.
• Has close or household (i.e., share the same apartment or house) high-risk contacts including but not limited to:

• Persons greater than or equal to 65 years of age.
• Children less than or equal to 5 years of age.
• Residents of nursing homes.
• Persons of any age with significant chronic medical conditions such as:

• Chronic pulmonary disease (e.g., asthma).
• Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects).
• Chronic medical conditions requiring medical follow-up or hospitalization during the past 5 years (e.g., insulin-dependent diabetes mellitus, renal dysfunction, hemoglobinopathies).
• Immunosuppression or cancer.
• Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, seizures).
• Persons who are receiving long-term aspirin therapy.
• Women who are pregnant, trying to become pregnant, or breastfeeding.
• Has a body mass index (BMI) less than or equal to 18.5 or greater than or equal to 35.
• Smokes more than 4 cigarettes or other tobacco products on a weekly basis or any type of vaping/e-cigarette use more than 4 times per week.
• History of facial reconstructive procedures or nasopharyngeal malformation.
• Positive for Hepatitis B or Hepatitis C infections.
• Complete blood count (CBC) with differential outside of the NIH Department of Laboratory Medicine (DLM) normal reference range and deemed clinically significant by the PI.
• Grade 2 or higher Hemoglobin for female participants or Grade 1 or higher Hemoglobin for male participants.
• Chemistries in the acute care, mineral, and/or hepatic panels, and/or any of the following: lactate dehydrogenase (LDH), uric acid, creatine kinase, and total protein outside of the NIH DLM normal reference range and deemed clinically significant by the PI.
• Urinalysis outside of the NIH DLM normal reference range and deemed clinically significant by the PI.
• Clinically significant abnormality as deemed by the PI on ECG.
• Clinically significant abnormality as deemed by the PI on ECHO.
• Clinically significant abnormality as deemed by the PI on the PFT and/or spirometry.
• Recent acute illness within 1 week of admission to the NIH CC.
• Known allergy to any component of the interventional agent.
• Known allergy to treatments for influenza (including but not limited to oseltamivir, nonsteroidals).
• Known allergy to 2 or more classes of antibiotics (e.g., penicillins, cephalosporins, fluoroquinolones, or glycopeptides).
• Receipt of influenza vaccine within 8 weeks prior to enrollment.
• Receipt of blood or blood products (including immunoglobulins) within 3 months prior to enrollment.
• Receipt of any unlicensed drug within 3 months or 5.5 half-lives (whichever is greater) prior to enrollment.
• Receipt of any unlicensed vaccine within 6 months prior to enrollment.
• Self-reported or known history of current alcoholism or drug abuse, or positive urine/serum test for drugs of abuse (i.e., amphetamines, cocaine, benzodiazepines, opiates, or metabolites, but not tetrahydrocannabinol or metabolites).
• Self-reported or known history of psychiatric or psychological issues deemed by the PI to be a contraindication to protocol participation
• Known close contact with anyone known to have influenza in the past 7 days.
• Known close contact with anyone known to have COVID-19 in the past 14 days.
• History of COVID-19-related complications, including, but not limited to: inpatient hospitalization, required the use of oxygen, and/or on-going sequelae.
• Non-English speaking participants.
• Any condition that, in the judgment of the PI, is a contraindication to protocol participation or impairs the volunteer s ability to give informed consent.