Influenza Challenge Study to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2, Clade 3C3a) Influenza Strain
Condition: Influenza
MeSH terms: Influenza, Human
Intervention: Influenza RG-A/Texas/71/2017 (H3N2) Challenge; Placebo
Intervention description: RG-A/Texas/71/2017 (H3N2) is an infectious influenza virus and requires handling at BioSafety Level 2. The challenge virus will be administered intranasally in a volume of approximately 0.5 mL per nostril. Intranasal challenge will be carried out using the Intranasal Mucosal Atomization ( MAD Nasa(TM)) Device attached to a 1 mL syringe.; Sucrose phosphate glutamate (SPG) inoculum
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: A/Texas/71/2017; Influenza; Influenza Challenge Study; Recombinant H3N2; Recombinant H3N2 Influenza Strain; Safety

Summary:

      An open-label, dose-ranging influenza challenge study in healthy adult volunteers to
      determine the optimal infection dose and safety of a recombinant H3N2 (A/Texas/
      A/Texas/71/2017 (H3N2, clade 3C3a) influenza strain. The goal of this study is to find a
      challenge virus dose that is safe and can achieve a symptomatic influenza Attack Rate (AR)
      that will be sufficiently high for utilization in future vaccine or intervention studies. The
      optimal dose of the three considered is broadly defined as the minimum challenge virus dose
      that elicits the highest AR without meeting safety-stopping criteria. Additionally, viral
      recovery, clinical symptoms, and immune responses over the post-challenge period will be
      described by challenge dose group. This study will last for up to 1 year depending upon the
      number of challenge cohorts enrolled given the adaptive dose-escalation design. The
      populations are healthy males and non-pregnant, non-breastfeeding females aged = 18 and < 46
      years of age with a serum HAI antibody titer of </=1:40 against influenza A/Texas/71/2017
      (H3N2), clade 3C3a. The study will enroll and challenge up to 106 (plus 8 shams) healthy
      adult volunteers with the H3N2 (A/Texas/71/2017 (H3N2), clade 3C3a) influenza virus challenge
      strain. The primary objectives are: 1) To determine the optimal infectious dose of a
      recombinant influenza virus (A/Texas/71/2017 (H3N2), clade 3C3a) to be used as a clinical
      challenge strain in future vaccine efficacy or intervention studies as assessed by viral
      shedding and clinical symptoms. 2) To describe viral detection by quantitative and
      qualitative Reverse Transcription - Polymerase Chain Reaction (RT-PCR) from study subjects at
      baseline and post-challenge. 3) To document clinical symptoms from self-reported surveys and
      standardized symptom scales at baseline and post-challenge.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provide written informed consent prior to initiation of any study procedure

          2. Are able to understand and comply with planned study procedures and be available for
             all study visits

          3. Agree to remain an inpatient for at least 7 days after challenge AND until they have
             no viral shedding*, determined by qualitative Reverse Transcription - Polymerase Chain
             Reaction (RT-PCR) beginning on Study Day 6

               -  No viral shedding is defined as two negative RT-PCR tests 12 or more hours apart

          4. Healthy* males and non-pregnant, non-breastfeeding females aged > / = 18 and < 46
             years of age at enrollment

             *Healthy is defined in inclusion criteria #11. NOTE: Female subjects of childbearing
             potential must have a negative serum pregnancy test at screening, a negative urine
             pregnancy test upon admission to the confinement unit AND a negative pregnancy test
             before any Chest x-ray (CXR) (if > / = 7 days have passed since a serum pregnancy
             test).

          5. Women of childbearing potential* must agree to use or have practiced true abstinence**
             or use at least one acceptable primary form of contraception* for at least 30 days
             prior to challenge

               -  Not of childbearing potential - post-menopausal females (defined as having a
                  history of amenorrhea for at least one year) or a documented status as being
                  surgically sterile (hysterectomy, bilateral oophorectomy, tubal
                  ligation/salpingectomy, or Essure(R) placement with history of documented
                  radiological confirmation test at least 90 days after the procedure).

               -  True abstinence is 100% of time no sexual intercourse (male's penis enters the
                  female's vagina). (Periodic abstinence [e.g. calendar, ovulation, symptothermal,
                  post-ovulation methods] and withdrawal are not acceptable methods of
                  contraception).

                    -  Acceptable forms of primary contraception include monogamous relationship
                       with a vasectomized partner who has been vasectomized for 180 days or more
                       prior to the subject receiving the influenza challenge virus, intrauterine
                       devices, birth control pills, and injectable/implantable/insertable hormonal
                       birth control products. Must use at least one acceptable primary form of
                       contraception for at least 30 days prior to challenge and at least one
                       acceptable primary form of contraception during the remainder of the study
                       or approximately 57 days after confinement.

             NOTE: These criteria are applicable to female subjects in a heterosexual relationship
             AND of child-bearing potential. These criteria do not apply to subjects in a same sex
             relationship.

          6. Non-habitual smoker* of tobacco, e-cigarettes or marijuana

             *Non-habitual smokers are those who smoke no more than four cigarettes, other tobacco
             products, e-cigarettes (to include vaping and Juuling products) or marijuana in a week
             and agree not to smoke cigarettes, other tobacco products, e-cigarettes and/or
             marijuana products during participation in the study.

          7. No self-reported or known history of alcoholism within the last 2 years and agrees to
             abstain from alcohol for at least one week before admission and throughout the
             confinement period.

          8. No self-reported or known history of restricted drug use* for at least 30 days prior
             to challenge and agrees to abstain from restricted drugs for at least one week before
             admission and throughout the confinement period

          9. Negative drug urine toxicology result on screening (i.e., amphetamines, cocaine, and
             opiates) and on admission to the confinement unit (i.e., amphetamines, cocaine, and
             opiates)*

             *Select drug use may be allowed at Investigator's discretion (e.g., prescribed
             amphetamines for ADHD)

         10. Agree not to use the listed prescription or over the counter medications* within 7
             days prior to and through confinement period, unless approved by the investigator

             *Oseltamivir, zanamivir, peramivir, baloxavir marboxil, amantadine (generic) and
             rimantadine (Flumadine and generic), aspirin, intranasal steroids, decongestants,
             antihistamines, and other non-steroidal anti-inflammatory drugs (NSAIDs)

         11. In good health*, and do not have clinically significant medical, psychiatric, chronic
             or intermittent health conditions including those listed in Exclusion Criteria

             *Good health, as determined by medical history, medication use and physical
             examination to evaluate ongoing chronic medical or psychiatric diagnoses or
             conditions, defined as those that have been present for at least 90 days, which would
             not affect the assessment of the safety of subjects or the immunogenicity of
             challenge. These medical diagnoses or conditions should be stable for the last 90 days
             (no hospitalizations, emergency room (ER) or urgent care for condition (excluding
             musculoskeletal conditions) and not listed in Exclusion Criteria. Subjects may be on
             medications only if the condition or disease is stable and not deteriorating, if the
             medical intervention (such as device or medication) was not available during the
             maximal inpatient period of time, medications are not listed in the Exclusion Criteria
             and pose no additional risk to subject safety or assessment of adverse events. This
             also includes no change in prescription medication, dose or frequency as a result of
             new symptoms or deterioration of the medical diagnosis or condition in the 90 days
             prior to enrollment. Any prescription change that is due to change of health care
             provider, insurance company, etc., or that is done for financial reasons, as long as
             in the same class of medication, will not be considered a deviation of this inclusion
             criterion. Any change in prescription medication due to improvement of a disease
             outcome (e.g., lowering of the dosage or frequency), as determined by the site
             principal investigator (PI) or designated clinician licensed to make medical diagnoses
             and listed on Form FDA 1572, will not be considered a deviation of this inclusion
             criterion.

         12. Vital signs as follows:

               -  Pulse is 47 to 99 beats per minute, inclusive

               -  Systolic blood pressure is 85 to 139 mmHg, inclusive

               -  Diastolic blood pressure is 55 to 89 mmHg, inclusive

               -  Saturation of Peripheral Oxygen (SpO2) >/= 95%; Respiratory Rate (RR) </= 18

               -  Oral temperature is less than 100.6 degrees Fahrenheit

         13. Eligibility laboratory values White Blood Cell (WBC), Absolute Lymphocyte Count,
             Hemoglobin (Hgb), Platelets (PLTs), Alanine Transaminase (ALT) and Creatinine(Cr) are
             within acceptable parameters*

             *Labs within normal range or grade 1 abnormalities deemed not clinically significant
             by a study investigator are considered acceptable

         14. Body mass index (BMI) > 18.5 and < 40 kg/m2 at screening

         15. Other screening tests Electrocardiogram (ECG) and Chest x-ray(CXR) are within normal
             reference range or not deemed clinically significant by the Principle Investigator(PI)
             or appropriate sub-investigator*

             *Designated clinician licensed to make medical diagnoses and listed on the Form FDA
             1572

         16. Negative test for Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), and
             hepatitis C virus (HCV) at screening

         17. Negative respiratory virus panel by BIOFIRE(R) FILMARRAY(R) respiratory panel by
             bioMérieux or by Luminex xTAG(R) on Day -2, and Day -1

         18. Negative RT-PCR test for severe acute respiratory syndrome coronavirus 2(SARS-CoV 2)
             on screening and Day -2

         19. Hemagglutination Inhibition Test (HAI) antibody titer </=1:40 against influenza
             A/Texas/71/2017 (H3N2) at screening

         20. Receipt of the recommended number of doses of an (Emergency Use Authorization) EUA
             authorized or licensed coronavirus disease of 2019 (COVID-19) vaccine product = two
             weeks prior to confinement

        Exclusion Criteria:

          1. Presence of self-reported or medically documented significant medical or psychiatric
             condition(s)*

             *Significant medical or psychiatric conditions include but are not limited to:

               1. Respiratory disease (e.g., chronic obstructive pulmonary disease [COPD], asthma)
                  requiring daily medications [Inhaled, oral or intravenous (IV) corticosteroids,
                  leukotriene modifiers, long and short acting beta agonists, theophylline,
                  ipratropium, biologics] or any treatment for respiratory disease exacerbations
                  (e.g., asthma exacerbation) within the last 5 years

               2. Presence of any febrile illness or symptoms suggestive of a respiratory infection
                  within two weeks prior to challenge

               3. Significant cardiovascular disease (e.g., congestive heart failure,
                  cardiomyopathy, ischemic heart disease) or history of myocarditis or pericarditis
                  as an adult.

               4. Neurological or neurodevelopmental conditions (e.g., epilepsy, stroke, seizures,
                  encephalopathy, focal neurologic deficits, Guillain-Barre syndrome,
                  encephalomyelitis or transverse myelitis).

               5. Ongoing malignancy or recent diagnosis of malignancy in the last five years
                  (excluding basal cell carcinoma of the skin)

               6. Presence of an autoimmune disease.

               7. Immunodeficiency of any cause.

               8. History of diabetes.

          2. Presence of immunosuppression or any medications that may be associated with impaired
             immune responsiveness*

             *Including, but not limited to, corticosteroids exceeding 10 mg/day of prednisone
             equivalent, allergy injections, immunoglobulin, interferon, immunomodulators,
             cytotoxic drugs, or systemic corticosteroids or other similar or toxic drugs during
             the preceding 12-month period prior to screening. Low dose topical and intranasal
             steroid preparations used for a discrete period of time are permitted.

          3. Known allergy or intolerance to treatments for influenza (including any neuraminidase
             inhibitors or baloxavir marboxil).

          4. Known allergy to two or more classes of antibiotics (e.g., penicillins,
             cephalosporins, fluoroquinolones, or glycopeptides).

          5. Known allergy to excipients* in the challenge virus inoculum.

             *Sucrose, KH2PO4, K2HPO4, L-glutamic acid (in SPG diluent)

          6. Receipt or planned receipt of any investigational drug/investigational
             vaccine/licensed vaccine, except for a licensed or emergency use authorized
             coronavirus disease of 2019 (COVID-19) vaccine product, within 30 days prior to the
             date of challenge.

          7. Prior enrollment in an influenza virus challenge study with an influenza virus of the
             same subtype within the past 2 years.

          8. Currently enrolled in any investigational study or intends to enroll in such a study
             within the ensuing study period.*

             *Co-enrollment in an observational study, an investigational study in a
             follow-up/post-vaccination stage, or a study involving a licensed drug or biologic may
             be allowed at the investigator's discretion.

          9. Receipt of any influenza vaccine four months prior to challenge or plans to receive
             influenza vaccine during the study (approximately 57 days after challenge).

         10. History of a previous severe allergic reaction to any drug or biologic with
             generalized urticaria, angioedema, or anaphylaxis.

         11. Receipt of blood or blood products during the six months prior to the planned date of
             challenge.

         12. Plans to donate blood or blood products during the study. (approximately 102 days).

         13. Any condition (including medical and psychiatric conditions) that, in the opinion of
             the Investigator, might interfere with the safety of the subject and/or study
             objectives.

         14. An ongoing symptomatic condition for which subject has had or has ongoing medical
             investigations but has not yet received a diagnosis or treatment plan e.g., ongoing
             fatigue without a diagnosis.

         15. Known close contact with anyone known to have or suspected to have a respiratory viral
             illness within 7 days prior to challenge.

         16. Significant abnormality altering anatomy of nose/nasopharynx (including significant
             nasal polyps), clinically significant nasal deviation, or nasal/sinus surgery within
             180 days prior to challenge.

         17. History in the last five years of chronic or frequent intermittent sinusitis.

         18. Recent history (180 days) of epistaxis or anatomic or neurologic abnormality impairing
             the gag reflex or contributing to aspiration.

         19. Currently using an internal cardiac device such as a pacemaker or other implanted
             electronic medical devices.