H1N1v Virus Challenge Study in Healthy Subjects
Condition: Influenza
MeSH terms: Influenza, Human
Intervention: Influenza A/Bethesda/MM2/H1N1 Challenge
Intervention description: Reverse-genetics derived live A/California/04/2009/H1N1-like influenza virus passaged six times in Vero cells.
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Maximum age: 49 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: A/Bethesda/MM2/H1N1 Virus; Challenge; Dose Escalation; Healthy Subjects; Influenza; Live virus

Summary:

      This is a study of a reverse-engineered, Good Manufacturing Practice (GMP) grade,
      antiviral-sensitive, influenza A/Bethesda/MM2/H1N1 virus (A/California/04/2009/H1N1-like)
      infection to assess the effect of pre-existing immunity on clinical and immunological
      responses. Up to 80 healthy adult subjects will undergo intranasal inoculation with
      A/Bethesda/MM2/H1N1 virus, and their clinical manifestations, viral shedding and
      immunological responses will be characterized. The Primary Objective for this study is to
      evaluate the association of symptomatic Reverse Transcription-Polymerase Chain Reaction
      (RT-PCR)-positive influenza virus infection post-challenge and pre-existing Hemagglutinin
      Inhibition Test (HAI) antibody titers.
    

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 seven days after challenge, and until they
             have no virus shedding,* determined by qualitative RT-PCR for a minimum of two
             consecutive days post-challenge.

               -  For a minimum of seven days post-challenge (Study Day 8).

          4. Healthy* males and non-pregnant, non-breastfeeding females**, aged >/= 18 and </=49
             years of age, inclusive, at enrollment.

             *Good health is defined in inclusion criteria 10.

               -  Females subjects of childbearing potential must agree to have a serum pregnancy
                  test at screening, a urine pregnancy test before Chest X-Ray (CXR) performed (if
                  more than 7 days have passed between CXR and serum pregnancy test), and a urine
                  pregnancy test upon admission to the inpatient unit prior to CHI, and results
                  must be negative.

          5. Women of childbearing potential* must agree to use or have practiced true abstinence**
             or use at least 1 acceptable primary form of contraception***,****.

             These criteria are applicable to females in a heterosexual relationship and
             child-bearing potential (i.e., the criteria do not apply to subjects in a same sex
             relationship).

             *Not of child bearing 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 for180 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 admission and at least one acceptable primary form of contraception
             during the remainder of the study.

          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 or marijuana in a week for more than three months 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 or drug use within the last 30 days
             and agrees to abstain from alcohol and drugs* for at least one week before admission
             and throughout the inpatient period.

             *Including forms of marijuana not included in criterion 6.

          8. Negative drug urine toxicology result on screening (i.e., amphetamines, cocaine, and
             opiates) and on admission to the challenge unit (i.e., amphetamines, cocaine, opiates,
             and cannabinoids).

          9. Agree not to use the listed* prescription or over-the-counter medications within 7
             days prior to inpatient stay and through inpatient stay, 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).

         10. In good health* and not have clinically significant medical, psychiatric, chronic or
             intermittent health conditions including those listed in the Subject 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 the Subject 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 Subject 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.

         11. Does not have 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 for symptom.

         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; SpO2 >95%; RR<18; oral temperature is less than 100.0 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.

         14. Body mass index (BMI) >18.5 and <35 kg/m^2 at screening.

         15. Other screening tests (ECG and CXR) are within normal reference range or not deemed
             clinically significant by the 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 blood draw.

         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).

        Exclusion Criteria:

          1. Female subject who has a positive pregnancy test on screening or admission, is
             breastfeeding or planning to become pregnant from 30 days prior to challenge through
             the end of the study.

          2. Presence of self-reported or medically documented significant medical or psychiatric
             condition(s)*.

             *Significant medical or psychiatric conditions include but are not limited to:

               -  Respiratory disease (e.g., chronic obstructive pulmonary disease (COPD), asthma)
                  requiring daily medications (Asthma medications: inhaled, oral, or intravenous
                  (IV) corticosteroids, leukotriene modifiers, long and short acting beta agonists,
                  theophylline, ipratropium, biologics) currently or any treatment of respiratory
                  disease exacerbations (e.g., asthma exacerbation) in the last 5 years

               -  Presence of any febrile illness or symptoms suggestive of a respiratory infection
                  within two weeks prior to Controlled Human Infection (CHI).

               -  Significant cardiovascular disease (e.g., congestive heart failure,
                  cardiomyopathy, ischemic heart disease) or history of myocarditis or pericarditis
                  as an adult.

               -  Neurological or neurodevelopmental conditions (e.g., epilepsy, stroke, seizures,
                  encephalopathy, focal neurologic deficits, Guillain-Barre syndrome,
                  encephalomyelitis or transverse myelitis).

               -  Ongoing malignancy or recent diagnosis of malignancy in the last five years
                  excluding basal cell carcinoma of the skin, which is allowed.

               -  An autoimmune disease.

               -  An immunodeficiency of any cause.

               -  A history of diabetes.

          3. 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.

          4. Known allergy or intolerance to treatments for influenza (including but not limited to
             oseltamivir, baloxavir marboxil, acetaminophen).

          5. Known allergy to two or more classes of antibiotics (e.g., penicillins,
             cephalosporins, fluoroquinolones, or glycopeptides).

          6. Known allergy to excipients in the challenge virus inoculum.

          7. Receipt or planned receipt of any investigational drug/investigational
             vaccine/licensed vaccine within 30 days prior to the date of CHI.

          8. Prior enrollment in any influenza virus challenge study.

          9. Currently enrolled in any investigational study or intends to enroll in such a study
             within the ensuing study period.

         10. Receipt of any influenza vaccine six months prior to challenge or plans to receive
             influenza vaccine within 60 days post-challenge.

         11. History of a previous severe allergic reaction of any kind with generalized urticaria,
             angioedema, or anaphylaxis.

         12. Receipt of blood or blood products during the six months prior to the planned date of
             challenge.

         13. History of blood donation during the two months prior to the planned date of challenge
             and or plans to donate blood for the duration of the study.

         14. Any condition, to include medical and psychiatric conditions, that in the opinion of
             the Investigator, might interfere with the safety of the subject and/or study
             objectives.

         15. Known close contact with anyone known to have influenza 7 days prior to challenge.

         16. Acute medical condition with new prescription medication use in the last 30 days.

         17. Significant abnormality altering the anatomy of the nose/nasopharynx* clinically
             significant nasal deviation, or nasal/sinus surgery within 180 days prior to
             challenge.

             *Including significant nasal polyps.

         18. History in the last five years of chronic or frequent intermittent sinusitis.

         19. Recent history (180 days) of epistaxis or anatomic or neurologic abnormality impairing
             the gag reflex or contributing to aspiration.