Pilot Influenza Challenge Study

This experimental pilot study is designed to develop methods to analyze viral complexity shed after experimental human infection with influenza A virus, a necessary first step in the development of mucosal transmission models. While the initial influenza CHIM study at SLU employed an H1N1 influenza strain, in this study, an H3N2 strain will be used. Data reported from the first-in-human, dose-finding study for the DMID- and CIVICs-developed, RG-A/Texas/71/2017 (H3N2). Similarly, while the use of different clinical scoring rubrics prevents direct comparisons, illness observed during DMID 18-0010 was reported to be very mild, and lacked a sham inoculum comparator group, but the raw data are not available for review. In contrast, with RG-A/Texas/71/2017 (H3N2), participants reported a mean cumulative MJS of 25.8 (range 18.3 to 34.1) from day 2 through day 8; the MJS ranges from 0 to 36 for each measurement. In contrast, both of the sham inoculated participants had a cumulative MJS of 1.0. These observations are consistent with comparisons between H1N1 and H3N2 during naturally acquired infection. Thus, the H3N2 CHIM may be more amenable to studies of shed virus and mucosal immunity, and to provide a wider dynamic range of influenza illness against which to test vaccine and treatment countermeasures in the future. This study will examine the genetic diversity of shed influenza virus particles in small (<5µm) versus large (≥5µm) exhaled particles, as well as in nasopharyngeal swab samples, and compare the viral diversity in these specimens stratified by baseline serum microneutralization titer and nasopharyngeal mucosal IgA titers. While this is a small, exploratory study, not powered for statistical significance of endpoints, the aim is to develop the methods necessary for future, larger scale studies to apply this practical knowledge to further understand mucosal immune correlates of protection against influenza A disease. This understanding will be valuable for the development and testing of new influenza vaccines that better leverage mucosal immunity against influenza infection and transmission.

This is a CHI study of Influenza RG- A/Texas/71/2017 (H3N2) influenza, clade 3C3a virus to assess clinical response, immunological response, and safety. The study population will be healthy participants (male and non-pregnant, non-breastfeeding females) between the ages of 18 to 45, inclusive. Up to 12 participants will receive H3N2 virus CHI. Clinical manifestations, viral shedding, and immunological responses will be characterized.

Influenza RG-A/Texas/71/2017 (H3N2) influenza, clade 3C3a virus CHI will be performed using a 12 mL dose of approximately 1.86 x10^6 TCID50/mL, which has been shown to induce 60% or higher rates of MMID. The primary objective of the study will be to evaluate the association of MMID post-challenge and pre-existing virus-specific HAI titers in healthy participants. MMID is defined as the presence of both of the following, assessed through Day 8:

• Viral shedding detected by any approved positive RT-PCR assay from a NP swab, and
• Any one or more of the following symptoms or signs or laboratory findings, as related to the study agent; Arthralgia, Chest tightness, Chills, Conjunctivitis, Nasal congestion, Sinus Congestion, Coryza, Decreased appetite, Diarrhea, Dry Cough, Dyspnea/Shortness of Breath, Fatigue/Tiredness, Fever (>38.0°C), Headache, Lymphopenia (<1000 cells/mL), Myalgia, Nausea, Oxygen Saturation Decrease by ≥3% from baseline, Productive Cough, Rhinorrhea, Sore Throat, and Sweats.

During Study Days -30 to -3 (Screening Period), participants will provide informed consent to participate in this study. They will undergo a review of medical history, physical examination by a study physician, and screening laboratory tests. During this period, participants will also have a posteroranterior (PA) and Lateral chest X-ray (CXR), and a baseline 12-lead ECG.

After screening, eligible participants will be admitted to an inpatient challenge unit (Day -2). Up to twelve participants will be enrolled of which up to 6 participants will have H3N2 challenge titers <40 and up to 6 participants will have H3N2 challenge titers >40. The plan is to enroll participants with the broadest range of MN titers. Based on the results of the MN titers, participants may be healthy but may not be enrolled. Backup participants may be admitted into the inpatient unit to ensure sufficient number of volunteers undergo CHI, given the potential for drop-outs, presence of new exclusionary criteria, and/or pre-challenge evidence of viral respiratory infection among participants. A review of eligibility criteria, and baseline clinical assessments, safety blood tests, influenza virology, and immunology tests will be performed and the participants will have approximately a 48-hour window to decide if they would like to drop out of the study and leave the inpatient unit before CHI. Participants must have no evidence of a respiratory viral infection as determined by multiplex respiratory virus RT-PCR assay testing prior to CHI (positive results prior to CHI will exclude the subject from the challenge, and additional participants may serve as replacements). On Day -1, participants will be trained on the influenza patient related outcomes Flu-PRO Survey Instrument and Validation Diary.

On Day 1, eligibility and clinical status will be reviewed. If criteria for proceeding with challenge are met, participants will receive A/Texas/71/2017 (H3N2), clade 3C3a CHI. 0.5 mL of RG-A/Texas/71/2017 (H3N2) influenza, clade 3C3a will be delivered in each nostril of a recumbent participants per study SOP. Backups will be discharged from the inpatient unit prior to challenging other participants if not needed to replace ineligible participants or participants declining to proceed with CHI.

After CHI, participants will complete daily self-assessments using the Flu-PRO Survey Instrument and Validation Diary through 14 days post-challenge to generate a symptom severity score. Participant clinical status will be monitored closely. Safety labs will be performed at scheduled times. Participants will undergo scheduled blood draws, and nasal swab collections for immunology and virologic laboratory testing. Quantitative and qualitative evaluation of influenza will be done after CHI on Day 7. Participants will also undergo qualitative evaluations for evidence of influenza by multiplex respiratory virus RT-PCR assay. Participants will speak/breathe into the PathoSift Pro which is a Bioaerosol Sampler device for 15-30 minutes every other day while in the confinement unit to collect airborne viruses. Participants will remain blinded to the results of their respiratory virus testing until they meet discharge criteria. An ECG will be performed at Day 6 on all participants, and as clinically indicated at any other time.

Following CHI, participants will remain in the inpatient unit for a minimum of seven additional days and will be discharged only if 1) they have two consecutive negative influenza tests (that are performed on days 7 and 8) for influenza A using a multiplex respiratory virus assay (BIOFIRE® FILMARRAY® or Luminex xTAG®), AND 2) have been afebrile (<38.0°C), have a room air Saturation of Peripheral Oxygen (SpO2) ≥95 and have been clinically and hemodynamically stable for at least 48 hours. In addition, participants may have residual and/or resolving symptoms of influenza illness. It is expected that most participants will shed the challenge virus for three to five days post exposure.

If participants are still shedding virus on Day 8, they will remain in the challenge unit, be offered one dose of baloxavir marboxil (a full treatment course), and they will continue to have NP swabs tested daily until there are two negative influenza tests performed on consecutive days and meet clinical discharge criteria described above.

Any participant who develops serious related or unrelated signs or symptoms during inpatient stay will receive appropriate and as clinically necessary escalation of care (e.g., cardiologist consultation for cardiac symptoms or transfer for evaluation at the Emergency Department). Any participant who experiences complications or sequelae due to CHI will be followed until resolution and/or stable, and will be referred for appropriate specialized care as clinically necessary. All participants will be followed for approximately 90 days post-challenge. Additional follow-up will be performed at in-person Visits 9 (Day 15), 10 (Day 29) and 11 (Day 61). Participants will also undergo scheduled blood draws and nasopharyngeal (NP) swabs for immunology and virologic laboratory testing during this follow up period. A final follow-up by telephone will occur on Visit 12 (Day 91).