A Pilot Study of the Effects of Pre-Existing Immunity on Influenza A/Texas/71/2017 (H3N2) Virus Shedding After Human Challenge in Healthy Participants

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.