Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment

Abstract

Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer 'Donors' (n = 52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). 'Recipients' randomized to Intervention (IR, n = 40) or Control (CR, n = 35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p = 0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols.

Fig 1. Schematic of study design showing timelines, environmental controls and monitoring, physical segregation arrangements, exposure intervention, and volunteer movements during quarantine study.

DFA: direct fluorescence assay; RH: relative humidity; NPS: nasopharyngeal swab.

Fig 2. Trial profile.

Intervention Recipients: wore face shields, used hand sanitizer every 15 min and only allowed to touch face with single-use wooden spatula; Control Recipients: did not use face shields or the specified hand hygiene protocol.

Fig 3. Viral detection in Donors by day of exposure event.

A) Columns show the proportion of all infected donors (n = 42) who were qRT-PCR positive for viral shedding for coarse (>5μm) and fine (≤5μm) aerosols, and nasopharyngeal swabs. B) Mean and standard deviation error bars for qRT-PCR cycle threshold values from the positive nasopharyngeal swabs (n = 19 on day 1; n = 34 on day 2; n = 35 on day 3; n = 31 on day 4). C) Virus quantified (log₁₀ RNA copies) from detectable exhaled coarse (n = 6) and fine (n = 14) breath aerosols by qRT-PCR; the boxes show the inner-quartile range (IQR) with a band to indicate the median, and whiskers extending to highest and lowest data points within 1.5 IQR.