Minimal Transmission in an Influenza A (H3N2) Human Challenge-Transmission Model with Exposure Events in a Controlled Environment

Background: Uncertainty about the relative importance of modes of influenza transmission, particularly airborne droplet nuclei (aerosols), fuels controversy concerning recommendations for healthcare worker protection during pandemics. In-depth review by an expert panel, a proof-of-concept study, and an international workshop concluded that human challenge-transmission studies in well-controlled environments would be the most promising approach to fill this critical knowledge gap. Methods: Healthy, seronegative volunteer 'Donors' (N=52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). Seronegative 'Recipients' randomised to Intervention (IR, N=40) or Control (CR, N=35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitised frequently to limit large droplet and contact transmission. Numbers of Donors and days of Recipient exposure were increased compared to proof-of-concept to increase secondary attack rate (SAR). Symptoms were monitored and viral shedding in nasopharyngeal swabs and exhaled breath viral aerosols were quantified by reverse-transcriptase PCR (qRT-PCR). Serological specimens were analysed for evidence of seroconversion. Findings: Intranasal inoculation produced an infection rate of 81% (42/52); 60% (25/42) of infected Donors had influenza-like illness, 14% (6/42) had fever, and 26% (11/42) had mild or no symptoms. Viral aerosol shedding was observed from 26% (11/42) of the infected Donors. One transmitted infection was confirmed by serology in a CR, yielding a SAR of 2·9% among CR, 0% in IR (p = 0·47 for group difference), and 1·3% overall. Interpretation: The SAR observed was significantly less than 16% (p<0·001) expected based on the proof-of-concept study SAR considering that there were twice as many Donors and days of exposure to Recipients. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols. The low SAR limits this study's ability to provide definitive evidence regarding modes of transmission. Trial Registration: (ClinicalTrials.gov number NCT01710111). Funding Statement: U.S. CDC, Cooperative Agreement: Grant Number 1U01P000497-01. The views expressed in this paper are those of the authors and do not necessarily represent the official position of the funding agency. Declaration of Interests: JSN-V-T and BK declare previous consultancy fees from H-Vivo plc, unrelated to the current work. JSN-V-T is currently seconded to the Department of Health and Social Care (DHSC), England; the views expressed in this paper are not necessarily those of DHSC. RLW, AG and AM are employees of H-Vivo plc each of whom hold shares and /or share options in the company. All other authors declare no conflicts of interest. Ethics Approval Statement: This trial includes written informed consent from healthy volunteers in accordance with the principles of the Declaration of Helsinki, in compliance with UK regulatory and ethical (IRB) requirements, and registered with ClinicalTrials.gov (number NCT01710111).