Evaluating Modes of Influenza Transmission (EMIT-2): Challenges of a Controlled Human Influenza Virus Infection Transmission Trial (CHIVITT)

A previous controlled human influenza transmission trial produced minimal transmission using nasal inoculation of an egg adapted virus. Therefore, we implemented a new trial with naturally infected Donors. We recruited healthy Recipients for four, two-week hotel quarantine cohorts and naturally infected, qRT-PCR confirmed Donors for two cohorts. Five Donors (mean age: 21; 80% female; two H1N1, three H3N2, one for cohort 24b and 4 for 24c, Jan-Feb 2024) exposed Recipients (mean age: 36; 55% female, eight in cohort 24b and 3 in 24c) in a hotel room with limited ventilation but a high air recirculation rate. We collected exhaled breath, ambient and personal bioaerosols, fomite swabs, and sera, and analyzed samples using dPCR and fluorescent focus assays, hemagglutination inhibition (HAI) assay, and enzyme-linked immunosorbent assay (ELISA). Compared with previously studied community-acquired influenza cases, we detected viral RNA (44%) and culturable virus (6%) less frequently and measured fewer viral RNA copies (79 - 8.9x103 copies/30-min) in Donors exhaled fine aerosols. One of 23 surface swab samples was culture positive. At admission, 8 of 11 Recipients had HAI titers [≤]10 but 9 of 11 had stronger binding antibody responses than Donors against vaccine strains corresponding to Donor viruses. No Recipient developed influenza-like illness, PCR-positive respiratory samples, or serological evidence of infection. Potential explanations and insights regarding lack of transmission include importance of cough and seasonal variation in viral aerosol shedding by Donors, of potential cross-reactive immunity in middle-aged Recipients with decades of exposure, and of exposure to concentrated exhaled breath plumes limited by rapid air mixing from environmental controls that distributed aerosols evenly. Future trials over multiple seasons, Donors that cough, younger recipients, and environments that preserve normal exhaled breath plumes will be required to observe transmission from naturally infected Donors under controlled conditions and generate new insights into influenza transmission dynamics. Author SummaryHuman-to-human influenza virus transmission under controlled conditions could provide insights leading to better control of epidemics and pandemics. However, a previous study using laboratory adapted viruses produced minimal transmission. Therefore, we aimed to study transmission from people naturally infected with circulating viruses. We recruited four cohorts of healthy volunteer Recipients to stay in a quarantine hotel for two weeks. We could not recruit Donors for the first two cohorts. In the last two cohorts, one Donor exposed eight Recipients in the first and four Donors exposed three Recipients in the second. The Donors coughed infrequently and shed less virus into the air than we had observed during previous influenza seasons. No Recipients became infected. Possible explanations include that people infected during mild influenza seasons or who cough very little may be minimally contagious. Our middle-aged Recipient cohorts were older than Donors and possibly less susceptible to infection because of additional years of vaccination and infection. Finally, environmental controls in the hotel distributed aerosols evenly but reduced short-range exposure to concentrated clouds of exhaled breath that may play an important role in transmission. New designs will need to address these issues.