A rare human challenge-style trial shows that even with poor ventilation and prolonged exposure, influenza may fail to spread unless viral shedding, host susceptibility, and air dynamics align just right.
Study: Evaluating modes of influenza transmission (EMIT-2): Insights from lack of transmission in a controlled transmission trial with naturally infected donors. Image credit: Pixel-Shot/Shutterstock.com
In a recent study published in PLOS Pathogens, researchers conducted the EMIT-2 trial to examine how influenza virus transmission occurs under controlled conditions, rather than to definitively identify a dominant transmission route. Contrasting previous studies that primarily used lab-grown viruses, the present trial recruited donors with naturally acquired influenza to expose healthy recipients in a quarantine hotel setting.
Unexpectedly, despite creating conditions favorable for transmission, such as low ventilation and prolonged social interaction, study findings reported that zero transmission events occurred among the 11 recipients. The authors suggested several possible explanations for the lack of transmission, including donors exhibiting mild symptoms (e.g., infrequent coughing), recipients showing evidence of pre-existing cross-reactive immunity, and environmental air mixing likely reducing exposure to concentrated exhaled breath plumes.
Preventing flu spread remains a guessing game
Seasonal influenza is reported to place a substantial burden on global public health systems, yet the specific mechanisms by which it spreads ("transmits") from person to person remain debated within the medical and scientific community.
Public health officials presently categorize transmission into three modes: inhalation (of fine aerosols), direct deposition of spray (droplets), and touch (fomites). However, the relative importance of these routes is poorly understood, thereby complicating the development of effective prevention strategies.
A previous study (EMIT-1) attempted to map these routes using volunteers infected with a laboratory-adapted strain of the virus, but it resulted in almost no transmission, an outcome attributed to the lab virus being too weak.
Researchers subsequently hypothesized that using wild-type or community-acquired influenza, rather than laboratory-adapted strains, would result in higher viral shedding and more infections.
Testing real-world flu spread inside a quarantine hotel
The present study (titled EMIT-2) was designed to test this hypothesis, aiming to observe transmission in real time to better understand the conditions under which influenza transmission may or may not occur. Specifically, the researchers sought to assess whether breathing shared air alone is sufficient for infection, or whether coughs and sneezes play a critical role.
The research team utilized a quarantine hotel model to create a controlled human influenza virus transmission trial (CHIVITT). The study recruited healthy adult Recipients (mean age 36) and Donors (mean age 21), the latter of whom had tested positive for influenza and reported symptom onset within the previous 48 hours.
Study participants were housed in separate rooms but were required to interact during exposure events in a designated room designed to simulate a stuffy, poorly ventilated space. The room had a ventilation rate of approximately 0.25 to 0.5 air changes per hour, but fans and dehumidifiers were run at high speed to ensure the air was well mixed.
To explore the relative contribution of different transmission pathways, recipients were randomized into two groups.
Intervention Recipients (IR): wore face shields and sanitized hands every 15 minutes. This reduced exposure to large droplets and to touch transmission, while leaving inhalation exposure broadly similar to that of controls.
Control Recipients (CR): used no protective equipment, exposing participants to all potential transmission routes.
Over several days, donors and recipients spent more than 82 cumulative hours together playing games, doing yoga, and talking to generate breath aerosols. The study analyzed viral loads from mid-turbinate swabs, saliva samples, and a specialized Gesundheit-II machine that captures and quantifies exhaled breath aerosols.
Zero infections despite prolonged close-contact exposure
The study's most unexpected finding was the complete absence of transmission. None of the 11 recipients developed influenza-like illness, and all PCR tests and serological (antibody) analyses remained negative for infection.
Study analyses suggest three non-mutually exclusive factors that may help explain these outcomes:
Low donor source strength: the donors were, coincidentally, surprisingly mild cases. During 30-minute breath sampling sessions, the median cough count was zero. While viral RNA was detected in 44 percent of fine aerosol samples (particle size ≤5 micrometers), the quantity was low, ranging from 79 to 8,900 copies per sample. Crucially, only 1 of 16 breath samples (6 percent) contained culturable (live, infectious) virus. The authors note that influenza aerosol shedding is highly variable between individuals, and that a small subset of infected people may account for a disproportionate share of transmission.
Possible recipient pre-existing immunity: although the recipients had low levels of strain-specific antibodies against the donor viruses (measured by hemagglutination inhibition (HAI) assays), further testing via ELISA revealed they had higher baseline binding antibody responses than the donors. This finding is consistent with, but does not prove, the presence of cross-reactive immunity accumulated from prior influenza infections or vaccinations, which may have reduced susceptibility.
Environmental air mixing: while the room had poor ventilation, mechanical systems rapidly mixed the air. Modeling and simulations suggest that this mixing likely prevented the formation of short-range, highly concentrated breath plumes. Although viral RNA was detected in room air (75 copies per cubic meter), the resulting dilution may have reduced exposure below the infectious dose required to overcome recipient immunity.
Flu transmission may require a rare perfect storm
The present study, despite producing unexpected findings, challenges the assumption that any symptomatic individual is necessarily a high transmission risk. Rather than identifying a dominant transmission route, the results suggest that successful influenza transmission may require a perfect storm: a donor with high infectious aerosol output, often associated with frequent coughing, a recipient lacking protective pre-existing immunity, such as younger individuals or children, and environmental conditions that allow concentrated exhaled breath to linger rather than rapidly disperse.
The authors also note that donor symptom severity and infectiousness may vary across influenza seasons and recruitment contexts, potentially influencing observed transmission outcomes.
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