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Professor Carl Heneghan and Tom Jefferson highlighted how difficult it is for someone to transmit an influenza-like illness (“ILI”) to another person.  They highlight experiments, or challenge studies, done long before Covid with rhinoviridae which causes common colds.

“If you have followed these experiments and paid attention, just like the authors, you might conclude how difficult it is to transmit ILI experimentally, even in everyday work that includes close contact and touching.

“These famous experiments are relevant to coronaviridae transmission. Although rhinoviridae and coronaviridae lock on cell membranes using different receptors … the only difference … seems to be the length of incubation and shedding,” Prof. Heneghan and Jefferson wrote.

SARS-CoV-2 is a coronavirus of the coronaviridae family of viruses.  A human challenge study for SARS-CoV-2 funded by the UK Vaccine Taskforce was published in March 2022. Unvaccinated participants were given an infectious dose of a “wild-type” of SARS-CoV-2 virus intranasally – with nose drops. Only 18 out of 34 (53%) participants developed PCR-confirmed infection – all symptoms were mild to moderate.

Why were human challenge studies not conducted earlier in the “pandemic”? And if it was known that it is so difficult to transmit ILIs, it begs the question: why did governments move so quickly to shut down businesses, hospitals and schools to “slow the spread”?

By Prof Carl Heneghan and Tom Jefferson

Respiratory viruses have been the source of investigation for at least a century. Shope, the discoverer of swine influenza and Smith, Laidlaw and Andrewes, discoverers of the human variety, could not visualise the agent, although they could filter it from human washouts. They knew the agent was there, but visualisation had to wait until the advent of the electron microscope a few years later. 

However, through several studies and serendipity, researchers soon realised that the influenza virus was not the only “kid on the block”. Various other viral respiratory agents were discovered after influenza, each with a different shape and structure but all more or less causing the same signs and symptoms: those of influenza-like illness (“ILI”).

For each of these newly discovered agents, the questions posed by researchers could be categorised broadly into three themes: 

1. What is the portal of entry into the human body, and how does it transmit? 
2. What is the incubation period, and how serious is the clinical picture the agent can cause?
3. Can we reproduce the clinical picture experimentally, and what interventions prevent or ameliorate influenza-like illness?

Apart from the UK Common Cold Unit in Salisbury, two other distinct and distinguished scientists carried out vital respiratory viruses research, both based in the USA: the University of Wisconsin at Madison group and the University of Virginia (“UVA”) at Charlottesville group. 

Both groups studied the many causative agents of ILI with particular attention to the most common: rhinoviridae (“rhin” means “nose” and infections cause the common cold) – RV – and coronavirdae (named for their appearance: “corona” means “crown”). 

Like the Common Cold Unit, they studied the transmission of the agents using challenge studies. A technique we described in Riddle 6. 

Here we will concentrate on the Wisconsin group and leave the work of UVA to the next instalment.

Several studies made the headlines. In 1984, the Wisconsin group summarised some of their most famous experiments on rhinovirus.

In the small room experiment of 14 volunteers, 5 were “donors” (symptomatic volunteers who had been infected with a rhinovirus challenge and were shedding the agent, as identified by culture), and 9 were “recipients” (uninfected volunteers). Although there was no ventilation and the participants mingled, sang and played cards, none of the “recipients” was infected.

For the next experiment, the Wisconsin group used 11 donors and 11 recipients who shared a sealed dormitory for 12 hours for three days but did not use the same washing facilities and had no physical contact with each other, minimising the risk of transmission by fomites (i.e., surfaces). This time three recipients developed colds, but only one shed the specific RV 55 strain used in the challenge.

In another famous experiment, 11 infected donors kissed 11 recipients for under a minute. The researchers recorded 16 episodes of oral contact but only one infected recipient.

No airborne transmission experiments were possible because the researchers could not isolate any rhinovirus from the air.

In nine of the colds which developed in the experiments, the Wisconsin researchers could not isolate RV55, the strain used in the challenge. These were likely to be episodes of ILI originating outside the experimental conditions. 

If you have followed these experiments and paid attention, just like the authors, you might conclude how difficult it is to transmit ILI experimentally, even in everyday work that includes close contact and touching.

These famous experiments are relevant to coronaviridae transmission. Although rhinoviridae and coronaviridae lock on cell membranes using different receptors – with complicated names, think of them as docking stations spread throughout our bodies – the only difference between clinical pictures associated with these agents seems to be the length of incubation and shedding.

Once again, it seems difficult to reproduce challenge study infections in everyday settings such as dormitories, rooms, and communal areas. 

But Wisconsin apart, has anyone tried anything similar with SARS-CoV-2? Yes, in a human challenge study, 18 of 34 young unvaccinated recipients became infected.

There are three central issues. First, why did we abandon the human challenge approach; second, why have we deferred to poor-quality observational studies and models? Finally, what can we learn from the past to inform the future? 

If we can’t address these three issues, how can we reproduce the clinical picture experimentally and test the interventions to prevent or lessen influenza-like illness?

About the Authors

Carl Heneghan is a professor of Evidence-based Medicine at the University of Oxford, Director of the Centre for Evidence-Based Medicine (“CEBM”) and NHS Urgent Care general practitioner (“GP”) who regularly appears in the media. Tom Jefferson is a clinical epidemiologist and a Senior Associate Tutor at the University of Oxford.  Together they write articles on a Substack profile titled ‘Trust the Evidence’.

The above article is the seventh in a series titled ‘The SARS-CoV-2 transmission riddle’.  In the first five parts of the “Riddle” series, they discussed how poor quality and superficial science has led to research waste and misled the globe as to the number of active covid cases, the incidence of hospital-acquired covid and the number of deaths directly attributable to SARS-CoV-2.  In Part 6 and the following chapters, Prof. Heneghan and Jefferson briefly examine what was known about human coronoviridae and other main respiratory viruses, their characteristics and transmission. You can find the articles in the series below:

• Part 1 – By our reckoning, 6.6 billion SARs-CoV-2 tests have been done. worldwide. Such use, on an industrial scale, is unprecedented and helped distort perceptions.
• Part 2 – We need clarity in the evidentiary rules about how viruses spread.
• Part 3 – Binary PCR positivity is a meaningless test result on its own
• Part 4 – Poor methods lead to waste, misleading research and failure to address uncertainties.
• Part 5 – Model methods are black boxes, their limits are not explained, the data they are based on are highly suspect, and their predictions do not translate into everyday life – but all the rest is fine.
• Part 6 – The contribution of the Common Cold Unit to the study of coronaviridae.
• Part 7 (above) – The contribution of the University of Wisconsin to the study of coronaviridae and rhinoviridae.