Clearing the Air Around Influenza

Challenge studies

The experiments on human transmission are called challenge studies (or Controlled Human Infection Model—CHIM). Their history dates back at least to Edward Jenner's smallpox experiments over 200 years ago. In the mid-1960s, the director of the Common Cold Unit wrote, “Human volunteers have played a larger part in the study of the common cold than in the investigation of almost any other disease.”

Challenge study methods and their results have proved to be a treasure trove of knowledge. For example, they help us understand if the agent caused the disease, the minimum infectious dose required for the portal of agent entry, and the effectiveness of drugs, vaccines and other interventions. The agents most subjected to challenge studies are influenza and rhinovirus. 

The typical challenge study involves a group of volunteers with little or no immunity to the challenge strain and no factors that can complicate the course of the experimental infection. These volunteers must also tolerate and observe the rules of pre-challenge isolation (to avoid the chance of natural infection). 

The essence of challenge studies is to cause infection in otherwise healthy people. Volunteers are usually assigned randomly to a challenge containing a replication-competent virus or identical placebo and followed up with a series of observations or tests. Influenza challenge is usually dropped in the nose, but it could be a contaminated surface or aerosol spray.

Challenge studies represent the highest form of controlled experiment for understanding transmission. Still, they do not necessarily result in infection or, indeed, the appearance of symptoms in the challenged arm of the experiment, as you can see in this reproduction of original Common Cold Unit studies:

This page from one of Tyrrell’s books illustrates the problem - look at the figures in the “not infected” column.

In a SARS-CoV-2 challenge study published 2022 at the Royal Free Hospital in London, 36 unvaccinated healthy 18-29-years were challenged with an infectious dose of wild-type SARS-CoV-2.  Eighteen participants became infected with mild-to-moderate symptoms- None developed serious symptoms, and two remained asymptomatic. The average time from exposure to viral detection and early symptoms (incubation period) was 42 hours, significantly shorter than Ferguson’s Imperial Report 9 modelled estimate of 5.1 days. 

The results of challenge studies may not be entirely generalisable for community-acquired infections, given the likely differences in exposure and populations. Even in a perfect experiment, you must put results in their context and interpret them. However, the mystery remains about how some volunteers with no discernible immunity are not infected when challenged intranasally.

Now that we have a basic overview of the “Flu,” we understand that it is an inexact colloquial term that hides a mysterious and fascinating story. Telling this story in detail is difficult because it has become a trough for decision-makers' careers and pharmaceutical profits.

The uncertainty encapsulated in the term “influenza” has given way to a certainty where people pretend to predict the “behaviour” of this and that virus, thus betraying crass ignorance of basic microbiology. Viruses, unlike bacteria, cannot replicate on their own. They must infect cells and use their internal organelles to manufacture millions of copies. So, they are not classed as living beings; they do not have a central nervous system. Viruses can no more “behave” than a knife or chair can. They are objects. 

Another pioneering researcher was a GP from Cirencester, Dr Edgar Hope-Simpson.

He studied acute respiratory illness where it is most observed - primary care.

Hope-Simpson's first post was as a Resident Medical Officer, where he worked six and a half days a week. Therefore, it is unsurprising that he wanted to move to general practice. In 1945, he moved to Cirencester, where he became heavily influenced by the work of William Pickles. 

Pickles had published Epidemiology in Country Practice. The book reports on how careful observations can determine the links between the transmission of infectious diseases between families, farms, and villages. It also details the research a general practitioner could conduct on common diseases.  Hope-Simpson modelled his approach on Pickles's work, exchanging visits with him. A year after taking up his post in Cirencester, Hope-Simpson created the Cirencester Research Unit. 

Without formal epidemiological or research training, Hope-Simpson described how viral respiratory disease epidemics can start with an explosive phase that peters out relatively soon afterwards. He later described the seasonality of influenza patterns, which may be explained by the temperature sensitivity of some of the known viral respiratory agents. A century before, William Farr had shown that epidemics (if left unchecked) seemingly follow similar patterns. A first acute phase peaks and then declines to either disappear or provide constant low-level transmission. The sheer capriciousness of the “Flu” led Hope Simpson to conclude that it was not an infectious syndrome, or rather, the viruses that lay dormant everywhere were activated and not passed on. 

As head of the University of Virginia (UVA) group, Gwaltney’s research on acute respiratory infections was prodigious and meticulous in its methods. It manifestly helped our understanding of SARs-COV-2. Although it is difficult to determine the most important publications, we selected four.

In 1972, The UVA team conducted an 8-year study of Coronavirus 229E and OC43 in 433 working adults in the winter and spring from 1963 to 1970. Serological testing was used to confirm infection; it required a rise in antibodies during the acute phase of the illness and in the recovery period (so-called serum pairs).  The highest percentage of positives for either virus was 13% for 229 E in winter and spring. In some years, there was no apparent circulation of one or the other. The researchers found high re-infection rates in subsequent years. Symptoms were generally mild. In 1964, they also tested asymptomatic adults randomly: 229E antibodies were present in 3% of people in winter and spring and 0.4% in the remaining seasons. OC43 was found in 5% of people only in the winter and spring. 

In 1973, they studied the transmission of rhinovirus colds by self-inoculating 25 adults with common colds. They discovered that Rhinovirus could be transferred from the nose to the hands of infected people and back to the nose or their conjunctiva. In addition, infected people could (but not always) transmit the virus by repeatedly touching non-infected volunteers’ fingers or face. 

In the often cited 1984 lecture, Gwaltney assessed the relationship between meteorological variables and respiratory viral activity. At the time, he concluded there was little evidence of an association (i.e. experimental and observational evidence did not support the contention that cold weather facilitated influenza-like illness). However, he noted a relationship between indoor humidity and the incidence of Rhinovirus symptoms, which forms the basis for the so-called Hemmes hypothesis.  Rhinovirus circulation was high from April until September. Although the number of episodes was lower during the summer, the fraction of influenza-like illnesses attributable to rhinovirus was more significant. As indoor humidity declined as people started heating their homes, rhinovirus declined, and other agents, including coronavirus, became more prevalent. Gwaltney also referred to the 8-year study and noted a sudden increase in influenza-like illness whenever daily temperatures declined abruptly, which fits with the temperature sensitivity hypothesis of activation of respiratory viruses. 

Finally, Gwaltney’s and Hendley’s five postulates (mentioned in the 3rd and 4th episodes of the series) for respiratory virus transmission are the last notable output we chose. At the time, there were no accepted standards for assessing routes of microbial transmission. We have shown this situation persists today, leading to misinformation, certainty statements about the modes of transmission that do not reflect the evidence and massive research waste.  These postulates are well founded, and although they need integration with clinical and molecular data, they provide likely proof of transmission if fulfilled. Gwaltney and Hendley applied four of their five postulates to rhinovirus transmission by the three modes or routes: contact, air (large droplets) and aerosol. They concluded that the balance of evidence favoured contact. 

As Science is cumulative, we should assimilate knowledge gradually—those who proffer simplistic solutions to complex problems without knowing what is already known should be treated with the caution they deserve. The transmission of respiratory viruses is a puzzle to be solved. Gwaltney and Handley provide early theories that accelerated our understanding. Their studies informed us about the seasonality of respiratory viral infections, reinfection rates, asymptomatic cases and apparent competition between strains.

This is the fifth of the old geezers’ simplified recap of what is known about ILIs.