COVID-19. Can Historical Antivirals Be of Use?
April 8, 2020
Tom Jefferson, Carl Heneghan
Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford
When the US Army pulled out of the UK at the end of World War II, they left behind Harvard Hospital, a complex of Nissen huts and one-story buildings near Salisbury.
Harvard hospital was one of the so-called D-Day hospitals built to care for the casualties of the Normandy campaign and infectious disease cases. The complex and its content was donated to the British people in 1945, in a gesture of typical American generosity.
Soon after, the empty buildings were occupied by the Medical Research Council’s Common Cold Unit (CCU). The CCU ran 1,006 studies between 1946 and 1989, the year before its closure. An act that seemed inevitable at the time, but which now has the distinct appearance of scientific vandalism.
In 2000 one of us (TJ) carried out a review of all the studies from the MRC archives and an extensive series of interviews with the CCU’s last director, the late Dr David Tyrrel CBE. From that material, a subset of 243 comparative studies formed the source of a systematic review. The sources were not all publications but the actual reports, sometimes in longhand, written for each study.
Typically a set of volunteers would be housed in Harvard Hospital and be subjected to transmission, isolation, prevention or treatment after a “challenge” with a variety of common cold agents. The same agents that cause influenza-like illness. Amongst them were two of the viruses first identified and isolated in humans at the CCU in the 1950s and most associated with common colds and influenza-like illness: Rhinovirus and Coronavirus. The challenge usually consisted in squirting a dose of saline containing a viral agent cultured and harvested in the CCU lab and observing either the mechanism of transmission in a highly controlled environment or intervening with a variety of experimental compounds showing promise.
We are now making the review, which was withdrawn because of lack of funding to keep it updated, available.
Access the review: Antivirals for the common cold.
This review was withdrawn from The Cochrane Library, as of issue 3, 2004. The lead author (TJ) reported that the reviewers could no longer update it. Lack of funding to update the review is the main reason for its withdrawal.
Research recommendations within the review (see page 12): “Further assessment of the effects of dipyridamole, ICI 130, 685, Impulsin (palmitate) and Pleconaril in preventing the common cold should be carried out. Assessment of the effects of dipyridamole initially could involve a case-control study prior to the conduct of a clinical trial. The common use of the drug (currently used to prevent transient ischaemic attacks, strokes and prevent formation of thrombi in circulatory disorders) should make a study of such a design relatively easy to organise.
Attention should be paid to the development of compounds with a non-virus specific action.”
It includes a small placebo-controlled study of the Intranasal compound 7-thia-8-oxoguanosine (known as NARI 10146). NARI is a nucleoside analogue with proven immune-modulatory activity which was tested against coronavirus 229E in the summer of 1989, shortly before the closure of the CCU in a small study in 40 volunteers. There did not appear to be any difference in the effects of the compound but confidence intervals were large.
Other surprisingly effective treatments against coronaviridae were interferon and dipyridamole (the latter from a Bulgarian trial).
We hope that the availability of this historical record will aid the search for possible treatments against COVID-19 based on molecules that have shown promise in the past and test them in larger population trials.
Beyond this pandemic, we consider there is a need to refocus efforts on all respiratory viruses. We need to research their ecology and transmission and identify effective preventive and treatment measures both at population and individual level. These measures must include non-pharmacological and behavioural interventions. A wider public health perspective is required for public health problems such as the one we are facing now.
Keeping our past in mind may help us avoid falling into Burke’s category of “Those who don’t know history are destined to repeat it” and save lives.
Tom Jefferson is an Epidemiologist.
Disclosure statement is here
Carl Heneghan is Professor of Evidence-Based Medicine, Director of the Centre for Evidence-Based Medicine and Director of Studies for the Evidence-Based Health Care Programme. (Full bio and disclosure statement here)
Jon Brassey is the Director of Trip Database Ltd, Lead for Knowledge Mobilisation at Public Health Wales (NHS) and an Associate Editor at the BMJ Evidence-Based Medicine
Disclaimer: the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.
