The Smallpox Precedent

Pharmacopoeia raiders are busy, looking for Covid-19 remedies that might be hiding in the long list of tried, tested and safe drugs. I did this for smallpox a long time ago, when it was discovered that the antibiotic rifampicin blocked its growth. It turned out that the effective dose was far too high to be useful. The smallpox strain I used in this work was called Butler. It had been isolated in Rochdale during a big outbreak in 1952. Most of the 138 cases had never been vaccinated. Nobody died, because the causative virus was variola minor, very closely related genetically to classical smallpox – variola major – but very different in its clinical effects: v. minor with a case fatality rate in the unvaccinated of less than 1 per cent and v. major with a rate higher than 20 per cent.

Smallpox entered the historical section of medical textbooks when its eradication was declared at the 33rd World Health Assembly in May 1980. Coronaviruses are very different from pox viruses, whose DNA genomes have more than 180 genes and, until the discovery of the giant Mimiviruses and Pandoraviruses, were thought to be by far the biggest viruses; coronavirus RNAs have fewer than 10. Covid-19 vaccines won’t appear until 2021; Jenner’s vaccine was introduced more than 200 years ago. Mutation rates indicate that smallpox has been infecting humans for more than two thousand years; Covid-19 is brand new. But they have some things in common.

Consider New Zealand. Its attitude to Covid-19 today is exactly the same as it used to be to smallpox, a foreign virus to be kept out by border controls and quarantine. It was successful with smallpox; the country’s last outbreak was in 1913, caused by variola minor brought in by a Mormon missionary from the United States, which led to 1892 cases. Its Covid-19 outbreak has been a little smaller (1557 confirmed and probable cases); some case clusters were caused by virus brought from the US.

Consider ‘virus escapes from laboratories’. Donald Trump has been a proponent of the notion that the pandemic started with the escape of Covid-19 from the Wuhan Institute of Virology. Any discussion of lab escapes and the difficulties in establishing the facts has to take into account the dramatic and tragic events surrounding smallpox in Birmingham in 1978. Ali Maow Maalin, the last case of naturally occurring smallpox in the world, developed a rash on 26 October 1977 in Merca, Somalia. He had variola minor. But his wasn’t the last case of smallpox. Hilda Whitcomb developed variola major on 7 September 1978. She had contracted her infection from her daughter, Janet Parker, who had fallen ill on 11 August 1978; the virus that infected her had come from Birmingham University’s Department of Medical Microbiology on the floor below the studio and dark room where she worked as a photographer. How this happened was never established, in spite of a detailed investigation that reported to Parliament, and a twelve-day trial with many witnesses, although two were missing because Parker’s infection had been fatal and the head of department had committed suicide.

All that can be said today is that the lab in Birmingham in 1978 was a lot less virologically secure than the labs in Wuhan were in 2019, to judge from the published images. I visited the Birmingham lab in March 1978 and vaccinated myself afterwards.

Consider Leicester. Currently facing a renewed lockdown because of a rise in Covid-19 case numbers, in the 19th century it pioneered hospital and home quarantine for smallpox control – the ‘Leicester system’ – because of strong local opposition to vaccination. Infected families remained in their houses under supervision for 16 days, and wages were paid by Leicester Corporation. The Royal Commission on Vaccination published a detailed report on a smallpox outbreak in the city of 357 cases. It ran from August 1892 until December 1893 and was controlled by quarantine. In the same year the commission published another report on the smallpox outbreak in Warrington. It ran from May 1892 until May 1893, had 667 cases, and was controlled by vaccination. The Leicester system became a vitally important part of the World Health Organisation’s global smallpox eradication programme. It is the bedrock of Covid-19 controls today.

And consider variola minor. A forgotten virus. Although genuine smallpox, it was often perceived by the public to be something else because of its low mortality. First showing itself in Florida in 1897, it became firmly established across the US. Case numbers peaked there in 1920 at 109,458 with 291 deaths. With the exception of one year, annual case numbers were greater than 17,000 (often many more) until 1932. Then they declined, and by 1944 the virus had disappeared. In 1910 it had spread to Brazil, where it was called alastrim, and where it persisted until 1971. It also spread to Africa and to Europe, causing an epidemic in Switzerland with more than 5000 cases between 1921 and 1926. It became established in England in 1919 and caused a major epidemic lasting until 1935 with more than 81,000 notified cases and 209 deaths. The first infections were identified in Norfolk and Suffolk. The virus then trundled through England and Wales, causing local epidemics. At first it was busiest in central areas and the North, then in South Wales, then the southern Midlands, and finally in London and points south. Case numbers peaked at 14,753 in 1927. The last case, in 1935, was in Norfolk.

The fade-out of the epidemic has never been explained. There was no social distancing. It had nothing to do with herd immunity. At the start of the epidemic the national level of vaccine uptake was about 45 per cent. As the epidemic progressed uptake levels fell, reaching 35 per cent at its end, percentages far short of those needed for herd immunity, calculated for smallpox on the basis of its R number to be at least 70 per cent. The virus even came and went in Gloucester, a hot-bed of anti-vaccination sentiment where only 20 per cent of infants had been immunised. A temporary smallpox hospital was established at Brockworth aerodrome as the outbreak was growing. Brockworth is now the location of the Gloucestershire NHS head office, exculpatorily called Edward Jenner Court, and the site of an early Covid-19 drive-in testing centre.

Smallpox shows overdispersion, like Sars. Long before statisticians had coined the term, smallpox experts had observed it; not every case was equally likely to transmit the disease, some started outbreaks (superspreader events) while others didn’t, and some outbreaks fizzled out even though there were still many susceptibles. For variola minor it has been calculated that the most infectious 20 per cent were responsible for 60 per cent of cases. It is a big weak spot for a virus when a majority of infections are started by a minority of cases because it substantially raises the likelihood that the efficient application of the Leicester system will lead to its extinction. It happened to Sars, and to variola minor, and to Covid-19 in China and New Zealand. Our virus is the same as theirs. I am an optimist.