In Focus The global eradication of smallpox and the work of Frank Fenner CR Robert George and William Rawlinson Virology Division, SEALS Microbiology Prince of Wales Hospital Randwick, NSW 2031, Australia Email: [email protected] The 1950s and 1960s represented a golden era in scientific poxvirus research. Multiple obituaries document his life, achieve- – discovery when many believed science would solve the ments, and his death in November 20102 10. world’s greatest problems. It was the era when colour tele- A DNA virus called variola (Orthopoxvirus, Poxviridae) causes vision was introduced and the role of DNA described, space smallpox. Case fatality rates varied depending on the infection type, programmes, the introduction of vaccines for polio, measles reaching up to 30% in the historically most common form variola and mumps, and the structures of proteins began to be major11. Smallpox has influenced the course of history and deci- described. Many discoveries were controversial, but there mated populations. For example, historians have debated whether was a strong belief science was taking the world forward and up to one-third of the Aztec population was decimated by smallpox reducing medical problems rapidly. The Intensified Small- in 1520 after Hernando Cortes accidently introduced the virus thus pox Eradication Program (ISEP) won united support from facilitating the European conquest of South America12. Elsewhere, both the Union of Soviet Socialist Republics (USSR) and the native Virginian inhabitants were depopulated to one-third of their United States of America (USA). The initiative was passed by former number in 1689, and numerous North American tribes were only a small margin (two votes) and came on the back of affected13. Similarly, Australian Aborigines suffered widespread several failed disease eradication programmes1. variola following European colonisation of Australia14. In remedy, As documented in Professor Yenen’s accompanying paper, small- various methods were attempted to control the disease with varying pox was a scourge with a long history of different interventions that success. There were numerous methods tried, and this included had been only been partially successful. Contrary to this long history establishing dedicated hospitals (in 1374 a Japanese Emperor estab- of partially successful interventions using different methods in lished a smallpox hospital after repeated epidemics)15, and many different countries, the ISEP was unequivocally successful globally. different vaccination methods, as documented elsewhere in this The programme resulted in eradication of smallpox in every country volume of Microbiology Australia. Variolation, a method of expos- where case-notification was undertaken, marking the first infectious ing skin to material from smallpox pustules and thus inducing disease of humans to be eradicated via human intervention. It immunity had been employed by several cultures, and was even- demonstrated that coordinated vaccination programmes could tually introduced to Great Britain (see Professor Yenen’s accom- succeed on a global scale despite political, economic and scientific panying paper). Utilising this technique, in 1793, Haygarth barriers. Instrumental to documenting the ISEP’s success was proposed an eradication programme for Great Britain16. In 1796 Professor Frank Fenner, an Australian scientist and clinician who Edward Jenner famously demonstrated immunity in an individual was elected Chairman of the committee certifying the programme’s inoculated with a related poxvirus from a cow’s udder17. It may success, the Global Commission for the Certification of Smallpox have seemed that resolution was within grasp. However, another Eradication (GCCSE). His work had put Australia at the forefront of 184 years would pass before Fenner announced to the World Health poxvirus research, and he was closely associated with international Assembly that smallpox had been eradicated. In the intervening MICROBIOLOGY AUSTRALIA * SEPTEMBER 2014 10.1071/MA14043 165 In Focus period, incremental steps were made, and slowly the burden of Frank Fenner’s role in certifying smallpox eradication (as described disease was reduced. Cowpox was gradually replaced with vaccinia in interviews in 1992–1993 with Dr Max Blythe) was to meet over as the vaccine. Freeze dried vaccine was introduced, and national three successive years, organising 21 international commissions that vaccination programmes begun by many nations. By 1950, although visited all countries where smallpox had been endemic since 1967. in decline, the disease remained endemic in areas of Central and The goal was to obtain signatures from every country verifying that South America, Africa, and Asia1. In 1958, Professor Victor Zhdanov, no cases of smallpox had occurred, thereby certifying disease the chief of Soviet delegation to the World Health Assembly pro- elimination. In retrospect, it is interesting to see the degree of posed a global eradication programme that resulted in resolution cooperation between the USA and USSR, with meetings of the WHA11.54 planning eradication within 10 years1. While some monkeypox committee in Moscow in 1969 in the midst of the cold success was achieved (for example, China), eradication was not war. It is also interesting that, similar to recent early, mistaken achieved within the ambitious timeframe, in part due to resource diagnoses for other viruses, Russian investigators mistakenly be- constraints. In response, in 1967 the World Health Organization lieved that white-pock variants of monkeypox were identical to (WHO) launched the IESP with the renewed objective of global vaccinia virus. They were not, and were subsequently shown to be eradication, with the Smallpox Eradication unit headed by Donald laboratory contaminants, again as has occurred with some recent Henderson from 1966 to 1977. emerging viruses. Financial support was provided through a special budget of US$2.4 Although it is not the intention here to revisit all of the considerable million per annum to the IESP, a figure overshadowed by the achievements of Frank Fenner, it is important to note that his estimated US$315 million spent during the life of the programme18. training, interests and skills made him an ideal candidate for the Meanwhile smallpox remained endemic in 31 countries, with position as Chair. He was predominantly a scientist of viruses 10–15 million cases of annually19. Decisions were made to reduce including poxviruses of humans and animals, but was trained the risk of early failure1. Reference centres were established for originally in medicine, with a research degree early in his career vaccine, and a quality programme established to ensure all vaccines (1942). During World War II, he served as an officer in the Australian used (including those produced in endemic countries) met strict Army Medical Corps in Australia, Palestine, Egypt, PNG and Borneo. standards regarding potency, stability and purity. The approach This included clinical work, as well as specific studies of malaria, and involved systematic vaccination, with rigorous surveillance and as pathologist in a general hospital. He had interests and training in containment, whereby cases were reported weekly and special tropical medicine,and duringsmallpox certification, he visited many containment teams targeted outbreaks20. Rewards were paid to of the tropical countries to review eradication first hand. Further, he those who identified new cases21. This approach uniquely engaged undertook research in different institutes – the Walter and Eliza Hall and empowered local staff, whilst also minimising depletion of Institute in Melbourne (studying mousepox), the Rockefeller in New vaccine. York (studying tuberculosis), and the John Curtin School of Medical Research in Canberra (studying myxoma, then as Director gaining Between 1975 and 1977, smallpox had been contained to Bangla- management experience). He was also the President of the Inter- desh, Ethiopia, Kenya, and Somalia. The last case from Ethiopia was national Committee on Taxonomy of Viruses (1970–1975), and his on 9 August 1976, from Kenya on 5 February 1977, and from Somalia attention to detail combined with writing skills contributed to this on 26 October 1977 (the last wild case)22,23. At this time, the GCCSE work, and the subsequent publication 7 years following eradication was established to certify the eradication of smallpox, with Frank of the definitive text on smallpox history and eradication – Smallpox Fenner elected Chair. Eradication was defined as no cases from a and its eradication. This unique combination of basic science, country for 2 years21. Between inception of the GCCSE and 8 May research, medical, managerial, and specific knowledge of pox- 1980 when the final report was presented to the World Health viruses made him an ideal Chair for the GCCSE, that culminated Assembly, ongoing field studies, many of which Frank Fenner in his announcement to the World Health Assembly that smallpox directly participated in, were performed to ensure no further cases was eradicated. occurred24. It was only after this work had been completed that the GCCSE was able to report: ‘1. Smallpox eradication has been It is possibly less well known, but equally relevant, that Professor achieved throughout the world. 2. There is no evidence that Fenner was a key member (and subsequently Chair) of the com- smallpox will return as an endemic disease’. The GCCSE made 19 mittee examining whether animal viruses, specifically monkeypox