Variola is one of a group of closely related viruses, but humans are its only natural host.
People gathered here will recognize many of the features that made smallpox a candidate for eradication, because most of them apply also to rinderpest, excepting only perhaps only the heat stability of the vaccine, which for smallpox vaccine is exceptional.
The history of smallpox control goes back many centuries. Variolation – inoculation with scab material from a mild smallpox case – was known in China in the fifteenth century and spread to Arabia and Africa. It was introduced into Western Europe from Constantinople in the early 18th century by Lady Mary Wortley Montagu – wife of the British ambassador to the Ottoman Empire – with great success. The problem with variolation was the “vaccine” was the same as the disease virus, and the major complications were actual smallpox, and the initiation of new smallpox outbreaks in the community. Variolation was replaced in the 19th century with vaccination – inoculation with different but related viruses – cowpox and vaccinia viruses – which did not cause major disease, did not cause outbreaks, and gave life-long protection. This was the origin of the term vaccination.
After the 19th century, continuous research and development improved the production and administration of vaccine, so the WHO was able to undertake the massive task of global eradication in the second half of the last century.
This slide gives a brief looks at milestones in the eradication campaign, including the last case in India, which had suffered greatly from smallpox in the 20th century, and the last endemic case globally in Somalia in 1977. I have highlighted the very last case in the world, in 1978, precisely because it was NOT endemic. It was the result of a laboratory accident that occurred after natural transmission was halted globally. I don’t want to denigrate the scientists in that laboratory in Birmingham, they were dedicated people who had contributed significantly to the eradication campaign, and the accident was just that – an accident. But it is one of the major lessons we learn from the smallpox eradication campaign – that once the disease is eradicated, the remaining stocks of the virus pose the greatest risk of re-emergence. These stocks, which are under human control, can undo all the hard work of the men, women and organizations that worked so hard to save humanity from this scourge. This is as true for rinderpest as for smallpox. It will be true for polio, and eventually also for PPR. How we handle, and regulate, rinderpest virus stocks is critical to how well we can protect ourselves from a re-emergence, and it will significantly inform the handling and fate of polio and PPR virus stocks when those diseases are eradicated.
Only an organization with the reach and reputation of WHO could have made this work, and it was exhaustive, with over 850 virus laboratories written to, of which 75 had variola virus, over all WHO regions.
I move now onto the sequestration of variola virus stocks after eradication. The stocks are centralized in just two locations in the world. This was not originally the case, the number of laboratories holding the virus was gradually reduced in the run-up to, and following, certification of eradication. This was not least because the accident in the UK focussed attention on the risks associated with multiple repositories. There were 8 laboratories in Europe holding the virus in 1978; by 1979 this had reduced to 3. These reductions were voluntary on the part of individual member states. They were made at the request of WHO, but as the result of considered decisions by individual member state governments.
There is no doubt that reduction in the number of holdings has reduced the risk of an accidental release, but we should be clear on one point. We should not wait for an accident with rinderpest to persuade us that the number of laboratories holding rinderpest virus needs to be reduced. We must take a good hard look at food security, and risk to our neighbours as well as ourselves, to inform decisions.
As everyone here is aware, FAO and OIE have put considerable effort into raising awareness of the risks posed by unregistered stocks of rinderpest virus, and asking governments, laboratories and scientists if they are aware of any stocks under their control. This follows the example of the WHO with variola virus, but even so, some variola stocks escaped the attention of those holding them. There is no indication that forgotten stocks were deliberately hidden, the evidence is that they were genuinely forgotten, almost certainly because the person who had stored them had moved elsewhere, retired, or possibly even died. As recently as July 2014, forgotten ampoules of variola virus were found while clearing a cold room in Bethesda, USA. The ampoules were rapidly and appropriately transported to the WHO repository at the CDC in Atlanta, where the virus was ascertained to be still viable. After that it was destroyed under witness by the WHO. So I cannot emphasize enough that member states need to be rigorous in responding to requests from FAO and OIE to confirm the existence or not of stocks of the virus.
But the reduction in number of repositories holding variola virus is not the only important factor in maintaining global freedom from smallpox. Equally important is the oversight of the repositories by the WHO. It is very important for member states to be assured that stocks of the virus are held in a manner that is totally committed to minimizing the risk of accidental release, and that the repositories have appropriate resources to accomplish this for the long term. This is somewhat burdensome. The laboratories are expensive to maintain, and require long-term financial commitment. Also, in the WHO model, the repositories must bear the cost of the biennial inspections, which are comprehensive and time consuming. And the reports of the inspections are published on the WHO website. But all this is necessary to ensure that the virus is handled properly, because an accidental release has consequences for all member states – indeed, confirmation of a single case of smallpox would constitute a WHO global emergency. This is a huge, and onerous, responsibility for the countries that maintain repositories.
I come now to the rationale for retaining variola virus, after the eradication of smallpox. There has always been international debate on the rationale for retaining stocks of the virus, and there are voices raising genuine arguments on both sides.
Smallpox is a human disease, killing people not animals, and the procedures for controlling an outbreak are necessarily different from those required for controlling an animal disease. In particular, there is a need for medicines to help people who have contracted the disease but have not been vaccinated. This requires antivirals, and a major rationale for maintaining variola stocks has been to facilitate the development of antivirals.
The traditional smallpox vaccine has known side-effects and is particularly dangerous for those who are immunocompromised, for whatever reason (e.g. cancer patients, HIV patients, hereditary immune deficiency patients), and a further reason to maintain the virus stocks has been to facilitate the development of safer vaccines.
And importantly also, it has been necessary to produce modern diagnostics for smallpox, and these have required validation against variola virus.
With the possible exception of diagnostics, these arguments do not apply to rinderpest.
Smallpox occupied an ecological niche in human populations, and it kept other, related viruses out of that niche. The eradication campaign artificially moved the vaccine into the niche, and expelled variola virus. Then, because the vaccine could not continue in the niche without human action, the niche became empty, and available. What we have seen in the passing years is increased incidence of monkeypox in humans, as the monkeypox virus moves into the orthopoxvirus niche in humans. The emergence of human monkeypox was unanticipated because it had not previously been able to compete with smallpox in the human niche, and the possibility of a similar situation arising with a relative of rinderpest should not be ignored. It is much less of a concern than re-emergence of rinderpest itself, but it is not something we can ignore, especially in the early years after eradication.
I could have shown this slide at the beginning, but I decided it would be more informative here, towards the end of my talk. What we are discussing in these three days matters. Eradication of a disease like rinderpest leads to a cessation of vaccination, and this leads inevitably to the loss of immunity in the population. A re-emergence of rinderpest has the potential to be more devastating than the worst outbreaks before eradication. The photos here were taken from the 2001 foot-and-mouth disease outbreak in the UK in 2001, which lead to the mass slaughter of sheep, pigs and cattle, with monetary losses estimated at around 12 billion pounds. You can see the scale of the slaughter in this aerial photo, with these large agricultural buildings almost dwarfed by the fire trenches dug to burn the carcasses. It stopped the export of susceptible animals and animal products until the country was again certified as free. It shut down internal transport of animals within the country, and had knock-on effects on other industries when large sections of the countryside were effectively quarantined. It even postponed a general election, because voters could not attend polling stations in affected areas. We should not underestimate the sheer cost to a country of being the only country with an outbreak in a region that is otherwise free from a disease. And for countries or regions where cattle are vital for food security and/or economically or culturally important, the hazards of re-emergence of rinderpest are almost too awful to contemplate.
So in summary, identification of lab’s holding stock is essential. If you don’t know where it is, you can’t look after it. And if only a few people know where it is, then eventually no one will remember it is there.
Oversight and regulation of stocks is essential. Accidents have occurred with smallpox, and the last one could have undone all the work of the eradication campaign.
We must be vigilant for the emergence of related viruses, whether known or unknown.
Importantly we must also be aware of the possibility of re-synthesis of the virus. The WHO was concerned about this for smallpox as far back as 1980, and it is no less an issue for rinderpest. This is why all research with the virus must be regulated in the post-eradication era, and the wider scientific community must be aware of that regulation.
And lastly, diagnostic methods and disease surveillance must keep up-to-date with changing technology, as that technology changes in the regions that are most vulnerable.
Lessons learnt from smallpox eradication and post-eradication strategy