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Smallpox was eradicated in 1980, but the virus still exists in WHO controlled depositories. Edward Hammond maintains that stocks should be destroyed to prevent the disease re-emerging, but John Agwunobi insists further research is essential for global security
NO: Smallpox, one of the great killers in human history,1 remains dangerous. Malicious use of smallpox remains a threat because almost certainly clandestine stocks exist.2 3 4 Despite the 33rd World Health Assembly's endorsement of the recommendation that all countries should destroy all live smallpox virus stocks, or transfer them to World Health Organization authorised, maximum containment repositories, we cannot be certain this is the case.2 3 4 The United States believes that the global community should avoid any action that would jeopardise the important research on Variola virus conducted at the two authorised repositories of the virus. Destroying the virus would be irreversible and short sighted, for the reasons spelt out below.
Smallpox poses an important public health risk, particularly since the population has no immunity and there are no safe, effective treatments. Variola virus released by mistake or intentionally would be a public health emergency of international concern, as the revised International Health Regulations (2005) recognise.5 It would require a coordinated international response because modern, rapid, mass movement of people and multifocal outbreaks could result in smallpox spreading widely.2 3 4 6 In part because of this threat, the World Health Assembly authorised retention of the official stocks of live virus in 1999 and again in 2002.
To mitigate the threat of smallpox, scientists in the US and elsewhere, under the auspices of WHO, are cooperating in open, time limited research with live Variola virus. An international expert WHO advisory committee reviews the research and reports annually on its progress.7 The research agenda focuses on the need to improve diagnostics and to develop antiviral drugs and safer, effective vaccines against smallpox.8
Vaccination was central to the successful eradication of smallpox.2 3 4 In the past, smallpox vaccines were made with live Vaccinia virus. However, these vaccines are contraindicated for various groups of the population because of illnesses such as cancer, HIV, heart problems, and dermatitis or treatment with immunocompromising therapies.9 Adverse reactions to the vaccine in these people can be life threatening.9 10
Some have argued that access to live Variola virus is no longer needed for research on vaccines; however, members of the WHO advisory committee on Variola virus research disagreed on this in the 2004 and 2005 recommendations.7 Continued studies are essential to verify that newer, safer vaccines can neutralise live Variola virus, which is a direct indicator that antibodies are conferring virus specific immunity.11 Added assurance that a replacement vaccine confers protection could come from studies with an animal model.12
Currently, we have no effective antiviral drugs for smallpox infection. The basic research required to develop drugs to treat smallpox was largely discontinued when the disease was eradicated. Little work was done until 1995, when the possibility of secret stocks led US scientists to begin searching for antiviral drugs. Since then, scientists have devised assays to screen for promising compounds. But even with hundreds of laboratories at work on drug development, producing the first drug for a disease takes years, and because of the restrictions on Variola virus research, only the two WHO authorised laboratories can use live Variola virus for drug development. Nevertheless, scientists have developed three candidate drugs and have been given regulatory approval to begin evaluating their safety in humans and efficacy in primate models.
The US Food and Drug Administration requires proof that a drug is effective against live Variola virus before it will give it a license. This is because some drugs have shown activity against surrogates such as monkeypox virus but reduced or no activity against Variola virus.13 The process to complete the necessary studies to convince national drug regulatory agencies that such drugs are safe and effective can be lengthy.
Since healthcare professionals have not seen cases of smallpox for almost 30 years, it is likely early cases would be misdiagnosed or undiagnosed. In the event of an outbreak, public health officials will need better laboratory diagnostic abilities to enable early, accurate recognition and response efforts. In the report of its seventh meeting, the WHO advisory committee notes that reference laboratories might need more than one diagnostic test reliably to distinguish Variola virus infection from infection with other orthopoxviruses.14 Accurate diagnosis is especially important given the serious consequences of misdiagnosing smallpox. Although various laboratories have developed several new diagnostic tests, they require validation.14
The development and licensure of better diagnostics, safe and effective drugs, and safer vaccines against smallpox will take time. Setting an arbitrary date to complete scientific research is premature and short sighted. As long as there is a possibility that terrorists could use smallpox to wreak havoc, WHO supervised research must continue so scientists can develop the tools needed to combat an outbreak of smallpox effectively and efficiently.
Competing interests: None declared.