Experts: Regulatory issues are main reason for keeping smallpox virus


May 18, 2011 (CIDRAP News) – When the World Health Assembly (WHA) considers the fate of the remaining stocks of smallpox virus this week, the debate is likely to be framed in part by a report from a group of independent experts that says the only strong reason for keeping the virus is to satisfy strict regulatory requirements for new vaccines and antivirals.

The experts, who were commissioned by the World Health Organization (WHO), recommended in a report released quietly last December that researchers and regulatory authorities should work together to find new ways to test smallpox vaccines and antivirals so that the remaining stocks of variola (smallpox) virus can be destroyed.

The panel "noted with concern that the only compelling scientific and public health reason to keep live variola stocks is to meet current restrictive regulatory requirements for vaccine and drug development," the report states. "It, therefore, recommends that researchers and regulatory authorities meet and jointly define future alternative models for testing vaccines and drugs against variola virus, in preparation for destruction of variola stocks."

The report goes on to suggest identifying a "limited number of strains of variola virus for such testing, and to retain only these for this limited use."

The expert panel, called the Advisory Group of Independent Experts (AGIES), made the recommendation after studying a lengthy report by a WHO committee on progress in smallpox research and development.

That review, by the WHO's Advisory Committee on Variola Virus Research (ACVVR), said researchers made significant progress in developing vaccines and antivirals from 1999 to 2010, and it suggested that the continued use of variola virus in testing of these products would permit greater confidence in their efficacy. At the same time, the committee noted that it's now technically possible to recreate the virus from scratch, since its genome has been sequenced.

Smallpox as a disease was eradicated in the 1970s, but supplies of the virus have been kept by the United States and Russia since then. Research on vaccines and antivirals has continued out of concern that terrorists might have secret supplies of the virus and try to use it in biological attacks.

The WHA, composed of delegates from all WHO member countries, agreed in 1996 that the virus stocks should be destroyed. But the assembly has postponed calling for that step four times in response to the argument that more countermeasures research was needed. The delegates are scheduled to take up the issue on May 20.

US urges keeping stockpiles
In recent months experts have published a number of articles arguing for and against destroying the virus stocks. But the US and Russian officials who hold the real power to keep or destroy them have signaled that they're not ready to get rid of them. The virus samples are held at the US Centers for Disease Control and Prevention (CDC) in Atlanta and Russia's State Research Center for Virology and Biotechnology in Novosibirsk.

Two days ago US officials at the WHA meeting introduced a resolution to retain the virus stocks, US Health and Human Services (HHS) Secretary Kathleen Sebelius said in remarks she prepared for a press briefing yesterday.

"We're concerned that the smallpox virus may still exist outside the official repositories and could be released unintentionally or used as a bioweapon," Sebelius said. "The WHO's own review of the smallpox research program concluded definitively that additional research is needed to protect public health should this occur."

Sebelius said keeping the virus samples is necessary to continue the research, whose results she vowed the United States would share widely. She added, "Let me be clear: We are committed to the eventual destruction of the virus stocks."

Sebelius told reporters that the virus stocks would be kept for at least another 5 years, according to an Associated Press report on her press conference yesterday. Other recent reports have said that Russian officials likewise favor keeping the virus samples.

The WHO has an emergency stockpile of 32.6 million doses of smallpox vaccine stored in Switzerland, according to an online report related to the WHA meeting. Nearly all (92%) of the stockpile is "second-generation" vaccine. Five member states—France, Germany, New Zealand, the United Kingdom, and the United States—have pledged another 31 million doses to the WHO if needed.

Countermeasures progress
The ACVVR report, which was released with the AGIES review in December, notes that progress has been made on two safer smallpox vaccines and three smallpox antiviral drugs.

The conventional smallpox vaccine, consisting of live vaccinia virus, a relative of variola, carries serious risks for some people, such as those who have eczema or weak immunity. Researchers, the report notes, have developed vaccines using attenuated vaccinia virus: modified vaccinia virus Ankara (MVA) and LC16m8. The US government has ordered 20 million doses of MVA (Imvamune) from Bavarian Nordic for the Strategic National Stockpile.

The ACVVR report also notes that three antiviral drugs look promising for smallpox. The drugs—cidofovir, ST-246, and CMX001—inhibit variola replication in cell culture and multiple animal models. CMX001 is a cidofovir "prodrug" that can be given orally.

SIGA Technologies, maker of ST-246, announced last week that it was awarded a $433 million contract to provide 2 million doses for the US stockpile.

Keeping samples to enhance research
The ACVVR's review of smallpox research says that smallpox vaccines can be tested against other orthopoxviruses in animals but that tests against the smallpox virus itself would provide better assurance of their effectiveness. The report was prepared by leading variola researchers.

"Since smallpox has been eradicated, the efficacy of new generation vaccines will need to be tested using poxviruses related to variola virus in animal protection studies, and safety and immunogenicity studies in humans," the report states. "However, confidence in the ability of these vaccines to protect against smallpox would be increased by use of live variola virus for in vitro neutralization tests and non-human primate studies."

The report takes a stronger stance on using variola virus in testing of antivirals: "Because smallpox . . . was eradicated by mass vaccination, the effectiveness of these drugs can only be demonstrated using variola virus-infected animal models in non-human primates."

The ACVVR was less certain about the need to use variola virus to validate new diagnostic tests for smallpox. The report says many diagnostic assays, most of the using nucleic acids, have been developed, but none have been approved for clinical use. "The possible need for live variola virus for regulatory review of assays is being discussed at the time of writing," it says.

While suggesting that keeping the virus stockpiles would enhance countermeasures research, the report also points out that it's now possible to synthesize the virus. Nearly complete genome information is now available for 48 geographically distinct variola isolates, it says.

"It is now technically possible to synthesize the entire variola virus genome from scratch, using only publicly available sequence information, and to reconstitute infectious virus using currently available techniques of molecular biology," it adds.

AGIES takes different view
The AGIES report does not call for immediate destruction of the virus stocks, but the independent experts clearly saw much less of a case for keeping them. The 10 experts were from India, Oman, Brazil, China, Thailand, South Africa, Kenya, Australia, Germany, and Canada.

The experts expressed doubts about the value of using variola virus to try to duplicate human smallpox in monkeys, saying this has led to "highly artificial models and outcomes that do not resemble human disease" and is also impractical, given the stringent regulations governing such research.

"Therefore, AGIES felt that it may be more appropriate to focus on improving the animal models that use infection with other orthopoxviruses," such as monkeypox, cowpox, rabbitpox, and mousepox viruses, "since these appear to be appropriate and adequate surrogates of human variola virus infection," the report says.

It adds that the only reason for trying to develop animal models of smallpox is "to meet the current stringent regulatory requirements." The experts believe that "a more productive approach would be for the regulatory requirements for vaccine and drug approval for variola virus infection to be reconsidered, given that human infection with the virus no longer occurs."

On the other hand, the report says that the ACVVR's argument that variola virus may be indispensable for testing antiviral drugs "appears reasonable, at least for in vitro testing." The report summary states, "Assuming that regulatory issues around vaccine and drug testing are resolved, the only indication for use of live VARV [variola virus] is to test the efficacy of drugs in vitro."

In other judgments, the AGIES said live variola virus is not needed for further development of diagnostic tests and there is no public health need to sequence any more virus isolates. The group also said research on safer smallpox vaccines should continue.

On security issues, the AGIES report:

  • Calls for new strategies to address the potential for making of the variola virus from scratch, including adoption of national policies
  • Says the WHO should seek updated reports from all countries on their stocks of variola virus DNA
  • Recommends that US and Russian authorities report to the WHO on which segments of variola DNA have been distributed to which laboratories

See also:

AGIES report "Comments on the Scientific Review of Variola Research, 1999-2010"

WHO ACVVR report "Scientific Review of Variola Virus Research, 1999-2010"

Report of the ACVVR's 12th meeting in November 2010

May 17 prepared remarks by HHS Secretary Sebelius

Report by the WHO Secretariat to the WHA on smallpox stocks issue

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