A virus lives on

The World Health Assembly decides to retain existing stocks of the smallpox virus for continued research into new vaccines, without setting a future date for their destruction.

IN a controversial move that could have far-reaching consequences, the 55th World Health Assembly (WHA) on May 18 went back on its six-year-old resolution to destroy the current stockpiles of smallpox virus variola and decided to retain them indefinitely for international research. This reversal is a clear fall-out of the heightened fears of bioterrorism built up chiefly by the United States in the wake of post-September 11 anthrax attacks.

Endorsing the recommendation made by the World Health Organisation's (WHO's) 32-member Executive Board in January, the WHA decided to retain the existing stocks of variola virus to allow continued research into new vaccines and anti-viral drugs against smallpox "on the understanding that steps should be taken to ensure that all approved research would remain outcome-oriented and time-limited and periodically reviewed". Since smallpox was effectively eradicated in 1979, stocks of live virus exist only in two high-security laboratories - the Centres for Disease Control and Prevention (CDC), Atlanta, U.S., and the Russian State Centre for Research on Virology and Biotechnology (VECTOR), Koltsovo, Novosibirsk.

The last case of naturally occurring smallpox was in Somalia in 1977 and in 1980 the WHO declared the disease to have been completely eradicated globally. One of the key factors that enabled eradication of smallpox, the disease that had afflicted mankind for centuries and has no treatment even today, through an intensive worldwide immunisation campaign between 1967 and 1979, is the fact that the only known host of the variola virus is the human body.

At its January 14-18 meeting, the WHO board accepted the advice of its Director-General Gro Harlem Brundtland and the advisory committee for variola virus research that ongoing research would not be completed by end 2002 - the deadline set in 1999 for the destruction of virus stocks. Brundtland had said: "The research programme should be completed as quickly as possible and a proposed new date for destruction should be set when the research accomplishments and outcomes allow consensus to be reached on the timing of destruction." Given the history of the issue, it is unlikely that consensus would ever be reached.

Indeed, in a speech to the board the U.S. Assistant Surgeon-General Kenneth Bernard said that continued research into improved vaccines was vital in the wake of the September 11 attacks and subsequent anthrax scare. "We regard the potential release of smallpox as a critical national and international security issue... We are currently making progress in research designed to develop new tools against smallpox... The need for new drugs and vaccines is particularly acute in parts of the world with large populations of immuno-suppressed people such as those with HIV/AIDS for whom the current vaccine would be potentially lethal." Russia too echoed these views which found all-round support among the 32 members, including Japan, which had been earlier among the front-ranking opponents, along with Brazil, Cuba, India and China, to the idea of retaining the stocks.

China, which like India is not currently a member of the board, was the lone voice of dissent. It wanted a final deadline for destruction without any excuses for further delay. Interestingly, in contrast to its the earlier stand on the issue, the Indian representative to the meeting apparently sat quietly through the deliberations. India's current disposition towards the U.S. would seem to have dictated its endorsement of the WHO's policy reversal.

Since Edward Jenner discovered it in 1796, the conventional vaccine is based on live vaccinia, the causative virus of cowpox. It is estimated that the current world vaccine stock is about 110 million doses, including 500,000 doses maintained by the WHO at its Collaborating Centre for Smallpox Vaccine in Bilthoven, the Netherlands. The centre also holds the seed virus used to produce the vaccine.

Since the vaccine itself does not require the variola virus, the Global Commission for the Certification of Smallpox Eradication recommended in December 1979 that any remaining stocks of the virus (isolated from infected blood, tissue samples) should be destroyed or transferred to one of the four WHO-designated reference laboratories in the U.S., the U.K., South Africa and Russia. This was endorsed by the WHA in May 1980. However, by the end of 1983, all variola stocks in South Africa were destroyed and those in the U.K. were transferred to the CDC.

Consequently, today all known stocks of the virus have been consolidated at the two WHO collaborating centres at the CDC and VECTOR. The CDC is a repository of 451 smallpox virus samples and the Russian collection contains about 150 samples. Of course, there is no guarantee that somewhere in the world there is not another potential source of virus - the corpse of a person who died of smallpox and is buried in the Arctic or Siberian permafrost, or a virus vial unknowingly retained in some laboratory, or samples deliberately retained by some country out of a suspicion of the motives of the Russian and U.S. governments or out of intentions of biowarfare.

To clear the way for the subsequent destruction of these stocks, the two laboratories undertook cloning and sequencing of deoxyribonucleic acid (DNA) fragments of selected virus strains under high-containment biosafety level 4 (called P4) conditions. Since 1983 such clones have been kept in a few laboratories in the U.K., the U.S., Russia and South Africa. Because the cloned DNA fragments had the potential to create a smallpox-like virus by recombination with vaccinia or monkeypox viruses, the WHO required the registration of all clones of variola DNA and restricted their use and distribution. Arguing that the clones obviated the need for the infectious virus for reference purposes, the WHO Ad Hoc Committee on Orthopoxvirus Infections resolved in 1986 that the virus stocks be destroyed "if no serious objections were received from the international health community".

At the May 1990 WHA, the U.S. declared that technological advances now allowed the entire virus genome to be sequenced within three years and offered to destroy all the virus stocks at the CDC. In December 1990, the WHO Ad Hoc Committee on Orthopoxvirus Infections endorsed the proposal for sequencing of the virus genome jointly by the U.S. and Russia. It also decided that the remaining virus stocks be destroyed by December 31, 1993, provided sufficient sequence information was available and serious scientific objections were not raised. By December 1993, Russian and U.S. scientists had successfully sequenced the genomes of two strains of variola major - Bangladesh 1975 and India 1967 - and one strain of variola minor - Garcia 1966. (Variola minor is a milder form of the virus with a much smaller mortality rate of 1 per cent as compared to 30 per cent in variola major.) At present 10 different strains of variola have been sequenced completely.

While the larger ethical issue of whether humanity has the right to exterminate a living species deliberately does pose a dilemma, purely from a research perspective, the scientific community has been divided on the issue and has debated on it extensively since 1991. The proposed destruction by 1993-end did not come about because of this division of opinion among researchers and public health specialists. Those supporting destruction argued that once sequencing is complete, the virus itself is no longer necessary and, once destroyed, smallpox ceases to be a potential threat to public health, be it from accidents, military use or terrorism. On the other side of the question, it was argued that having the virus in its functional form offers much more information for science than the mere record of its genetic code can possibly impart. It was further held that the smallpox virus has evolved along with its host, humans, and its strategies to evade the human immune system are very specific, but are only beginning to become known.

The 1996 WHA adopted a resolution recommending that destruction should take place on June 30, 1999. The three-year period was given to achieve a broader consensus before a final decision was taken. In 1998, a WHA survey of the positions of its 191 members revealed that of the 79 countries that responded, 74 were in favour of destruction. Russia was against it while the U.S., the U.K., France and Italy were undecided. Between 1990, when the U.S. offered to destroy its stocks - and so did Russia - and 1998 there had been a change in their respective perspectives. In January 1999, the Ad Hoc Committee also found itself lacking in unanimity over the issue.

Two factors were responsible for the change in the U.S. position. One, a disclosure by a Russian defector, Ken Alibek, former deputy director of the Russian Bioweapons Programme, that following termination of mass vaccination, and in the atmosphere of the Cold War, Russia had developed facilities to produce the virus in tonne quantities in a month and had even weaponised the virus. Two, a 1998 report by the U.S. National Academy of Sciences' Institute of Medicine (IOM), which assessed the scientific need for live variola virus without, however, addressing the costs that may be involved in such research and weighing the risks of release of the virus and its re-emergence.

"The most compelling reason for long-term retention of live variola virus stocks is their essential role in the identification and development of antiviral agents for use in anticipation of a large outbreak of smallpox," the IOM report said. It also said that live virus would be necessary for the development of novel types of vaccine. It also favoured live or "replication-defective" virus for the study of variola pathogenesis and the response of the human immune system. The smallpox virus has very different biological properties. If this could be understood, it would reveal more about the human immune system, it was argued.

Accordingly, in April 1999, a month before the 52nd WHA, President Bill Clinton sought a delay in the proposed destruction of the virus. The White House statement said that the President's decision was based on a consensus recommendation of his advisers, reflecting agreement among all departments, and also the fact that the administration cannot be certain that destruction of the declared stocks will eliminate all the virus in existence. U.S. media reports then quoting officials said that the U.S. believed that Iraq, North Korea and Russia had bioweapon programmes based on the smallpox virus. Indeed, Donald A. Henderson, Director of the Johns Hopkins Centre for Civilian Biodefence Studies, who directed the WHO smallpox immunisation campaign and who is a former adviser in the Clinton administration, believes that a desire to be able to retaliate in the event of a biological attack was behind the administration's reversal which he claimed emanated from the Defence Department.

The 1999 WHA, influenced by the U.S. stand, agreed by consensus to the "temporary retention, up to but not later than 2002, of the existing stocks of variola virus for the purpose of further international research into antiviral agents and improved vaccines, and to permit high-priority investigations of the genetic structure and pathogenesis of smallpox." While affirming that the final elimination of all variola virus remained the goal of the WHO and all member-states, the resolution said that "any such research shall be conducted in an open and transparent manner only with the agreement and under the control of WHO."

In a perceptive article written in October 2001, Henderson and Frank Fenner analysed the various research priorities identified by the expert group and argued why the deadline set by the 1999 WHA should be adhered to. They looked at the development in the research areas identified: the development of a more attenuated, less reactogenic vaccine; and the development of an antiviral drug that could be used in the treatment of smallpox. An associated important area was the evaluation of a suitable animal model in the absence of any known non-human host for smallpox.

Two candidate vaccines, which produced satisfactory antibody levels but produced less side effects in animal tests, had been identified. But, for obvious reasons they could not be tested in an area where smallpox was endemic. Therefore, an assurance of their efficacy was no longer possible. From that perspective, administrations would procure more of the proven vaccine thus foreclosing the rationale for further research on modified vaccines, they argued. "It would seem appropriate that future research efforts be directed at mitigating the possible effects of adverse reaction through the use of anti-vaccinial drugs or monoclonal antibodies," they argued.

Questioning both the feasibility and wisdom of pursuing the development of antiviral drugs, Henderson and Fenner pointed out the high cost (about $500 million, which no government was ready to invest) of developing a new anti-microbial drug and the fact that it would take eight to 10 years of research and development to bring it to the market. Added to this would be the large sums of money that would be required to build up and maintain stockpiles of reasonable size of the drug for possible future use. Secondly, here too there would be a lack of proven efficacy of the drug, however effective it may appear in a surrogate host with a surrogate virus in the absence yet of a viable variola/monkey model. An anti-viral drug, they argued, might be more useful in preventing the disease in immune-compromised patients who would be at risk of "progressive vaccinia" disease if vaccinated. Research efforts should focus on an anti-vaccinial drug, which could be more thoroughly evaluated through animal studies, and such studies would not require retention of the variola virus, they said.

Running counter to this perspective, the WHO committee on variola virus research reported to the board that "significant components of this research, most notably refinement and use of an animal model developed in 2001 and the development of antiviral drugs, were unlikely to be completed by the end of 2002." It further stated that to study the animal model (cynomolgus monkey), further access to live variola virus was necessary after the expected 2002 destruction date. This the board endorsed, and based on this the Director-General recommended retention of stocks without setting a deadline.

An Indian expert in biological warfare, Kalyan Banerjee, former Director of the National Institute of Virology (NIV), Pune, and a former member of the National Security Advisory Board (NSAB), is furious with the WHA decision. As a dissenting member of WHO's Ad Hoc Committee, he has reasons to be furious. He feels that continuing research with the smallpox virus may enable the U.S. military to develop it as a bioweapon. In the wake of the September 11 events, the U.S. proposes to have a stockpile of 286 million doses of the vaccine by the year end, enough for every U.S. citizen. 'So where is the rationale for developing a new vaccine with live virus?" he asks, echoing the point raised by Henderson and Fenner.

Criticising the U.S.' unilateral decision to retain the stocks indefinitely, Banerjee accuses the WHO of having become a "cat's paw" in the issue. "Research does not need the live virus and there is no justification in retaining the stocks. The people of the world and the WHO worked hard to eradicate smallpox, only to leave the most potent bioweapon in the hands of the custodial powers," he said.