Tuesday, Nov 23, 2004
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By N. Gopal Raj
IN MAY 1980, the World Health Assembly jubilantly declared that "the world and all its people" had "won freedom from smallpox." For the first time, an infectious disease that was humanity's scourge for thousands of years had been successfully eradicated, and vaccinations against it could stop. Eight years later, the World Health Assembly resolved to similarly wipe out poliomyelitis.
Polio is caused by a virus that first establishes itself in the bowels. In one out of 200 people, the virus then spreads to the nervous system and causes severe paralysis, especially among infants. Those infected excrete the virus, and poor sanitation and hygiene cause its spread. Although polio cannot be cured, it can be prevented by vaccination. As a result of global vaccination campaigns, the number of polio-endemic countries fell from 125 in 1988 to just six by the end of 2003.
If everything goes as planned, the transmission of wild poliovirus could end in India, Pakistan, and Afghanistan by early next year, and Africa could follow by the end of 2005, says David Heymann, WHO's representative for polio eradication. Then each WHO region (the Americas, Western Pacific, Europe, Africa, Eastern Mediterranean, and South-East Asia) has to complete its regional certification of eradication. Three years later, the Global Certification Commission will decide whether it can certify polio as eradicated throughout the world. Such global certification of eradication could happen in 2009-2010 if things went ideally, Dr. Heymann told The Hindu .
Even when such certification of eradication is issued for polio, there would be an important difference from smallpox eradication. The certification would only be that wild polioviruses had been eliminated. The very weapon that WHO has relied on in its global campaign the oral polio vaccine (OPV) has become an important factor in creating uncertainty over when all polioviruses can be eradicated. Developed by Albert Sabin, OPV is made from live, but weakened, strains of the poliovirus. OPV was "nearly ideal" for use in polio eradication, observed Olen Kew and fellow scientists in a paper published in the Bulletin of the World Health Organisation. OPV was easily administered, which facilitated its widespread use, induced intestinal immunity that helped recipients resist infection, and provided durable immunity. Moreover, the live viruses in OPV could spread to unvaccinated contacts and immunise them as well.
But viruses that use RNA (ribonucleic acid), rather than DNA for their genetic material mutate more rapidly and therefore evolve much faster than DNA-based organisms. Polioviruses are among the most rapidly evolving of all RNA viruses, point out Dr. Kew and the other scientists in their paper. Genetic analysis has shown that the attenuation of the polioviruses used in OPV was the result of just a few mutations in the viral genome. "After ingestion, OPV replicates in the human intestine, with the generation of many mutants" and some of these mutants could possess the neurovirulence of wild polioviruses, observed Neal Nathanson and Paul Fine in a commentary published in the journal Science in 2002. A high proportion of the children given OPV, "perhaps 30% or more," would excrete revertant strains that are called vaccine-derived polioviruses (VDPVs), they say.
Such mutant polioviruses can cause what is termed `vaccine-associated paralytic polio' (VAPP) in children who have been administered OPV. Although over 30 per cent of OPV recipients excrete VDPVs of enhanced virulence, VAPP occurs only at a rate of approximately one case for every 750,000 to one million children receiving their first dose of OPV, say Bruce Aylward and Stephen Cochi in a published paper. According to them, the global VAPP burden had been estimated at 250 to 500 cases annually. But T. Jacob John, a leading virologist formerly with the Christian Medical College (CMC) at Vellore and a person who has been closely involved with India's polio eradication effort, believes that a realistic estimate could be as high as 400 to 800 cases worldwide each year, with 100 to 200 cases a year in India alone.
In recent years, it has turned out that vaccine-derived polioviruses can hold even greater dangers than causing VAPP. After more than ten years of being free of polio, the Caribbean island of Hispaniola reported outbreaks of the disease in the summer of 2000. Genetic analysis soon showed that the polio was not caused by wild polioviruses but had originated with OPV strains used for vaccination. "The outbreak VDPV had recovered two of the most important biological properties of wild polioviruses: the capacity to cause severe paralytic disease in humans and the capacity for extensive person-to-person transmission," remarked Dr. Kew and other researchers in their paper in Science on the Hispaniola outbreak. These strains that more closely resemble wild polioviruses have been termed `circulating vaccine-derived polioviruses' (cVDPV). After Hispaniola, cVDPV outbreaks were reported from the Philippines and Madagascar, and evidence of past cVDPV outbreaks have emerged in Egypt, Poland and the former Soviet Union. In all these cases, it was found that poor hygiene and low vaccine coverage had created conditions where VDPVs easily infected unvaccinated children. As the VDPVs passed from child to child, they gathered virulence by mutating and swapping genes with other viruses.
There is an alternative to OPV `inactivated poliovirus vaccine' (IPV). Jonas Salk showed that when wild polioviruses grown in culture were killed and administered as an injection, it was a highly effective vaccine. Since the vaccine contained only dead viruses, it could not produce vaccine-derived viral strains. In April 1955, IPV became the first polio vaccine to be licensed, pre-dating OPV by some years. However, after OPV became available, its perceived advantages (mentioned earlier) and lower cost led to OPV becoming popular. In 1988, only Finland, France, Iceland, the Netherlands, Sweden and Denmark used IPV. But after the dangers of VAPP became evident, over 30 countries, including most of the developed nations, now use IPV, sometimes in combination with OPV.
The Global Polio Eradication Initiative was based on the assumption that all vaccination could stop once wild poliovirus circulation had ceased, observed Dr. Fine and others in a paper published in the Bulletin of the WHO. This expectation, in turn, was based on an assumption that the transmissibility of OPV viruses was limited and that these viruses would not persist long after OPV vaccinations ceased. "It now appears plausible that OPV-derived viruses will not disappear from the world on cessation of OPV vaccination in poor hygiene settings. Whether they might so disappear if such populations were to shift to IPV has not been demonstrated, but is a possibility that needs to be explored," they remarked.
"Today it is not clear if we can complete the job of polio eradication without IPV," according to Dr. Jacob John. In a review paper published earlier this year, Dr. John observed that not many studies had been conducted on how well IPV performed in developing country settings because of WHO's policy of using only OPV in these countries. But in the few studies of IPV in developing countries, "almost all" showed excellent results. He gave examples of three such trials done by CMC, including a large-scale one in North Arcot district of Tamil Nadu, and one where IPV had been successfully used to stop polio in Mumbai slums. Not only did IPV evoke a strong immune response, but it also generated immunity in the inner lining of the digestive tract (which was supposed to be one of OPV's advantages) and created a "herd effect" by reducing transmission of the virus to others. These were all qualities of a "good vaccine," he pointed out.
For the period between interruption of transmission and global certification of eradication, the WHO would continue to recommend that oral polio vaccine be used, says Dr. Heymann. In this period, countries should keep up vaccine coverage with OPV to prevent VDPVs from emerging and also maintain high levels of surveillance. But "after certification, oral polio vaccine must be stopped," he emphasises. WHO and UNICEF were preparing evidence-based guidelines to help countries make informed decisions about OPV cessation. WHO would not recommend IPV universally, but if countries wished to continue vaccinating after certification and wanted to change to IPV, "we will help them establish use of IPV," he told The Hindu .
In the late 1980s, the Union Government attempted to set up an IPV production unit in Gurgaon with technology from France and then backed away. With demand for IPV steadily rising in the rich countries and no new manufacurers of IPV, the vaccine's price was "exorbitant and remains unaffordable to low and medium income countries," says Dr. John. The Global Alliance for Vaccines and Immunisation (GAVI) and other groups were working to ensure that affordable IPV would be available when needed, according to an editorial by Dr. Heymann in the Bulletin of the WHO. "If there were more manufacturers, especially developing country manufacturers, we could be fairly certain that the price [of IPV] would come down," said Dr. Heymann when he spoke to The Hindu . But developing country manufacturers would need several years to get a product licence for IPV.
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