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Immunization Focus December 2002

SPECIAL FEATURE

Polio: can immunization ever stop?

An article in the last issue examined the progress of the worldwide effort to eradicate wild polio. Here, as the goal comes within sight, Immunization Focus learns about the difficult choices facing countries and the international community

DRC Polio

Living with polio: children at a rehabilitation center in the Democratic Republic of Congo, 2001
copyright WHO/GPEI

Nobody said it would be easy to get rid of poliovirus, and the last corners -- in India particularly -- are proving even harder than expected. But, as the worldwide polio eradication effort comes tantalisingly close to achieving its goal, policymakers face a new set of tough questions. If the world can soon be declared free of wild poliovirus, can countries then stop vaccinating their children against it, or should they continue forever? If they continue, what type of vaccine should they use? Would a world declared polio­free be safer with polio immunization, or without it?

Expect no instant answers. These questions are still being considered by those who advise the Global Polio Eradication Initiative (GPEI), a partnership spearheaded by WHO, Rotary International, the US Centers for Disease Control and UNICEF. But this is not a leisurely academic debate, and policy is evolving fast. Vaccine manufacturers need to know -- very soon -- what the world's broad requirements are likely to be beyond the next five to 10 years.

Since its launch in 1988, the GPEI's goal has always been to wipe out a crippling disease, such that vaccination could stop. But as the prospect of achieving the first aim comes within sight, the idea of stopping vaccination is increasingly being questioned. Immunization experts disagree, with some advocating a coordinated cessation of vaccination as the safest policy, and others insisting that immunization must continue indefinitely.

Science and politics

While the GPEI continues to work towards the goal of stopping polio immunization after the world is certified polio­free, its leadership acknowledges the uncertainty, and is working to establish an international consensus on what policy should be in what it calls the ``post­certification era''. ``What we need to do is gather the information,'' says Dr Bruce Aylward, coordinator of the GPEI at WHO in Geneva. ``Our goal should be to stop using oral polio vaccine if at all possible. Whether and how we can do so remains a question, but the weight of the evidence currently suggests that we can.''

1: If the world is certified polio­free, what are the risks then ?

The WHO and the GPEI identify the risks in the post­certification era as follows:

Risks from oral polio vaccine and viruses derived from it:

  • Vaccine­associated paralytic polio (VAPP) cases, estimated at around 250--500 per year;
  • Outbreaks of disease due to circulating vaccine­derived polioviruses (cVDPVs);
  • The persistence of VDPVs in a small number of individuals with primary immunodeficiency disorders, who can excrete live virus for many years.

Risks from wild poliovirus:

  • Accidental release from a manufacturing plant that makes inactivated polio vaccine from wild virus;
  • Accidental release of the virus into the environment from a laboratory storing any specimens;
  • Intentional release.

The Technical Consultative Group to the GPEI says that the following conditions would have to be met before vaccination against polio could be discontinued:

  • All wild poliovirus transmission stopped;
  • Effective containment of all laboratory stocks of polioviruses and IPV production sites;
  • Demonstration that VDPVs would not circulate for a prolonged period after the cessation of OPV;
  • Establishment of a global stockpile and production capacity for OPV to respond to any future outbreak.

Whether commentators agree or disagree with that view, the reality is that the debate has moved into a more political and public arena in the wake of September 11 2001. The media, especially in the US, have aired concerns that poliovirus could be used by bioterrorists on a non­immunized population in future. Highly influential voices have weighed in, not least Dr D.A. Henderson, who led the global campaign to eradicate smallpox and who now advises the US government on civilian biodefense issues. Henderson is firmly opposed to stopping the use of the oral polio vaccine and argues that those who favour doing so are taking the line of ``zealots, not scientists''.

So, what are the real issues? Would there be serious risks from an accidental or deliberate release of wild poliovirus into a population no longer immunized against it? What about the risks from the vaccine itself? WHO has set out (1) a framework for analysing and managing the various different types of risk (Box 1) and is overseeing studies to assess their scale. ``What we are trying to do is summarise any risks after certification and look at how those risks might change over time,'' says Dr David Wood, a virologist at WHO who is coordinating the studies.

Before looking at these risks one by one, it is first worth remembering the reasons why the eradication initiative has always aimed, ultimately, to stop vaccination. The mainstay of the eradication initiative has been the oral polio vaccine (OPV), which is based on live, weakened virus and stimulates a strong protective immune response to the wild virus. OPV is a generally safe vaccine but it can, very rarely, cause paralysis. Estimates are still uncertain, but this disastrous outcome may result from about 1 in every million doses given, affecting something like 250 to 500 people worldwide every year. If the burden of wild polio falls to zero, the risks of the vaccine could outweigh its benefits. ``The last thing we would want to do is inadvertently paralyse a child,'' says Aylward.

The risk of vaccine­associated paralytic polio is lower than, say, the risk of severe adverse events that accompanies existing smallpox vaccines. But it is nonetheless too high to be acceptable in many industrialized countries, where the burden of polio is now zero. In these countries, the more costly inactivated polio vaccine (IPV) is increasingly preferred, although there are questions about how strongly this vaccine would protect against polio in tropical developing countries where children are most heavily exposed to the virus. Nonetheless, if the polio burden reaches zero worldwide, the risks from the oral vaccine may be perceived as unacceptable by governments and the public in many more countries.

Another rationale for the goal of stopping vaccination with OPV was economic gain. During the 1990s, WHO estimated that the cost savings of eradicating polio and then stopping immunization could be as high as $1.5 billion a year by 2015. Clearly, those savings would be substantially less if immunization with OPV continued, and costs could even increase if IPV were widely adopted.

Risks from vaccine­derived viruses

Most of the risks from polio vaccine and from wild virus have been known for some time. But the rapid progress of the eradication initiative, and now a set of events in the last three years, have together forced researchers and policymakers to think harder about the impact of stopping immunization. In 2000 in Hispaniola (the Dominican Republic and Haiti), more than 20 individuals were paralysed and two died in an outbreak caused by poliovirus that was originally derived from OPV. The virus had reverted to behave more like the wild form (2). Further smaller outbreaks caused by these vaccine­derived polioviruses (VDPVs) have followed, in the Philippines in 2001 and in Madagascar this year. An earlier outbreak in Egypt is also now known to be due to VDPVs. Experts believe that more outbreaks will be found as surveillance continues in the absence of wild poliovirus and possibly declining immunization coverage.

All of the documented outbreaks arose in communities where immunization levels had slipped dangerously low and where conditions allowed vaccine­derived viruses to first regain the capacity to paralyse and then the capacity to circulate. The strains that had caused outbreaks had even recombined their genetic material with that of other species of gut viruses.

Scientists have long known that the weakened viruses in OPV can replicate in the gut and spread to household contacts of the vaccine recipient. But until 2000, few expected that such strains would persist for long enough to re­acquire both the capacity to paralyse and to spread widely in a community.

Professor Paul Fine at the London School of Hygiene and Tropical Medicine had argued (3), before the outbreak in Hispaniola in 2000, that VDPVs could persist in environments where poor hygiene favoured their spread, and that this could affect policies for stopping vaccination. He took no pleasure in seeing his concerns borne out in Hispaniola. ``Ideally, everybody would love to give up all polio vaccine,'' says Fine, ``but some of us feel that we are not in that position.'' For Fine, and others, the experience with VDPVs underlines the need to keep immunization coverage high enough to prevent their spread.

An alternative argument, expressed in a review article by Dr Walter Orenstein of the Centers for Disease Control and other members of the Technical Consultative Group to the GPEI, is that the recent vaccine­derived virus outbreaks are a strong additional reason for stopping immunization with OPV as soon as possible. While OPV is used, they argue, there will always be a risk that vaccine­ derived viruses will emerge and seed new outbreaks of polio in areas where immunization coverage is low (4). If massive, coordinated immunization campaigns are done before withdrawing the vaccine, the population's level of immunity will be high and the risk of VDPVs circulating will be low.

The fact is, no one will know either way until more research has been done. Wood at WHO says that there are some studies under way to monitor whether VDPVs emerge after population­wide immunization campaigns. In Cuba, he says, polio immunization is given in two ``pulses'' per year, not as a routine service, so a very high proportion of the population is immunized all at the same time. So far, circulating VDPVs have not been found in Cuba -- perhaps, says Wood, because the simultaneous immunization of so many people gives any escaping vaccine­derived virus very little time and very few hosts to go to. But how far can these findings from Cuba be generalised to other settings? Wood says that other studies are now under way, for example, in India, to see whether VDPVs emerge after campaigns in communities where routine immunization coverage is very low. However, some observers worry that such studies will be difficult to carry out and difficult to interpret.

Long­term carriers of vaccine­derived poliovirus

Most scientists see VDPV outbreaks as a serious concern. But there are other risks to consider. One is that people with certain rare inherited forms of immunodeficiency may continue to excrete VDPVs for years after immunization. So far, in the 40 years that the vaccine has been in use, only 19 such individuals have been identified worldwide, the majority in industrialised countries, and only four are known to be excreting virus today. No excretors of wild poliovirus have been identified.

According to the Technical Consultative Group (4), congenital immunodeficiency disorders occur in no more than 1 in 10, 000 births and of these at most 1% are likely to become long­term carriers of VDPVs. None have yet been documented in developing countries where conditions for the spread of polio are most favourable, despite some attempts to find them. Presumably such individuals would be unlikely to survive long after birth in environments where they are constantly exposed to infections. Importantly, people with acquired immunodeficiency disorders, such as AIDS, do not seem to be affected. But, as Wood points out, even if long­term excretors with primary immunodeficiencies are rare, the risk that they could seed new outbreaks is ``not zero''. Henderson argues that there are ``undoubtedly many more of these long­term excretors out there'', and compares the search for them with the search for a needle in a haystack. Aylward insists that they have been looked for, and not found. Monitoring studies continue.

2: Did he really say that?

On 27 October 2002, the influential leader of the former global campaign to eradicate smallpox was the subject of a provocative press report. ``The worldwide eradication of polio is unachievable and efforts should be abandoned, a senior federal health official said Saturday'', the story in the New York Times began.

Dr D.A. Henderson, the official in question, is known to have strong concerns about stopping immunization after wild polio is gone. What surprised many about the press report, however, was that Henderson now appeared to be advocating abandoning the struggle to get rid of the virus, when the number of countries where the virus is still spreading is lower than ever before. Even other researchers who have expressed doubts about stopping vaccination in the post­certification era, such as Professor Paul Fine at the London School of Hygiene and Tropical Medicine, were dismayed. ``We are almost there,'' he says.

Henderson explained his position to Immunization Focus. ``I believe the polio eradication initiative deserves our full support,'' he said. ``We must do all we can to assure that it succeeds.'' What he had intended to convey was that the World Health Assembly is now committed to the eradication of just two diseases, guinea worm and polio, and, given the problems and costs of both efforts, he is opposed to considering the eradication of any other disease for the foreseeable future. He is also anxious to distinguish between polio eradication and stopping polio immunization. ``It is important to bear in mind that the Assembly's commitment was to the eradication of polio, not the eradication of polio vaccine,'' says Henderson. ``These are two quite different goals and should not be confused.'' The aftermath of the eradication of smallpox, he argues, has taught us important lessons. As the effort to eradicate polio continues, he argues, ``We must begin to look more critically and realistically towards the longer term future to assure that we are providing for protection against polio, whatever the outcome of the eradication effort.'' Meanwhile, the strenuous activity under way in India, Nigeria and Pakistan should continue, said Henderson. ``Let us do our very best.''

Risks from wild poliovirus

There are also threats from the wild virus in a post­ certification era. First, could a virus escape by accident from a laboratory? Absolutely. The last person to die of smallpox was infected by an accidental release of the virus from a laboratory in Birmingham, England, in 1978, a year after the last known indigenous case of the disease. If polio immunization ceased, a growing population would be at risk of infection in such an event. Aylward believes that the containment of laboratory stocks of wild poliovirus is ``a major issue'', but the issues related to poliovirus are very different from those surrounding smallpox, because of the nature of the virus itself and the strategies for protecting populations from it.

In 1999 the World Health Assembly unanimously agreed to a containment policy for all poliovirus stocks. Countries agreed to list and survey all biomedical laboratories. Within the agreed policy, biomedical institutions will keep complete inventories of all infectious or potentially infectious materials; they will destroy any stocks that are non­ essential, and store any essential stocks of scientific value in secure, approved laboratories. Some experts question whether such conditions can be achieved in every lab in the world. ``Fecal samples, collected for many different reasons and held in freezers worldwide, may be inadvertently contaminated with wild or vaccine­derived polioviruses,'' wrote Fine and Neal Nathanson in a commentary in the journal Science (5). But Aylward believes that, with careful attention to oversight mechanisms and proper independent validation, effective containment can become feasible. Wood adds that many laboratories in resource­poor settings are now choosing to destroy stocks rather than attempt to store them.

Another potential risk is that the wild virus strains used to make inactivated polio vaccine could escape accidentally from a vaccine manufacturing plant. Before inactivation, the viruses that are used to make the existing IPV are virulent and could cause harm. One such escape has been documented: luckily, the person who became infected was free of symptoms. WHO has been working with manufacturers to develop guidelines for safer conditions.

Bioterrorist attack

Finally, there is the risk of bioterrorism. Most researchers think that poliovirus would make a weak bioweapon compared with, for example, smallpox or anthrax. ``If your goal is to disrupt the USA, polio ain't the thing,'' says Fine. ``Let's be a bit sensible here.'' The virus is spread primarily by the faecal­ oral route, and in a country with good sanitation, its spread would be limited; what is more, fewer than 1% of infections would be expected to result in paralytic disease, even in a susceptible population (4). However, some virologists and public health specialists argue that, however ineffective poliovirus is as a bioweapon, it could still be an effective means of terrorising a population.

Henderson points out that the terror factor could be especially powerful in an industrialized country where sanitation is good because of the somewhat higher risk of paralytic disease. In ``clean'' conditions, the probability of becoming infected within a given time is lower than in unhygienic environments, so the average age at which individuals become infected rises, and older children and adults are more likely to develop paralytic disease than young babies. ``Those of us who lived through the 1950s remember the paralytic disease. It was a pretty horrendous time,'' says Henderson. Aylward agrees, but points out that if polio vaccination stopped, it would take 15 or 20 years before any of the non­immunized cohorts reached early adulthood. Furthermore, should industrialized countries continue using IPV as most currently plan to do, the vaccine would act as a deterrent to any potential bioterrorist and the risk of harm would be far lower. Aylward says it is more important to concentrate on measurable and more predictable risks, such as vaccine­associated paralysis.

Current vaccine options

Given all the different types of risk, it is not surprising that some experts advocate an alternative path: instead of choosing between stopping OPV or continuing OPV, why not switch to IPV? This vaccine contains killed whole poliovirus rather than live virus, so it is associated with fewer adverse events. However, it is by no means a perfect solution. It must be injected rather than given by mouth, making administration more complicated and expensive to do and requiring more trained staff. If it is given to infants in routine immunization, in combination with other vaccine antigens in the early months of life, it may not elicit a strong immune response to all wild polioviruses. It has proved effective in the industrialised countries for routine immunization, but it is not thought to stimulate strong gut immunity. This raises questions as to whether it would protect children in environments where the risk of infection with poliovirus is very high, such as the overcrowded slums of some megacities. IPV is also inadequate for responding to outbreaks; OPV must be used in these circumstances.

Wood at WHO says that studies are under way to monitor the efficacy of IPV in countries that are currently making the switch. So far, these are mainly industrialized countries such as New Zealand, but studies in developing countries are also being planned.

Henderson is concerned that IPV may not be sufficiently protective in the tougher conditions of developing countries, and that its higher cost and more complex administration will eventually lead to a slump in coverage. For these reasons, he strongly advocates continuing to use OPV, arguing that the annual toll of paralysis directly caused by the vaccine is a price worth paying in return for keeping wild polio disease at bay.

Aylward stresses that countries will decide their requirements for themselves. ``This is not something that WHO can decide on,'' he says. Obviously any withdrawal of OPV would have to be internationally coordinated, but a trend to adopt IPV might happen in a more piecemeal fashion. At present, IPV supplies are far below what would be needed if many or all developing countries made the switch from OPV. The cost of the vaccine is also currently several times greater than the cost of OPV, although industry sources will name no figures. The producers would have to increase their capacity sharply to meet a greatly expanded need. The GPEI has now asked UNICEF, one of its partner members and the buyer of vaccines for the Expanded Programme on Immunization, to talk with the manufacturers of IPV -- which include Aventis Pasteur and GlaxoSmithKlineBio -- about prices and timeframes for scale­up in the event that many countries do decide to make the switch.

Manufacturers confirm that they need to know what the international community wants from them. Aventis Pasteur and GSKBio both make some IPV­ DTP combination products. Aventis Pasteur recently announced an investment of around $70 million in increased manufacturing capacity for viral vaccines such as IPV. GSKBio likewise has proposed investments in increased production for IPV, says Dr Walter Vandersmissen. ``But [GSKBio] insists on firm guidance and commitment of the public sector as to the future use of polio vaccines... the stakes to increase production are considerable, and cannot be implemented without a full and long­term agreement on the use and purchase of the vaccine.''

Stockpile

Even if demand for IPV increases, there will probably always be a need for a stockpile of OPV in the event of any future outbreak of polio. Individuals immunized with IPV take several weeks to develop immunity, whereas OPV triggers a much more rapid immune response, particularly in the gut, and is more effective for outbreak control. Any long­term policy for the post­certification era will require a stockpile of OPV to enable an emergency response to an outbreak.

It sounds straightforward enough, but even a stockpile poses technical, political and economic challenges. Scientists disagree about the length of time that live vaccine stocks could be kept, the feasibility of storing them appropriately, about whether any manufacturer would be prepared to make rolling supplies to replace ageing stocks, and about the willingness of the international community to foot the bill indefinitely. Aylward says these challenges can all be addressed. Henderson is less optimistic. Fine argues that most of the problems can be dealt with if the world has the political will to pay for decent immunization services for all its children.

Better vaccines

Ultimately, some researchers believe that the issues would be resolved if there were better polio vaccines. An oral vaccine without the risks of VAPP or mutation to disease­causing strains would be ideal, but, while some scientists believe such a vaccine is feasible, they admit it could take at least a decade to develop one; to prove that it would be safer than OPV would require trials involving, potentially, more than a million people. Another option is inactivated polio vaccine but made with weakened Sabin strains (those used in OPV) instead of wild­type strains. However, such vaccines would need to go through all the usual regulatory hurdles and could take years to bring to market. And the current set of decisions cannot wait that long.

In the meantime, northern India is in the middle of a wild polio outbreak. For Aylward, the interruption of transmission there still has to be top priority. And still, for now, the toughest challenge.

Phyllida Brown

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