Perspective: The Polio Eradication Endgame
As polio eradication nears realization, such real-world vaccination strategies could hold lessons for the future in AIDS vaccine development
By David L. Heymann and R. Bruce Aylward*
Recently, an 18 month old girl, one of the few children paralyzed by poliomyelitis last year in India, was filmed by an international camera crew documenting the final human-to-human chains of polio transmission. She had been hidden by her parents from the polio vaccination team each time it passed because of a misunderstanding about the safety of the vaccine, and her left leg had been paralyzed two months earlier by polio. Already by the time of filming, in the arms of her mother, she had learned to move her paralyzed leg by slipping her non-affected leg behind and lifting upward. This is surely the first of many other self-taught mechanisms she will use as she learns to move around the household and then in the community, as she copes for the rest of her life with a disability that could have been prevented. The irony and tragedy of her fate is to have lived at a time when polio vaccines were made accessible to every child in all countries, but missed out because her parents misunderstood.
In 1988 polio paralyzed approximately 1000 children each day in 125 endemic countries (See Figure 1). The polio eradication strategy that was developed over the following years includes three major activities aimed at establishing the levels of herd immunity required to interrupt transmission of wild poliovirus. The first of these activities is routine immunization of infants under one year of age using trivalent oral poliovirus vaccine (tOPV). The second is mass vaccination campaigns—national or sub-national immunization days in areas where wild poliovirus is identified and/or where the risk of infection is considered high—using tOPV targeted at all children under five years of age. Prior to conducting mass vaccination campaigns, district level micro-planning and mapping identify where children under the age of five years live and provide a framework for social mobilizers and vaccinators as they pass from community to community and house to house. The third activity underlies the first two, and is national and global surveillance of acute flaccid paralysis (AFP) among children under 15 years of age to identify all children paralyzed by polio virus, thus indicating the geographic areas where activities to interrupt polio transmission must be targeted or intensified.
Polio eradication activities have made tremendous strides since 1998. By 2000, the number of polio-endemic countries had decreased from over 125 to 20, and by mid-2003 the number had decreased to 6, with 784 children reported paralyzed that year by polio. Those six countries that still had endemic transmission of the wild poliovirus in 2003 were India, Pakistan, Afghanistan, Egypt, Niger, and Nigeria.
International spread of poliomyelitis
In August 2003, polio vaccinations were suspended throughout northern Nigeria because of false rumors that polio vaccine was contaminated—either with HIV at the time of manufacture, or from the deliberate addition of hormones to permanently sterilize young girls(1). Vaccinations remained suspended for approximately 12 months. During that period and since, genomic sequencing of the type 1 poliovirus that has caused outbreaks in 18 polio-free countries in Africa, the Middle East, and Asia has genetically linked these outbreaks to parent viruses in northern Nigeria. During this same period, three additional polio-free countries—one in Africa, two in southeastern Asia—were re-infected by type 1 polio virus genetically linked to India, reinforcing the understanding that as long as one country is infected with wild poliovirus, all countries in the world are at risk.
The response to imported wild poliovirus has been rapid and effective. Five synchronized vaccination campaigns using oral poliovirus vaccine were conducted in West and Central Africa, and serial campaigns were conducted by all the countries with imported virus. At the same time, serial campaigns continued in the six polio-endemic countries, and Saudi Arabia participated in control efforts by establishing polio vaccination requirements for those less than 15 years of age traveling to Saudi Arabia for work, tourism, or religious pilgrimage. By April 1, 2006 Egypt and Niger had become polio free, leaving four polio-endemic countries—India, Pakistan, Afghanistan, and Nigeria—and nine countries to which poliovirus has been imported—Yemen, Indonesia, Angola, Somalia, Niger (repeatedly re-infected across its common border with Nigeria), Chad, Somalia, Ethiopia, and Bangladesh (Figure 1).
At the same time that poliovirus spread internationally from Nigeria and India, observations within India and Egypt—two high population-density countries with continued indigenous transmission of poliovirus—suggested that the vast majority of children with paralytic polio had been vaccinated with at least three doses of trivalent oral poliovirus vaccine, most with many more. It has been known since the mid-1970s that seroconversion to types 1 and 3 polio virus after three doses of tOPV was significantly less than that for type 2(2). The higher type 2 seroconversion rates provide an explanation for the successful interruption of human-to-human transmission of type 2 poliovirus worldwide that occurred in 1999, while types 1 and 3 poliovirus continue to circulate. A call was therefore made to oral poliovirus vaccine manufacturers in October 2004 to develop and license monovalent type 1, and then type 3 monovalent oral poliovirus vaccines. By May 2005—using historical data from previously licensed monovalent vaccines—two companies licensed monovalent oral poliovirus vaccine type 1 (mOPV1), followed shortly afterwards by additional licensed mOPV1 vaccines, and by September 2005 a licensed monovalent type 3 oral poliovirus vaccine as well (mOPV3).
These monovalent vaccines are currently being used in campaigns in the four countries that have never interrupted transmission of the wild poliovirus, and in eight of the nine countries with outbreaks from imported wild poliovirus. In countries that have only type 1 virus circulating, mOPV1 is used exclusively; while in countries with both type 1 and 3 virus, mOPV1 and mOPV3 are used sequentially, guided by the local epidemiology. Seroconversion studies to better understand the full potential of monovalent vaccines are being conducted in India and Egypt, but epidemiologically these vaccines have proven their worth, shortening the time for full containment of type 1 poliovirus outbreaks in polio-free countries and interrupting transmission in densely populated areas such as Mumbai. With use of monovalent polio vaccines, continued government commitment and availability of funds, the goal of polio eradication remains fully in sight.
During early 2004 an outbreak of polio caused by type 2 poliovirus occurred in Guizhau Province, China, which was free of indigenous polio transmission for the previous 10 years, and genetic sequencing of this virus indicated that it was a circulating vaccine derived poliovirus (cVDPV), a virus with >1% difference from a parent oral poliovirus vaccine (OPV) virus strain by full VP1 sequence homology. With rapid and appropriately targeted vaccination campaigns using tOPV, the outbreak was rapidly contained.
It has been recognized since the late 1990s that polio outbreaks can be caused by cVDPVs. As of April 1, 2006, outbreaks arising from Sabin-derived poliovirus strains have been documented in Haiti and the Dominican Republic (2000-2001), the Philippines (2001), Madagascar (2002 and 2005), China (2004), and Indonesia (2005), with others such as in Egypt during the 1980s described retrospectively (See Figure 2)(3). Although the conditions that give rise to cVDPVs are still being studied, it is clear that attenuated vaccine viruses are able to regain neurovirulence and the capacity to circulate and cause outbreaks, but it appears that this is a rare event.
In addition, the prolonged excretion of vaccine-derived polioviruses by some persons with primary immunodeficiency syndromes (iVDPVs) has now been well documented, with 6 of the 30 known iVDPVs having had excretion longer than 60 months(4). The true incidence of such chronic iVDPVs remains uncertain, primarily because it has been documented mainly in persons with common variable immune deficiency, a syndrome that is often asymptomatic into early adulthood and therefore not fully detected because global and national surveillance for AFP targets children under 15 years of age. To date, all those who have excreted virus for longer than 60 months have lived in high income countries and iVDPV, like cVDPV, appears to be rare.
Of significance is the observation that acquired immunodeficiency syndromes, such as that caused by HIV infection, have not been associated with prolonged poliovirus excretion, and no iVDPV is known to have generated secondary infections with paralysis(5).
In September 2003, a WHO consultation group on oral poliovirus vaccines and vaccine-derived polioviruses concluded that the continued occurrence of 250-500 vaccine-associated paralytic poliomyelitis (VAPP) in OPV recipients or their contacts, along with regular outbreaks of cVDPV, would be an unacceptable risk for most, if not all, countries. Based on an evidence-based risk-benefit analysis, the group recommended eventual simultaneous OPV cessation in all OPV-using countries once polio transmission has been confirmed as interrupted worldwide(6).
In addition to the risk of cVDPV emergence and the long-term risk of iVDPV secretion after OPV-cessation, each of which would require an immediate outbreak response, there is the longer term risk of re-introduction of a wild, vaccine-derived or Sabin poliovirus strain from a laboratory where they are stored, or from an inactivated polio vaccine (IPV) production site where wild virus is grown for vaccine production. These risks must be reduced to an absolute minimum by decreasing the number of facilities storing, handling, and/or amplifying these viruses by destruction of living viruses, or in a very few countries ensuring that living polioviruses are placed and maintained under polio-biocontainment conditions that have been developed by an international consensus process.
To reach this goal, 158 countries have initiated and/or completed both a laboratory survey for wild poliovirus and infectious or potentially infectious materials (to be followed by similar surveys for Sabin polioviruses), and an industry survey to determine which IPV production sites will continue manufacture after eradication(7). Five countries have been identified that plan to maintain IPV manufacturing facilities after OPV-cessation: France, Canada, Belgium, Denmark, and the Netherlands, and facilities in these countries have begun to adapt their manufacturing processes to the required level of polio-biocontainment.
Based on perceived and real risks as outlined above, countries must develop national post-OPV polio vaccination strategies. It is believed that many countries with minimum or no risk will decide not to introduce IPV and completely stop polio vaccination. These countries will depend on a global surveillance capacity for polio, a stockpile of monovalent polio vaccines against types 1, 2 and 3, and an outbreak response mechanism that is being put in place under the International Health Regulations (2005), where polio is among four specific infectious diseases for which reporting is required(8). Countries that contribute a real international biohazard risk—because of continued handling, storage, and/or amplification of poliovirus—will be required to develop, fully implement, and maintain an IPV vaccination policy that will ensure high levels of polio immunity among laboratory workers, IPV production operators, and the general population.
The polio eradication endgame, including the complexities of OPV cessation, was not entirely foreseen in 1988 when the world embarked on the eradication of polio. tOPV, the workhorse of polio eradication, has nearly reached the end of its life-cycle, 50 years after its initial development, and IPV will be the vaccine of choice for those few countries that continue polio vaccination after OPV-cessation. As research and development continue for AIDS vaccines, the lessons from oral polio vaccine are clear: Vaccinology is often an evolutionary process, requiring successive generations of vaccines that are adapted to the changing epidemiology of the disease, and that compensate for any inherent risks of the vaccine itself.
Vaccine cessation also occurred after the certification of eradication of smallpox (variola), the only infectious disease to have been eradicated to date. Smallpox vaccine is made from vaccinia, and primary vaccination is associated with complications that range from vaccinial eruption at sites that are, or have previously been, eczematous to generalized vaccinia infection and post-vaccinal encephalitis leading to permanent neurological disability or death. With a case fatality ratio for post-vaccinal encephalitis of approximately 30%, the risk of fatal complications from smallpox vaccine is approximately one per million doses of vaccine administered, depending on the strain of vaccinia used in vaccine preparation(9). Because the risk of complication from vaccinia was considered greater than the risk of smallpox after eradication had been certified, cessation of smallpox vaccination was universal.
Stocks of variola virus held in laboratories around the world were then considered to be the greatest risk to smallpox eradication and this risk was dramatically illustrated by a laboratory accident resulting in a fatal case of smallpox in the UK in 1978(10). That highly-publicized event persuaded national authorities to either destroy virus stocks or transfer them for safe-keeping to designated high-security WHO-collaborating centres that were required to continue vaccinating all those who worked at these facilities.
In 1981, within a year following the certification of smallpox eradication, AIDS was identified for the first time in the US, after the international spread that would rapidly lead to endemicity had already begun. In 1984 the US practice of vaccinating military personnel as protection against the possible use of variola virus as a biological weapon led to recognition of a fatal link between smallpox vaccination and HIV infection; a young military recruit with latent HIV infection developed generalized vaccinia and AIDS following smallpox vaccination that led to death six months later(11). This demonstration of the fatal potential of smallpox vaccination in HIV-infected persons suggests that, had AIDS emerged earlier, it would have undermined chances for the eradication of a disease that depended on vaccination as the cornerstone for control.
It is fortunate that HIV infection does not create the same obstacle to polio eradication as it would have for smallpox—the window of opportunity to complete polio eradication remains open, and new and better adapted vaccines are now available. The challenge is to complete the job while the window remains open, and through a series of clearly thought out evidence-based OPV-cessation activities, safeguard against the reccurrence of a disease that shatters the dreams of parents and the lives of their children.
Lessons from the final challenges in polio eradication are important for the future in AIDS vaccine development. They suggest that optimizing the impact of future AIDS vaccines will require planning to ensure full acceptance and uptake, as well as the capacity to collect and assess the evidence required to adapt vaccines to the emerging AIDS epidemiology, and to compensate for any undesirable vaccine-related effects.
*David L. Heymann is the Representative of the Director General for Polio Eradication and heads the WHO Polio Eradication Initiative, World Health Organization.
R. Bruce Aylward is the Global Coordinator for Polio Eradication, World Health Organization and provides overall technical guidance on implementation of the polio eradication strategies.
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