Vaccination against polio should not be stopped

| The striking 50-year-long decline in the incidence of poliomyelitis has stalled in the past 7 years, which has led to calls for an urgent re-assessment of eradication and post-eradication campaign strategies. The current plan of eliminating the circulation of wild poliovirus so that further immunization will be unnecessary does not take into account recent scientific data and political realities that limit the likelihood that this strategy can sustain prevention of the disease. It is crucially important that high levels of population immunity are maintained against polio in the foreseeable future. NATURE REVIEWS | microbiology ADVANcE ONlINE PUBlIcATION | PersPecTIves Nature Reviews Microbiology | AOP, published online 29 October 2007; doi:10.1038/nrmicro1769 © 2007 Nature Publishing Group This multi-national effort was coordinated by national governments, the World Health Organization (WHO), Rotary International, the United States centers for Disease control, UNIcEF (The United Nations children’s Fund) and private donors. The campaign reduced poliomyelitis rates from an estimated 350,000 cases worldwide in 1988 to only 2,971 confirmed cases in 2000, and completely eliminated the disease that is caused by wild-serotype-2 poliovirus3. The 7 years that followed, however, were a mixture of successes and unanticipated setbacks and, despite a continuing reduction in the number of countries where circulation has never stopped (so-called polio-endemic countries), the global polio incidence remains at around 2,000 cases per year (FIG. 1). Officially, only four polioendemic countries remain: India, Pakistan, Afghanistan and Nigeria. The failure to eliminate wild poliovirus in these remaining countries has probably been due to political and/or public health problems (BOX 2), as well as the inherent biological characteristics of the virus (discussed below). The reintroduction of wild poliovirus from these endemic regions into areas that were previously considered to be polio-free, followed by international secondary spread, has caused disease outbreaks in at least 25 countries in the past few years. Challenges to the eradication programme Covert circulation of wild poliovirus. In 2004, wild polioviruses were identified that seemingly came ‘out of nowhere’. These viruses, which are called orphan polioviruses, presented with genotypes that were neither related to nor derived from any known contemporary viruses. Serotype-1 orphans were isolated in Sudan, and serotype-3 orphans were identified in Sudan and chad. The closest relatives of these orphan polioviruses had been isolated from central Africa 4–10 years earlier. Regardless of whether orphans reflect some failure of surveillance, isolation, identification or reporting, or whether they have emerged after long-term circulation without causing overt cases of polio, we should acknowledge that the absence of circulating wild polioviruses from official reports does not necessarily mean that they are absent from our planet. Thus, the number of countries in which endemic wild polioviruses are detected might be greater than four. Circulation of vaccine-derived polioviruses. Although the OPV is a highly efficacious vaccine that is safe when it is used in a population with pre-existing anti-polio immunity, it is genetically unstable. OPV descendents rapidly acquire neurovirulence and transmissibility that closely resemble the phenotypes of wild polioviruses (FIG. 2). Ironically, this genetic instability was used by Sabin during the isolation of the polio vaccines4, based on the understanding that each virus isolate contains a mixture of particles that express a spectrum of pathogenicity. As we now know, viral RNA-dependent RNA polymerases manifest high infidelity: each newly synthesized molecule of poliovirus RNA contains, on average, one mutation. Even clonal populations of poliovirus are highly heterogeneous ‘swarms’ of genotypes and phenotypes (reviewed in reF. 5). Sabin selected vaccine strains by adapting them to non-human cells, which resulted in attenuated neurovirulence in humans. During the subsequent passage in humans, however, the attenuating mutations are eliminated by natural selection. This leads to the restoration of the wild-type phenotype, for example, more robust replication, spreading and neurovirulence5,6. Even the OPV derivatives isolated from the faeces of a healthy vaccine recipient can exhibit a significant increase in virulence7. The rapid selection of viruses with improved fitness is not surprising as the genomes of the vaccine strains contain few major attenuating mutations (six in Sabin 1, two in Sabin 2 and three in Sabin 3)8,9. In humans, the reversion to neurovirulence by OPV strains causes VAPP at a rate of approximately 1 in 500,000 first-OPV doses10,11. Although this was an acceptable level in the early stages of polio control and eradication, it is now estimated that ~500 VAPP cases occur annually. Surprisingly, outbreaks of epidemic Box 1 | History and pathogenesis of poliomyelitis Poliomyelitis (from the Greek polios (grey) and myelos (marrow); also known as infantile paralysis) was first recognized as a distinct human disease by Jacob Heine in 1840. It affects motor neurons of the anterior horns in the grey matter of the spinal cord. A major causative agent of poliomyelitis is poliovirus — an RNA-containing virus that belongs to the Enterovirus genus of the Picornaviridae family — but other infectious agents, including some other enteroviruses, can also cause the disease. In most cases, the infection of non-immune individuals with poliovirus causes no, or mild and reversible, symptoms. However, in approximately 1% of cases (or less, depending on the virus serotype), irreversible paralytic disease develops owing to the death of muscle-innervating neurons. Without nerve stimulation, the muscles become weak and undergo atrophy, eventually resulting in so-called acute flaccid paralysis. Sometimes, infection spreads into the brain stem (bulbar or bulbospinal disease), which can result in paralysis of the diaphragm and a severe impairment of breathing. A respirator is often required to sustain life (see the photograph, which depicts patients with poliomyelitis in a hospital respiratory ward in Los Angeles, United States, in 1952). The disease is usually more severe in adults than in children and can be fatal. A young man with a withered leg and foot, which is characteristic of patients with poliomyelitis, was depicted on an Egyptian stele made between 1403 and 1365 BCE (before the Common Era). It is considered likely that poliovirus was circulating at that time, approximately 3,400 years ago, although alternative causes cannot be ruled out. Photograph courtesy of the Centers for Disease Control and Prevention, Georgia, USA. Nature Reviews | Microbiology P e r s P e c t i v e s | ADVANcE ONlINE PUBlIcATION www.nature.com/reviews/micro © 2007 Nature Publishing Group poliomyelitis caused by vaccine-derived strains were discovered only recently12. The original eradication strategy was based on the misconception that although revertant polioviruses possess increased neurovirulence, their transmissibility remains low and they quickly disappear from populations. This hypothesis was disproved in 2000 when it was shown that numerous cases of poliomyelitis in Hispaniola had been caused by circulating vaccine-derived poliovirus (cVDPV) type 1 (reF. 12). Retrospective analysis showed that an earlier outbreak by cVDPVs occurred from 1988 to 1993 in Egypt and was caused by a virus that was less than 10% different from Sabin-2 virus. circumstantial evidence suggests that the so-called genotype T of type-1 poliovirus that was circulating in Africa and Asia in the 1980s (assumed to be the wild type) was derived from Sabin-1 virus13. The outbreaks caused by cVDPV that have occurred since 2000 (TABLe 1) have been relatively limited compared with previous years, generally paralyzing only a few individuals each, although 30 and 46 victims were confirmed during the Egyptian and Indonesian outbreaks, respectively14 (see Note added in proof). As only 1 in several-hundred people who are infected with wild poliovirus develops paralysis15, the number of infected individuals who were associated with these outbreaks was higher by at least 100-fold. The limited spread of cVDPVs was probably due to the herd immunity that existed in the affected populations, although individual isolates of VDPV probably manifest varying degrees of virulence and transmissibility. Wild polioviruses also exhibit a wide range of virulence and transmissibility depending on their genetic properties and the immune status of their target populations. Indeed, in the pre-industrial era, when anti-polio immunity was almost universal, wild polioviruses caused only limited outbreaks. If allowed to continue to circulate, however, cVDPVs will probably evolve to become indistinguishable from wild polioviruses. Additional reservoirs of poliovirus. In addition to the epidemic causing cVDPVs, there are other sources of pathogenic OPV derivatives. Vaccine recipients that have inborn immunodeficiency may excrete virus, which has been called iVDPV, for several years. The excretion of iVDPV has been described in at least 30 cases14 and it can last for up to 20 years14,16. However, a search in the United States, Mexico, Brazil and the United Kingdom identified only a few cases of chronic polio carriers17, and the possibility that there are undiscovered polio excretors in the global human population of more than 6 billion people is probably a low, but undefined, risk. The evolution of the iVDPVs excreted by these patients appears to follow the same pattern as cVDPV, resulting in the early acquisition of increased pathogenicity18–20. Rare instances of the long-term excretion of OPV derivatives by healthy individuals who have no apparent immunopathology have also been documented21,22. Subpopulations that have low or nonexistent immunity have been detected in some countries that have adequate levels of immunization. Such ‘islands’ are formed either owing to religious beliefs (such as Amish communities in the United States) or socio-economic conditions (for example, the Roma in Romania), and they might create reservoirs of highly diverged VDPV that can produce paralytic polio23,24. Just as there are orphan wild polioviruses, there are also orphan VDPVs (also called ambiguous or aVDPVs14). Highly divergent aVDPVs have been isolated from sporadic cases of paralytic polio and healthy children in populations considered to be adequately immunized25,26. Moreover, aVDPVs are occasionally isolated from sewage in regions that have no reported cases of poliomyelitis27–30. The covert circulation of orphan wild polioviruses and the widespread occurrence of VDPVs that have properties approaching those of wild polioviruses seriously challenge the validity of the certification of regions as being ‘free from wild polioviruses’. certification is based on a failure to isolate wild poliovirus over a 3-year period. considering the intrinsic properties of poliovirus and the lack of an absolutely reliable surveillance network, this policy is based more on faith than on fact, and it is, in our view, potentially dangerous. In most of the regions that are certified as polio-free, various OPV-derived poliovirus populations with wild-like properties are still circulating. The evidence suggests that the phenotypes Nature Reviews | Microbiology 70,000