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British Medical Bulletin 62:213-224 (2002)
© 2002 Oxford University Press
Eradication and cessation of programmes
Vaccination and public health care
Division of Virology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, UK
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Abstract
IntroductionEradication of disease requires the eradication of the causative agent. Smallpox is the only human disease knowingly eradicated so far and, while poliomyelitis is likely to be the second, they present very different problems. All smallpox infections were apparent when significantly infectious, the vaccine was very easy to deliver and its effects easy to monitor, and it was incapable of causing the disease it was intended to prevent. In contrast, most poliovirus infections are silent, vaccination leaves no outward sign, and there is a low, but real, incidence of vaccine-associated poliomyelitis. While smallpox was eradicated by containment of infections by quarantine and vaccination, poliomyelitis requires mass vaccination campaigns to break virus transmission. Moreover, in contrast to smallpox, the strategies for stopping polio vaccination are still under discussion. The polio eradication programme on the other hand has made and continues to make strides towards its goal, and is a major triumph of public health interventions.
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Introduction |
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Eradication of a disease requires targeting the agent which causes it rather than the disease itself. In the UK, for many years the strategy for controlling congenital rubella syndrome (CRS) was to immunise females when they reached the age of 12 years, with supplementary immunisation of women as they planned families or after the birth of the first child1
. The males were thus left unimmunised and were sufficient in numbers to maintain the circulation of the wild-type virus. As no vaccine is completely effective and no vaccination strategy can guarantee that all susceptibles are immunised successfully, cases of CRS continued to occur as unprotected females were infected. The strategy now used involves immunisation of all children with the trivalent measles/mumps/rubella vaccine using a two-dose schedule, so controlling the circulation of the virus as well as the disease. Different strategies could lead to eradication of particular diseases including the improvement of water supplies or sewage handling or the eradication of a necessary insect vector. The only globally successful strategy to date, however, has been the use of vaccine, which resulted in the World Health Organization (WHO) declaring the eradication of small pox in 19802. Attempts to eradicate disease by vaccination require a vaccine which, if correctly used, slows transmission of the causative agent to unsustainable levels. The vaccine must be produced in sufficient quantities, delivered to the point of use in good condition, and administered to recipients correctly – all of which pose economic and logistic problems; funding is a major issue.
The culmination of the programme is the cessation of vaccination, which requires effective surveillance of disease and the containment of laboratory and other stocks of the agent to prevent its re-emergence, as well as consideration of the possible evolution of another agent to fill any ecological niche left vacant, or the use of retained or regenerated stocks in bioterrorism. The possibility must be considered that the vaccine itself may cause the disease it is designed to immunise against, and to develop strategies to deal with it.
While smallpox is the only disease knowingly eradicated by human intervention so far, poliomyelitis caused by wild-type poliovirus is likely to follow it in the near future. The diseases present very different problems.
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Smallpox |
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A number of factors made the eradication of smallpox technically feasible. Smallpox infections are obvious, and unless the infected individual is symptomatic, they are not infectious. Vaccination leaves a scar so that the vaccination status of individuals is easily assessed. Consequently, a policy of quarantine of infected populations and containment by monitoring and vaccinating susceptibles in the surrounding population was possible, and formed the basis of the eradication efforts, coupled with routine vaccination programmes.
The vaccine was easily produced, although the methods which involved scarification of animals and collection of lymph are unlikely to be acceptable today. It was cheap to manufacture, extremely stable in dried form, required no cold chain, and was easily delivered by skin scarification.
The cessation of vaccination involved surveillance schemes based on the obvious nature of smallpox infections and offering rewards for the reporting of confirmed cases – the reward increasing in value as the disease became ever rarer. Laboratory materials were contained, a process made easier by the fact that few materials would be unknowingly contaminated with the virus. Official stocks are now confined to one laboratory in the US and another in Siberia; it is suspected that there are other unofficial sources elsewhere. Fears that monkey pox or camel pox, for example, could evolve to take over the smallpox niche have so far proved unfounded, although re-emergence through bioterrorism has become a real cause for concern.
The origin of the smallpox vaccine remains unknown, although it may derive from horsepox. While it produced severe adverse reactions including encephalitis in some recipients, it never caused smallpox. Vaccine-associated cases of the disease were, therefore, not an issue. This is not the case for poliomyelitis, which presents more severe challenges than smallpox for a variety of reasons related to its virology and pathogenesis.
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Poliomyelitis and poliovirus |
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Poliovirus, the causative agent of poliomyelitis, is a member of the picornavirus family of the enterovirus genus which currently includes five subgenera largely assigned on molecular biological criteria. Poliovirus is classified in the C subgenus with several strains of Coxsackie virus A3
. The virus is a small, non-lipid containing, icosahedral particle made up from four proteins (VP1, VP2, VP3 and VP4) each present in 60 copies and forming a shell about an RNA genome of messenger sense about 7500 nucleotides in length.
The genome is covalently linked to a small, virus-encoded protein (VPG) at the 5'-end and includes a 5'-non-coding region of about 750 nucleotides involved in initiation of protein synthesis and RNA replication, before a single large open reading frame encoding the structural proteins and the non-structural proteins involved in replication. A short 3'-non-coding region terminates in a polyadenylate tract (Fig. 1). The sequences of many picornaviruses including polioviruses have now been determined and the atomic structures of different strains have been resolved. The molecular basis of the attenuation of the Sabin live vaccine strains in most common use has been extensively studied4.
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The pathogenesis of poliovirus infectious is still unclear in its details5
. However, in contrast to smallpox, most infections are asymptomatic, about 1% leading to paralytic poliomyelitis within 7–30 days after infection. Paralysis, or the major disease, may be preceded by general symptoms such as sore throat, termed the minor disease. The primary site of infection is the gut, and, in vaccinees, about 50% of infections last longer than 5–6 weeks and 1% for 10 weeks. However, hypogamma-globulinaemic patients deficient in humoral immunity can become persistently infected. Poliovirus exists in three serotypes (types 1, 2 and 3) such that infection with one serotype does not confer immunity to the other two. Vaccines, therefore, contain a strain representative of each type, and may be either composed of killed virus (as in the vaccines developed by Salk) or live attenuated strains (such as those developed by Sabin) which mimic natural infection of the gut. On rare occasions, estimated at 1 per 500,000 primary vaccinees, the live vaccines result in poliomyelitis (vaccine-associated paralytic poliomyelitis, VAPP). In addition, the vaccine strains are known to spread to contacts. This has been regarded as an advantage in that it increases the number of immune individuals; on the other hand, cases of VAPP also occur in contacts of vaccinees.
Live attenuated vaccines (oral poliovaccines, OPVs) have been most widely used in the global control of poliomyelitis because it has been proved that if they are correctly used they can break virus transmission. Inactivated poliovaccines (IPVs) have proved effective in many industrialised countries and there is an increasing trend to their use. Their ability to block intestinal transmission is not proven, and they are expensive.
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Vaccination strategies |
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In temperate climates, OPVs rapidly eliminated poliomyelitis (Fig. 2). However, for many years it had only limited effect in tropical countries. A number of possible reasons were put forward, including poor take because of other intestinal infections and poor quality of vaccine because of inadequate infrastructures. Another factor was probably the use of the vaccines in routine programmes, where a child is immunised at a specified age. In temperate climates, infections occurred mainly during the summer months. Thus, by immunising children at a set age in temperate climates, it was possible to reduce the number of susceptibles during the winter when virus was not circulating, so that there were eventually insufficient to maintain transmission in the summer. In contrast, where infection was year round, as in the tropics, it was a matter of chance whether a child was infected with a wild or vaccine virus and the pool of susceptibles did not decline sufficiently as a result of vaccination.
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The key to eradication of poliovirus transmission was, therefore, to immunise susceptibles all at once in campaigns6
, which eventually evolved into National Immunisation Days (NIDs)7, where the aim is to cover all children up to a certain age in a single day or over a brief period. Thus, there are no uninfected susceptible individuals for the wild virus to infect and transmission is blocked. It is generally assumed that resistance to infection is due to immune responses in the intestine generating gut immunity; it may also be due, in part, to competition between the vaccine strain established in the gut and the invading wild type.
Vaccination strategies currently use NIDs to supplement routine immunisation, and may also involve intense vaccination including house-to-house campaigns in particularly problematic areas. The consequence of the approaches taken are shown in Figure 3 which illustrates progress in eradication between 1988 and 1994. Since then, eradication has moved more rapidly, and, at the time of writing, poliomyelitis is confined to a number of countries in Central Africa and South East Asia, including Afghanistan and India, where there is either a very high population density or populations are difficult to access because of wars or geographical factors. The reader is referred to the WHO website for up-to-date information7. The Americas were certified free of polio in 1994, and the Western Pacific Region, which includes China, in 2000. While circulation of type I and type 3 poliovirus continues, no wild type 2 virus has been isolated since 1999 and it is possible that it has been eradicated.
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Certification of eradication |
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All cases of acute flaccid paralysis (AFP) surveillance in a country must be identified with appropriate studies, including attempts at virus isolation, to demonstrate that they are not caused by wild-type poliovirus. Other viruses such as enterovirus 70 and 71 have been associated with AFP, and the background rate due to these and other causes such as Guillan-Barre syndrome is considered to be 1 case per 100,000 head of population. This provides a good measure of the adequacy of surveillance and in some areas, such as the Western Pacific Region, acceptable rates have been achieved although this has rarely been the case in Europe or the US. Other methods have been used, including the characterisation of clinical or environmental isolates of poliovirus made in the course of other studies. If such polioviruses inevitably turn out to be vaccine derived, it is assumed that wild-type virus is not present. Environmental surveillance, as opposed to AFP surveillance, could be useful if it can be implemented, as it could detect silent circulation. The difficulty is to detect virus which may be present at low concentrations and may, in any case, be masked by vaccine derived virus where the country uses oral poliovaccine in immunisation programmes. The effort required and the relatively low sensitivity of the methods of environmental surveillance currently available mean that AFP surveillance remains the method of choice. Once natural circulation of wild-type poliovirus has stopped, clinical and laboratory specimens (which either have poliovirus or may do so) or the viruses used in industry to manufacture vaccines present a threat. The containment of such materials is essential to the certification of eradication8
. However, it is an immense task because of the widespread use of polioviruses in laboratories and the clinical specimens in which it may be found, which include faecal specimens taken for the investigation of gastrointestinal or parasitic disease. In principle, vaccination can cease when the wild-type virus is demonstrably eradicated provided the live vaccine virus does not cause the disease, as for smallpox vaccine, or if it does not persist for long enough for a susceptible cohort to accumulate in sufficient numbers to maintain virus circulation.
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Hazards of ceasing vaccination |
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It has been known since the first use of live poliovaccines that they alter on replication in the gut9
. The molecular basis of the attenuated phenotypes of the Sabin vaccine strains has been studied in depth over the years, as has the molecular evolution of the viruses in recipients4. The lack of virulence or attenuation of the type 2 and type 3 Sabin vaccine strains is attributable to two or three base positions which, when reverted, give rise to viruses of high neurovirulence for experimental animals. Isolates from vaccine-associated cases can be shown to have reverted at the relevant positions or suppressed the effect of the mutations by changes at other sites, consistent with the view that the mutations also attenuate the viruses for humans. The attenuation of the type 1 Sabin vaccine strain is more complex, involving several mutations in the capsid proteins; as for the type 2 and type 3 strains, however, a mutation in the 5'-non-coding region has been identified as affecting virulence. Single point mutations have been identified at bases 472, 480 and 481 for the type 3, type 1 and type 2 strains, respectively.
In addition, the type 3 strain possesses a mutation in the structural proteins which makes a step in the assembly of the virus capsid sensitive to high temperatures. Isolates from cases possess mutations which compensate for the effect of this destabilising mutation as shown by their location in the protein structure. The mutations are rarely simple reversions of the original mutation, and in some cases affect a later step in the assembly of the capsid. This demonstrates the precision with which the virus is able to adapt, as the resulting strains grow optimally at 37°C, the temperature of the human gut, in contrast to the vaccine strain which grows optimally at 33°C. It also demonstrates that it is possible to produce the same phenotype by different routes.
Healthy vaccinees rapidly produce exactly the same mutants with exactly the same phenotypes as VAPP cases. Reversion of the 5'-non-coding mutations occurs typically within 2–7 days and of the other mutations within 2 weeks. Moreover, in a high proportion of cases, particularly for type 3, viruses can be isolated from healthy vaccinees and VAPPs which are recombinants in which the structural proteins derive from one serotype and other portions of the virus from another. In fact, the excretion of recombinant type 3 viruses by vaccine recipients more than 11 days postimmunisation seems to be the rule.
The rapid adaptation of the virus to the gut can be followed by a gradual drift of the RNA sequence away from that of the initial infecting virus. In both epidemics and in cases of long-term persistent infections of hypogamma-globulinaemics, the rate of drift is surprisingly constant. For third base positions, which tend to have no effect on the amino acid encoded, and are therefore thought to have little phenotypic effect, the rate is of the order of 2.7% per base per year10,11.
Recently in Hispaniola and the Philippines, and previously in Egypt12, epidemic strains of poliovirus were identified which were derived from the vaccine strain. In Hispaniola, cases were observed in the Dominican Republic and Haiti from July 2000 to early 2001. The sequence of the capsid region of the virus showed it to be closely related to the Sabin type 1 strain and very different from the last confirmed cases of wild type 1 poliovirus in the island in 1989. However, the sequence differed from that of the vaccine to a degree suggesting that the virus had been circulating for about 2 years before it was detected. In addition, the epidemic viruses were recombinants in which the 3'-portion of the genome was derived from a virus other than the Sabin strains of any of the poliovirus serotypes; in fact, four different recombinants were identified, which had some sequences in common, implying an initial recombination event, followed by several others. The recombinant partner has not been identified with any confidence; but, in view of the fact that wild-type poliovirus was eradicated in 1989, it seems most likely that it is a non-polio enterovirus, presumably of the same subgenus as polio, and, therefore, probably a Coxsackie virus A type. A similar, independent, epidemic strain of poliovirus derived from the vaccine strain caused a recent small outbreak in the Philippines; it is also a recombinant with an unidentified partner assumed to be a non-polio enterovirus and, like the Hispaniola viruses, there is evidence that it had been circulating undetected for some time. Finally, between 1988 and 1993 in Egypt, the type 2 poliovirus isolated from cases of poliomyelitis came from a strain derived from the Sabin type 2 vaccine strain; it was also a recombinant.
The selection of strains of this type is related to the decline in vaccination coverage and NIDs once poliomyelitis is declared eradicated. There may also be a decline in surveillance as attention moves to other health problems. In Haiti for example, coverage was of the order of 50%, so that live virus in the form of the vaccine was continually being fed into half the susceptible population, while the remaining half were available to be infected by any transmissible virus that evolved. The rapid adaptation of poliovirus to the human gut would seem to make this inevitable. The surprising and still unexplained aspect is that all three incidents have involved recombination, most probably with viruses of subgenus C which has not previously been well documented. The selective advantage conferred by recombination is not known. The way to prevent such outbreaks is believed to be to maintain vaccine coverage at a high level; however, in the Dominican Republic and the Philippines, average coverage of 80% was reported, so the level required is probably uniformly high.
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Strategies for ceasing vaccination |
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The strategies for stopping vaccination remain a matter for discussion in the light of the outbreaks described above12
. It seems clear that a concerted approach is required, but opinions currently range from an eternal vaccination campaign, to an abrupt cessation of vaccination following a period of blanket coverage. An intermediate view is that inactivated vaccine should be used exclusively for a period, and many industrialised countries have changed their policies in recent years. Global use depends not only on adequate supplies and funding, but also on the question of whether IPVs can break transmission in tropical countries with poor hygiene and no use of OPVs, which is not unequivocally established.
Alternative, more radical views include the development of entirely novel vaccines which are either incapable of reversion to a neurovirulent form or are unable to spread from person-to-person. The ingenuity of the virus makes either approach potentially formidably difficult, but a number of possibilities have been suggested13–15.
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Re-emergence of poliomyelitis after eradication |
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Once vaccination ceases, there are a number of possible ways in which poliomyelitis could re-emerge, other than through undetected persistent pockets of infection or escape from laboratory stocks. Poliovirus may become a viable biological weapon as immunity wanes. Other possibilities include the evolution of non-polio enteroviruses to fill the niche left by poliovirus. It can be argued that polioviruses have their particular clinical effects because they infect cells through their unique and identified receptor site. The existence of only three serotypes of poliovirus (compared to the hundred or so rhinoviruses) could imply that antigenic structure is linked to receptor site usage. Thus, the infection of an individual with a subgenus C enterovirus could result in the selection of a poliovirus-like agent using the polio receptor which might be driven by an existing minimal immune response to the infecting virus16
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These are credible possibilities. However, the existence of long-term hypogamma-globulinaemic excretors of poliovirus provides a more immediate and known concern10,17–19. To date, there are just over 10 known or published cases of this type, most identified because they have presented with poliomyelitis. Examination of the virus being excreted suggests that some have been infected for many years. In some instances, virus excretion stopped spontaneously for unknown reasons after a few months. One patient in particular causes concern20. Type 2 Sabin-derived poliovirus strains have been isolated from the individual for 6 years, and the sequence data suggest that infection has been continuous for an additional decade, consistent with the known vaccine exposure. The patient remains healthy, but the virus excreted is neurovirulent in all animal models used and all molecular. markers of attenuation have been lost. Attempts to cure the infection have so far not been successful, but have included the use of oral immune globulin. The virus excreted is neutralised by polyclonal sera, but is not susceptible to pleconaril, an antiviral drug specific for picornaviruses; it is sensitive to ribavirin, however, and further attempts at treatment are planned in the near future. This category of patient is a significant hazard to permanent eradication of poliovirus. However, it is clear that most patients deficient in humoral immunity do not become chronically infected even when deliberately exposed17 and it is believed that HIV infection is not a risk.
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Responses to an outbreak in the post-eradication, post-vaccine era |
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Stocks of vaccine should be maintained to respond to a possible outbreak of poliomyelitis in the post-eradication, post-vaccine era. It is intended that such stocks will be used to control any anticipated epidemic although their nature is still under discussion. It is essential that surveillance be maintained at a high level so that should a case arise action can be taken quickly before it spreads. As most cases of polio infection are silent, this poses one more challenge to the successful and permanent eradication of the disease.
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Conclusions |
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The eradication of any disease depends on the eradication of the agent which causes it; factors such as the pathogenesis of the disease and the ability to detect circulation of the pathogen are crucial to its control. The eradication of smallpox and the progress that is being made in the Global Poliomyelitis Eradication Initiative illustrate both that eradication is possible, and that it is not straightforward.
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Footnotes |
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Correspondence to: Dr P D Minor, Division of Virology, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts EN6 5PD, UK
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References |
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[Abstract/Free Full Text] - Martin J, Ferguson GL, Wood DJ et al. The vaccine origin of the 1968 epidemic of type 3 poliomyelitis in Poland. Virology 2000; 278: 42–9[Medline]
- Centers for Disease Control and Prevention. Outbreak of poliomyelitis. Dominican Republic and Haiti, 2000–2001. JAMA 2001; 285: 1438
[Free Full Text] - WHO. New Poliovaccines for the Post-eradication Era. www.who.int/vaccines-documents/
- Macadam AJ, Ferguson G, Stone DM et al. Live attenuated strains of improved genetic stability. In: Brown F. (ed) Progress in Polio Eradication: Vaccine Strategies for the End Game. Developments in Biologicals, vol 105. Basel: Karger, 2001; 179–88
- Minor PD. Vaccines based on recombinant antigen strategies. In: Brown F. (ed) Progress in Polio Eradication: Vaccine Strategies for the End Game. Developments in Biologicals, vol 105. Basel: Karger, 2001; 179–96
- Gromeier M, Wimmer E, Gorbalanya AE. Genetics, pathogenesis and evolution of picornaviruses. In: Domingo E, Webster RG, Holland J. (eds) Origin and Evolution of Viruses. San Diego: Academic Press, 1999; 287–343
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