POLICY AND PRACTICE
A developing country perspective on vaccine-associated paralytic poliomyelitis
Poliomyélite paralytique postvaccinale : le point de vue des pays en développement
Poliomielitis paralítica asociada a la vacuna: perspectiva de los países en desarrollo
T. Jacob John
Adviser, Kerala State Institute of Virology and Infectious Diseases, Alappuzha, Kerala, India; Member of the National Technical Advisory Group on Immunization, Ministry of Health and Family Welfare, Government of India, New Delhi, India. Correspondence should be sent to 439 Civil Supplies Godown Lane, Kamalakshipuram, Vellore, Tamil Nadu 632 002, India (email: email@example.com)
When the Expanded Programme on Immunization was established and oral poliovirus vaccine (OPV) was introduced for developing countries to use exclusively, national leaders of public health had no opportunity to make an informed choice between OPV and the inactivated poliovirus vaccine (IPV). Today, as progress is made towards the goal of global eradication of poliomyelitis attributable to wild polioviruses, all developing countries where OPV is used face the risk of vaccine-associated paralytic poliomyelitis (VAPP). Until recently, awareness of VAPP has been poor and quantitative risk analysis scanty but it is now well known that the continued use of OPV perpetuates the risk of VAPP. Discontinuation or declining immunization coverage of OPV will increase the risk of emergence of circulating vaccine-derived polioviruses (cVDPV) that re-acquire wild virus-like properties and may cause outbreaks of polio. To eliminate the risk of cVDPV, either very high immunization coverage must be maintained as long as OPV is in use, or IPV should replace OPV. Stopping OPV without first achieving high immunization coverage with IPV is unwise on account of the possibility of emergence of cVDPV. Increasing numbers of developed nations prefer IPV, and manufacturing capacities have not been scaled up, so its price remains prohibitively high and unaffordable by developing countries, where, in addition, large-scale field experience with IPV is lacking. Under these circumstances, a policy shift to increase the use of IPV in national immunization programmes in developing countries is a necessary first step; once IPV coverage reaches high levels (over 85%), the withdrawal of OPV may begin.
Keywords: Poliovirus vaccine, Oral/adverse effects; Poliomyelitis/epidemiology/chemically induced; Poliovirus vaccine, Inactivated/therapeutic use/economics; Poliovirus/drug effects; Immunization programs; Developing countries (source: MeSH, NLM).
Lorsque le Programme élargi de Vaccination a été créé et qu'on a introduit le vaccin antipoliomyélitique oral (VPO), exclusivement utilisé par les pays en développement, les responsables nationaux de la santé publique n'ont pas eu l'occasion d'effectuer un choix éclairé entre le VPO et le vaccin antipoliomyélitique inactivé (VPI). Aujourd'hui, au fur et à mesure des progrès réalisés vers l'objectif de l'éradication mondiale de la poliomyélite due aux poliovirus sauvages, l'ensemble des pays en développement dans lesquels le VPO est employé sont confrontés au risque de poliomyélite paralytique postvaccinale (PPPV). Il y a peu encore, la PPPV était mal connue et l'analyse quantitative de ce risque limitée, mais on sait bien aujourd'hui que l'utilisation continue du VPO fait perdurer le risque de PPPV. L'interruption ou la diminution de la couverture vaccinale par le VPO augmentera le risque d'émergence de poliovirus circulants dérivés d'une souche vaccinale (PcDSV) qui reprennent des propriétés de type « virus sauvage » et risquent de provoquer des flambées de poliomyélite. Pour éliminer le risque de PcDSV, il faut maintenir une couverture vaccinale très élevée aussi longtemps que le VPO est utilisé, ou remplacer ce dernier par le VPI. Interrompre la vaccination par le VPO sans d'abord parvenir à une couverture vaccinale élevée par le VPI serait imprudent compte tenu de la possibilité que les PcDSV apparaissent. Un nombre croissant de pays industrialisés préfèrent le VPI et, comme les moyens de production n'ont pas encore été augmentés proportionnellement, son prix reste prohibitif et hors de portée des pays en développement pour lesquels, en outre, une expérience de terrain à grande échelle de l'utilisation du VPI manque. Dans ces conditions, une réorientation des politiques vaccinales visant à accroître l'utilisation du VPI dans les programmes de vaccination nationaux des pays en développement est une première étape nécessaire ; une fois que la couverture du VPI sera importante (supérieure à 85 %), le retrait du VPO pourra être amorcé.
Mots clés: Vaccin antipoliomyélitique Sabin/effets indésirables; Poliomyélite antérieure aiguë/épidémiologie/induite chimiquement; Vaccin antipoliomyélitique inactivé/usage thérapeutique/économie; Poliovirus humain/action des produits chimiques; Programmes de vaccination; Pays en développement (source: MeSH, INSERM).
Cuando se estableció el Programa Ampliado de Inmunización y se introdujo en los países en desarrollo el uso exclusivo de la vacuna antipoliomielítica oral (OPV), los dirigentes de la salud pública de los países no tuvieron la oportunidad de hacer una elección con conocimiento de causa entre la OPV y la vacuna antipoliomielítica inactivada (IPV). Hoy, a medida que se avanza hacia la meta de la erradicación mundial de la poliomielitis atribuible a poliovirus salvajes, todos los países en desarrollo en los que se usa la OPV se enfrentan al riesgo de poliomielitis paralítica asociada a la vacuna (PPAV). Hasta fechas recientes había poca conciencia de la PPAV y se habían realizado escasos estudios cuantitativos del riesgo, pero ahora se sabe perfectamente que el uso continuado de la OPV perpetúa el riesgo de PPAV. La disminución de la cobertura con la OPV o la interrupción de su administración aumentará el riesgo de que aparezcan poliovirus circulantes derivados de la vacuna que recobren propiedades similares a las del virus salvaje y ocasionen brotes de poliomielitis. Para eliminar el riesgo de que aparezcan estos virus habrá que mantener una cobertura muy elevada mientras se siga utilizando la OPV o habrá que sustituirla por la IPV. Sin embargo, debido a la posible aparición de poliovirus circulantes derivados de la vacuna, sería imprudente detener la vacunación con la OPV antes de haber alcanzado una alta cobertura con la IPV. El número de países industrializados que prefieren la IPV está en aumento, pero la capacidad de fabricación no se ha ampliado, por lo que su precio sigue siendo prohibitivo e inasequible para los países en desarrollo, en los cuales, además, no hay experiencia de campo a gran escala con la IPV. En estas circunstancias, el primer paso debería ser un cambio de política para aumentar el uso de la IPV en los programas nacionales de inmunización de los países en desarrollo; una vez que la cobertura de la IPV sea elevada (superior al 85%), se podrá empezar a retirar la OPV.
Palabras clave: Vacuna antipolio oral/efectos adversos; Poliomielitis/epidemiología/inducida químicamente; Vacuna antipolio de virus inactivados/uso terapéutico/economía; Poliovirus/efectos de drogas; Programas de inmunización; Países en desarrollo (fuente: DeCS, BIREME).
"From a humanitarian perspective, eradication provides the ultimate in health equity and social justice, bringing identical and universal benefits to every person globally" (1). This article examines how identical and universal these benefits have been. Industrialized countries used either the inactivated poliovirus vaccine (IPV) or the oral poliovirus vaccine (OPV), alone or in sequence, in routine immunization, and thereby rapidly controlled or even eliminated poliomyelitis caused by wild polioviruses (24).
WHO advocated OPV exclusively for developing countries both in the Expanded Programme on Immunization (EPI, established in 1974) and for polio eradication (from 1988) (5). The five promised advantages of OPV were low cost; ease of administration; high vaccine efficacy for low number of doses; mucosal immunity to stop virus transmission; and vaccine-related virus spread contributing to "contact immunization" (1, 57). Accumulated experience and evidence question the reality or impact of some of the putative advantages of OPV (811). Consequently, eradication has been an uphill task in developing countries, necessitating nearly 100% OPV coverage with 1015 doses per preschool child, given in EPI activities and through supplementary immunization campaigns (7).
The incidence of vaccine-associated paralytic poliomyelitis (VAPP) was considered low enough to qualify OPV as "one of the safest vaccines in current use" by WHO (12, 13). In the pre-EPI era, 600 000800 000 cases of polio occurred annually, the vast majority in developing countries. Many experts accepted VAPP as a price for the greater benefit of controlling wild poliovirus using OPV. The countries themselves, however, had no opportunity to make an informed choice between vaccines. While progress is made towards eradication, VAPP is now becoming more frequent than polio attributable to wild poliovirus infection (1416). How many VAPP cases, if any, are acceptable in developing countries? Will continued occurrence of VAPP jeopardize the very success of eradication? Will options to eliminate VAPP be affordable? These are essential questions to be solved from a developing country perspective.
The risk and burden of VAPP in developing countries
Clinically, VAPP is indistinguishable from polio caused by wild poliovirus, with an identical incubation period, range of severity and case-fatality rate (1221). In surveillance for eradication, poliovirus isolates from children with acute flaccid paralysis (AFP) are characterized as wild or vaccine-derived by reliable laboratory techniques. Identification of wild virus confirms "polio" but all other cases including VAPP are classified as "non-polio" (14, 15). Finding vaccine-derived virus in cases of AFP does not prove VAPP, as it may be a mere passenger infection. Applying specific diagnostic criteria, there were 139 cases of VAPP in Latin America in 198991 and 181 cases in India in 1999 (14, 15). Assuming an annual average of 45 cases in Latin America, the total in Latin America and India is 226 cases a year. Thus the annual global burden of 120 cases of VAPP expected by the WHO Technical Consultative Group (TCG) for Poliomyelitis Eradication is a gross underestimate (17). A realistic estimate could be as high as 400800 (16).
WHO determined the annual incidence of VAPP in European countries to be 0.43.0 per million vaccinated children and documented intercountry variations in its frequency (12 ,13). Disease surveillance to detect VAPP was recommended in countries using OPV, but was not included in the EPI (12, 13). Thus the risk of VAPP remained unnoticed in developing countries. Geographical variation in the risk of VAPP has been confirmed in all subsequent studies (24, 1416, 18, 19). Prior to the introduction of immunization, polio incidence showed considerable geographical variation, and its determining factors may also apply to VAPP (16). In India, the annual incidence of polio in the 1970s and 1980s was 2040 per 100 000 population (or 2 cases per 1000 children under five years of age), one of the highest in the world (2225). The incidence of VAPP in India, based on 181 cases in 125 million under-5-year-old children in one year, of 1.45 per million children per year, or seven cases per million birth cohorts, is also one of the highest in the world (16, 17). Developing countries with high incidence of polio should have been warned about VAPP, but its incidence was not prospectively assessed. Today, available data are inadequate to project a realistic incidence of VAPP in developing countries.
Norway introduced IPV in 1956 and shifted to OPV in 1967. During 196778 the frequency of vaccine-recipient VAPP was one per 400 000 vaccinated children and that of contact VAPP one per 100 000 vaccinated children, as a consequence of which Norway reverted to IPV in 1979 (3). In the USA, annual risk of VAPP was one case per 750 000 vaccinated children for an average of eight cases per year, for which reason OPV was abandoned in favour of IPV (18, 20, 21). In Latin America the risk was one case per 1.11.2 million first doses distributed, but risk for subsequent doses was "substantially higher than in the USA" (14). It is clear that VAPP occurs only if vaccine-related polioviruses infect children. There are geographical variations in the frequency of infection following the first or subsequent doses (811). The infection rate following one dose in a temperate region is achieved with three doses in India (811). To match the rate for three doses in the USA, 10 doses are required in India (9). Because of gross differences in the number of doses given in different settings, "doses of vaccine distributed" is not a suitable denominator for intercountry comparison of the risk of VAPP (16).
Outbreaks of VAPP, a warning signal
The attenuation of polioviruses has resulted in drastic reduction in infectiousness and transmissibility (9, 26). The median monkey oral infectious dose of Sabin virus (type 1) is 4 logs10 higher than that of wild virus (Mahoney strain) (9, 26). When 106.5 median cell culture infectious doses of Sabin virus (type 3), ten times higher than in OPV, were given to antibody-negative children in India, only 76% became infected (27). Vaccine-related polioviruses do not establish sustained circulation in the community, in contrast to wild polioviruses. Neurovirulence may re-establish by genetic reversion (28, 29). If both neurovirulence and transmissibility are regained, the resultant circulating vaccine-derived poliovirus (cVDPV) becomes wild-like (30). A cVDPV type 2 circulated for 10 years (198393) in Egypt, causing 32 cases of polio (31). A cVDPV type 1 circulated silently in the Dominican Republic and Haiti from 1998 and caused an outbreak of polio (21 confirmed and 15 probable cases) from July 2000 to July 2001, until interrupted by outbreak response vaccination (30). Since then, cVDPV has been detected in small clusters in Madagascar, the Philippines and Romania (32 and D. Wood, personal communication, 2003).
In Haiti, the national immunization days were discontinued and immunization coverage declined after polio eradication was certified in the Americas in 1991. The resultant population mix of non-immune children and recently immunized vaccine virus-shedding children offered the milieu for a revertant virus to spread silently and cause outbreaks, as seen in Egypt and Haiti (30, 31). If immunization coverage remains high, as in the Philippines and Romania, such revertants do not spread widely. Thus, both continuing OPV and its gradual or abrupt discontinuation may carry the risk of emergence of cVDPV. Any developing country wanting to discontinue OPV to avoid VAPP risks the emergence of cVDPV, unless children are adequately protected with IPV.
Even if cVDPVs emerge only rarely and in a distant community, they are a threat everywhere as they could circulate widely and be imported elsewhere. Therefore, rich countries using IPV are unlikely to discontinue it until OPV has been discontinued everywhere. This upsets the economic attraction of eradication the saving from discontinuing immunization (33). As the elimination of wild viruses was accomplished in most developing countries using OPV, the few remaining countries also must follow suit to achieve success without losing time to execute a change in policy. Therefore it is necessary to consider only the issue of eliminating the risk of VAPP using IPV where wild viruses have been eliminated. Once VAPP is also globally "eradicated", discontinuing polio immunization will become feasible. Thus, the availability and affordability of IPV and its suitability in EPI in developing countries are the critical aspects of the solution to the problems of sporadic VAPP and emergence of cVDPV. Discontinuing OPV in developing countries is in the best public health and economic interests of industrialized countries too.
IPV and the final phase of polio eradication
Well-off countries are replacing OPV with IPV to eliminate VAPP. Currently, 22 countries are using IPV exclusively and eight more have a sequential schedule of IPV and OPV (D. Wood, personal communication 2003). This situation has begun to evolve as richpoor disparity. Global public health leaders are divided on the acceptability of VAPP in developing countries. Some perceive the double standard, as developing countries will be exposed to a risk that the industrialized nations will avoid (34). The philosophical attraction of disease eradication is that it will achieve equity in health benefit globally (1). Equity demands that no child will develop polio attributable to wild poliovirus or vaccine-related virus. The hope expressed "that politicians in developing countries and zealous ethicists in the developed world ... will not demand, in the name of equity in health, a total switch to IPV" (35) deserves rejection. The opportunity to advance a developing country perspective, even if only in a journal article, is comforting. The immediate responsibilities of WHO and its partner agencies in polio eradication are to assess the economic repercussions of eliminating the risk of sporadic and outbreak VAPP, to alert developing countries and donors to the risk, and to design ways of minimizing and sharing the costs.
At present, very few manufacturers produce IPV and the production capacity is only 100 million doses (35). This is insufficient for meeting the increasing demand even from industrialized countries. Since demand outstrips supply, the price remains high. The volume of manufacture affects the cost of a vaccine. The current low volume of IPV manufacture was determined by low demand in previous years, which in turn was determined by the exclusive OPV policy in developing countries. A change in policy and an assured future market volume will encourage established manufacturers to augment, and new companies to invest in, IPV production. Such market forces are bound to lead to a reduction in the price of IPV. If IPV is combined with the diphtheriatetanuspertussis vaccine (DTP), one separate shelf item and additional health workerchild contacts and injections can be avoided, reducing the overall cost of polio immunization. Today, OPV is given both according to routine schedules as well as in annual pulse campaigns, increasing the cost of vaccine administration. Even after the certification of eradication of wild polioviruses, the continued use of OPV for an interim period for interrupting transmission of any lurking virus anywhere or its importation to new territories will have to be through pulsing, for the routine method was inadequate to halt transmission in the past. In Haiti the pulse campaigns were discontinued, paving the way for emergence of the outbreak of polio caused by vaccine-derived wild-like poliovirus (30). The large expenses for pulse campaigns will also be saved with the use of IPV under EPI.
The final question is about the suitability of IPV in the EPI system for assured interruption of unrecognized surviving, imported or introduced wild poliovirus or cVDPV anywhere. Experience with IPV in developing countries is meager on account of the policy to use exclusively OPV. There are several sources of information that IPV will be suitable, but they are not elaborated here (911, 36, 37). More details may be found in two recent publications (10, 11). However, the schedule of injections in EPI at 6, 10 and 14 weeks is not ideal in order to get the best antibody response in infants (3638). In countries where the frequency of antibody response to OPV is excellent, this schedule may not match it (3638). In contrast, where the frequency of response to OPV is low, which is the case in most developing countries, the IPV responses will be superior (12). Any deficiency in antibody response can be more than overcome with one booster injection of DTP-combined IPV in the second year of life (39, 40). Thus, the level of immune protection achieved at present by the fifth year of life with OPV (given in the EPI schedule plus annual 2-dose pulses until 5 years of age) can be matched with that achieved in the second year of life using IPV. Such an approach can be expected to offer better herd protective effect than that obtained with multiple doses of OPV (9, 10). From both the humanitarian and scientific viewpoints any polio paralysis should be prevented, not merely that caused by wild viruses. Therefore, polio eradication must be perceived as truly the zero incidence of poliovirus infection, both wild and vaccine-derived, in developed and developing countries (41).
Conflicts of interest: none declared.
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Submitted: 7 July 03
Accepted: 22 August 03
The opinions expressed are those of the author and do not necessarily represent those of the organizations and institutions to which he is affiliated.