Reaching the last one per cent: progress and challenges in global polio eradication

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Reaching the last one per cent: progress and challenges in global polio eradication Olen Kew Since its launch in 1988, the World Health Organization’s Global Polio Eradication Initiative has reduced worldwide polio incidence by >99%. The most dramatic progress was achieved up to the year 2000, the original eradication target date, but subsequent years have seen only limited progress in preventing the last 1% of cases. Recent gains in India and Nigeria have been offset by continued endemicity in Pakistan and Afghanistan, and repeated reseeding of wild poliovirus into polio-free areas has led to large outbreaks and re-established transmission. Although wild poliovirus type 2 was eradicated in 1999 and wild poliovirus type 3 may be nearing eradication, the continued emergence of circulating vaccine-derived polioviruses, especially type 2, presents ongoing challenges to stopping all poliovirus transmission. Address Division of Viral Diseases, G-10, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, GA 30333, USA Corresponding author: Kew, Olen ([email protected])

Current Opinion in Virology 2012, 2:188–198 This review comes from a themed issue on Emerging viruses Edited by Erica Ollmann Saphire and Heinz Feldmann Available online 7th March 2012 1879-6257/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coviro.2012.02.006

Introduction In 1988, the World Health Assembly resolved to eradicate polio worldwide by the year 2000, launching the World Health Organization (WHO) Global Polio Eradication Initiative (GPEI) [1,2]. This landmark resolution was made in light of dramatic progress by the Pan American Health Organization toward achieving the goal of eradicating wild polioviruses (WPVs) indigenous to the Americas by 1990, a goal reached in 1991 [3]. Global polio eradication is based on four key strategies: first, routine immunization of infants with trivalent oral poliovirus vaccine (tOPV); second, supplementary immunization activities (SIAs) with oral poliovirus vaccine (OPV) in the form of National and Subnational Immunization Days; third, targeted door-to-door ‘mop-up’ OPV immunization in areas of focal transmission; fourth, sensitive poliovirus (PV) surveillance [4]. The GPEI achieved early Current Opinion in Virology 2012, 2:188–198

rapid progress, reducing polio incidence worldwide by >99%, from an estimated 350,000 cases in 1988 to a low of 493 cases reported in 2001 (Figure 1), raising hope that a polio-free world would soon be realized [4]. Optimism was fueled by the eradication of WPV type 2 (WPV2) in 1999 and the certification of polio-free status of three WHO Regions: the Americas in 1994, the Western Pacific in 2000, and Europe (including countries in the Caucasus and Central Asia) in 2002 [5] (Figure 1). Optimism was reinforced by cessation of WPV transmission in many highly challenging settings: first, in areas of extreme biological risk (high population densities, large birth cohorts, poor sanitation and hygiene, tropical conditions) [6] such as Bangladesh (last case from indigenous WPV: 2000) and coastal West Africa (including southern Nigeria; last case from locally indigenous WPV: 2001); second, in conflict areas such as Sri Lanka (last case: 1993), Cambodia (last case: 1997), and Angola (last case from indigenous WPV: 2002); and third, in many resource-poor settings in Africa and Asia. The technical feasibility of polio eradication had been repeatedly demonstrated and WPV seemed destined to follow smallpox virus into extinction from the natural environment. By 2006, only four countries had never interrupted WPV transmission. However, the years 2000–2010 were marked by a stabilization of the global polio incidence at 500–2000 cases per year (Figure 1), by repeated WPV outbreaks in the continuously endemic reservoir countries, and by spread of virus to 39 other countries, leading to outbreaks, and, in at least four countries in Africa, re-establishment of endemic transmission [1]. In addition, the long-standing concern that derivatives of the Sabin OPV strains could circulate for prolonged periods in areas of low OPV coverage [7] was confirmed by the occurrence in 2000–2001 of an outbreak in Hispaniola (Haiti and the Dominican Republic) associated with a type 1 circulating vaccine-derived poliovirus (cVDPV) [8]. Independent cVDPV outbreaks have subsequently occurred in 17 other countries [9] (for updates see: http:// www.polioeradication.org/). The past two years have seen renewed progress in India and Nigeria, but continued challenges elsewhere [10,11,12,13,14]. As described below, the most encouraging signs have been in India, the country with the largest cohort of children <5 years of age, with a highly mobile population, and previously the world’s largest WPV reservoir [15]. Nigeria, also has seen a sharp decline (>80%) in WPV cases since 2009, but persistent local reservoirs remain in the northern states. Pakistan remains a major WPV1 reservoir with Afghanistan closely www.sciencedirect.com

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(a) Incidence of paralytic polio cases associated with wild poliovirus (WPV) infections worldwide, 1985–2011 (source: http://www.polioeradication.org/ ). Estimated cases are shown as gray bars; reported and virologically confirmed cases are shown as black bars; asterisks indicate case counts as of 03 January 2012. Arrows below three-letter codes for WHO regions (AMR, Americas; EUR, Europe; WPR, Western Pacific) indicate year of last detection of indigenous WPV. (b) Polio cases by serotype (WPV1, wild poliovirus type 1; WPV3, wild poliovirus type 3), 2007–2011. Introduction of bivalent OPV (bOPV; types 1 + 3) in late 2009 is indicated by the arrow. (c) Polio cases from endemic and imported WPV, 2007–2011. WPV in re-established transmission countries is coded as imported from their original endemic reservoirs of India and Nigeria (see Figures 2 and 3). (d) Polio cases associated with endemic and imported WPV1, 2007–2011 (IND, India; NIE, Nigeria; PAK, Pakistan). (e) Polio cases associated with endemic and imported WPV3, 2007–2011.

linked epidemiologically to it [11,16]. Spread of WPV from endemic reservoirs to polio-free countries continued into 2011, even as international cVDPV spread has been minimal. As the world’s largest public health initiative, the GPEI addresses challenges at many different levels: political, social, managerial, logistical, financial, epidemiologic, and www.sciencedirect.com

virologic. Progress toward overcoming these multiple barriers and eradicating polio is regularly reviewed by an Independent Monitoring Board of leading public health experts [12]. In this brief review, the global epidemiology and virology of polio are surveyed, with an emphasis on progress and challenges over the past five years. The consequences of repeated importations of WPV1 and WPV3 from the remaining endemic reservoirs Current Opinion in Virology 2012, 2:188–198

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are presented in view of widening immunity gaps in some polio-free countries and the growing risk of severe disease in older age groups. In addition to risks from indigenous and imported WPVs, the risks of recurring cVDPV outbreaks, especially those associated with cVDPV2, are discussed in the context of current and future immunization strategies.

Polio eradication: a virologic status report WHO classifies countries with WPV circulation into three categories: first, endemic countries; second, countries with re-established transmission; third, countries with imported WPV (Figures 1–3). The current classification scheme does not include cVDPV circulation, but cVDPV outbreaks are regularly monitored by WHO (http:// www.polioeradication.org/). Progress in polio eradication has been accompanied by a steady reduction in the genetic diversity of circulating WPVs. Of the 20 WPV1 genotypes and 17 WPV3 genotypes found in 1988 [17], only five genotypes remain (three WPV1 and two WPV3) (Figures 1–3), and diversity within those genotypes has generally declined in recent years, especially for WPV3. Endemic countries

The endemic countries are those that have never interrupted WPV transmission (Figures 2 and 3). At the

beginning of 2011, four countries were recognized as having been continuously endemic for polio: India, Nigeria, Afghanistan, and Pakistan [1]. By the end of 2011, that number may have decreased by one as a result of intensive efforts in India. Nigeria’s momentum toward eradication in 2009–2010 slowed in 2011. Pakistan has had a sharp increase in cases in 2011, and progress in Afghanistan is closely tied to progress in Pakistan. India

Three decades ago, India (population [2011]: 1.2 billion) was estimated to have had at least half the world’s polio cases, 200,000 cases per year [15], equivalent to one paralytic case every 3 min. As just one example, WPV was so deeply entrenched in the city of Mumbai that some children were simultaneously infected with all three WPV serotypes, and the polio burden in that one city was 1000 cases per year. WPV transmission in large Mumbai slums was so intense that local WPV lineages could be maintained for years. With the highly mobile Indian population, WPV spread efficiently within the country as well as internationally, to other parts of Asia, and to Africa, Europe, and North America. This began to change in the late 1990s with an ever increasing commitment to polio eradication by the government of India. The first major milestone in India, the eradication of WPV2 in Uttar Pradesh, marked the end of natural circulation of

Figure 2

Nigeria WPV1

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Re-established Transmission Current Opinion in Virology

Countries with known WPV1 transmission, 2009–2011. Countries (or areas within countries) that had not eradicated indigenous WPV1 are indicated by solid colors; countries with re-established WPV1 transmission are indicated by dark upward diagonal pattern; countries with imported WPV1 are indicated by wide upward diagonal pattern. Colors correspond to WPV1 genotypes indigenous to Nigeria (dark red), Pakistan and Afghanistan (blue green), and India (dark green). Spread of Indian WPV1 in 2010 from Tajikistan, to Turkmenistan, Kazakhstan, and the Russian Federation is indicated by circles enclosing wide upward diagonal patterns. The 2011 WPV1 outbreak in Xinjiang in Western China of WPV1 imported from Pakistan is indicated by an ellipse enclosing a wide upward diagonal pattern. The last case in India associated with WPV1 was reported on 13 January 2011. Current Opinion in Virology 2012, 2:188–198

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Figure 3

Nigeria WPV3

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Current Opinion in Virology

Countries with known WPV3 transmission, 2009–2011. Colors and patterns are as described for Figure 2. The last case in India associated with WPV3 was reported on 22 October 2010.

that serotype [18]. However, subsequent years saw a recurring cycle of WPV1 and WPV3 outbreaks, spreading from the major reservoirs of Uttar Pradesh and Bihar to other states. WPV3 cases fell sharply in 2010 after introduction of bivalent OPV (bOPV, types 1 + 3) [14,19], and the alternating WPV1/WPV3 cycle appears finally to have been broken in October 2010 (last WPV3 isolate) and January 2011 (last WPV1 isolate) [20]. The apparent eradication of indigenous WPV from India conclusively demonstrates that the GPEI strategy can prevail under conditions most favorable to continued WPV transmission: high population densities, large birth cohorts, poor sanitation and hygiene, and tropical to subtropical climates [6]. Similar conditions had been overcome previously, but the magnitude of the challenges in India were unprecedented, as the two highest-risk states have a combined population of 300 million, a combined monthly birth cohort exceeding 500,000, and continuous migration between them and into other parts of the country. While routine immunization was being strengthened, immunization campaigns were conducted monthly to assure protection of the growing cohort of newborns and infants, even though the per-dose efficacy of OPV in the highest risk communities was low [21]. Moreover, the last WPV reservoirs shifted between Uttar Pradesh and Bihar, with spread to other states. The Indian WPV1 genotype survives in central Africa (Figures 1 and 2) as a result of importations from Uttar Pradesh several years ago, but the home reservoir for that genotype has been silent for www.sciencedirect.com

over a year despite continued highly sensitive surveillance [20]. Nigeria

Nigeria (population [2011]: 167 million) is the only country in Africa never to have stopped WPV transmission. Nonetheless, the WPV genotypes indigenous to the southern states, with the greater intrinsic biological risks, were eradicated before 2002. Momentum was lost in the northern states by the suspension of SIAs in 2003–2004 [22], and continued social conflict. Persistent low rates of OPV coverage in northern Nigeria have resulted in the circulation through 2011 of all three PV serotypes: WPV1, cVDPV type 2 [cVDPV2], and WPV3 [23]. The unbroken transmission of cVDPV2 since 2005 is a strong indicator of widespread gaps in immunization because tOPV is highly effective in controlling all PV2 transmission. This view is reinforced by continued WPV3 circulation following SIAs using bOPV, whose use has all but eliminated WPV3 transmission in Asia [1,18] (Figure 1e). Northern Nigeria has been the source reservoir for outbreaks in southern Nigeria and across an importation belt in Africa extending from Senegal in the west to the Horn of Africa in the east (Figures 1–3 and Tables S1 and S2) (see below). Pakistan

Before the launch of the GPEI, Pakistan (population [2011]: 175 million) was estimated to have had at least 25,000 cases per year [24], and virus previously spread from Pakistan (and Afghanistan) to Iran, the Gulf States, Malaysia, and Albania. By 2000, intensified immunization Current Opinion in Virology 2012, 2:188–198

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sharply reduced polio incidence, but the national program has made only incremental progress over the past 10 years, with case counts running between 28 (in 2006) and 187 (in 2011, reported as of 03 January 2012) [16]. Despite these setbacks, WPV3 circulation in Pakistan appears to be highly localized to insecure areas along the northwestern border with Afghanistan. Environmental surveillance at multiple sites elsewhere within the country has repeatedly detected WPV1 but not WPV3. The two WPV3 cases in Pakistan represent the only WPV3 cases detected in Asia in 2011, and appear to underscore the unexpectedly high efficacy of bOPV against WPV3 [1,14] (Figure 1b,e). The commitment to the GPEI at the national level has not translated into effective performance in many locales [12]. WPV circulation appears to have been interrupted in much of Punjab, the most populous province, and Karachi, the largest city, only to be repeatedly re-established by WPV from insecure and under-performing areas [16]. Afghanistan

Afghanistan (population [2011]: 30 million) forms a common epidemiologic block with Pakistan [16]. Through a well-managed national immunization program [12], polio has been effectively controlled in the northern provinces, but circulation continues in the conflict areas in the southern provinces of Kandahar and Helmand, with spread to other parts of the country. Active migration between southern Afghanistan and southern Pakistan has maintained a corridor of WPV transmission between the two countries. Although the primary reservoirs are in Pakistan, focal WPV1 circulation has continued unbroken in southern Afghanistan [16]. Re-established transmission and importation countries

The re-established transmission countries are in Africa (Angola, Chad, the Democratic Republic of Congo [D.R. Congo]), whereas importation countries include those across the African importation belt, south and Central Asia, and the Russian Federation (Figures 2 and 3 and Tables S1 and S2). Nigerian WPV1 spreads west and east

Following suspension of SIAs in northern Nigeria in 2003–2004, WPV1 spread from Nigeria to 18 countries in 2003–2006, from Guinea in the west, to Yemen and Somalia in the Horn of Africa, to Indonesia at the southeastern rim of Asia, resulting in large outbreaks in several countries [22]. This wave of virus appears to have been rolled back in all countries except Kenya and Uganda, where it has persisted into 2011 (Figure 2 and Table S1). A second wave of WPV1 from Nigeria began in 2008, and spread to 14 countries, re-infecting many of the same countries that experienced the 2003–2006 outbreaks [25]. WPV1 imported into Chad from northeastern Nigeria in 2010 caused a large outbreak that has continued through Current Opinion in Virology 2012, 2:188–198

Box 1 Abbreviations. AFP

acute flaccid paralysis

bOPV

bivalent oral poliovirus vaccine (types 1 + 3)

cVDPV

circulating vaccine-derived poliovirus (serotype given by number suffix)

GPEI

Global Polio Eradication Initiative

GPLN

Global Polio Laboratory Network

IPV

inactivated poliovirus vaccine

iVDPV

immunodeficiency-associated vaccine-derived poliovirus (serotype given by number suffix)

mOPV

monovalent oral poliovirus vaccine (serotype given by number suffix)

OPV

oral poliovirus vaccine

PCR

polymerase chain reaction

PV

poliovirus

SIAs

supplementary immunization activities

tOPV

trivalent oral poliovirus vaccine

WHO

World Health Organization

WPV

wild poliovirus (serotype given by number suffix)

2011, resulting in re-established transmission in Chad and further export of WPV1 into the Central African Republic (Table S1). However, effective SIAs in the countries of West Africa again rolled back the imported Nigerian WPV1 [1]. Nigerian WPV3 spreads west and east

WPV3 from northern Nigeria spread east to Chad where it caused 79 polio cases between November 2007 and March 2011 [1] (Figure 3 and Table S2). Because the case:infection ratio for WPV3 is about sixfold lower than for WPV1 (Box 1), the actual number of WPV3 infections in Chad was probably high (100,000 or more). WPV3 spread from Nigeria and Chad to Cameroon (4 cases) and the Central African Republic in 2009 (14 cases). Nigerian WPV3 was repeatedly imported into Niger, where it caused 18 cases during 2009–2011. Virus originating from Nigeria spread to Mali (5 cases), Coˆte d’Ivoire (35 cases), and Guinea (3 cases) in 2010–2011 (Table S2). Indian WPV1 spreads southwest and north

Cross-border transmission of WPV1 from the core reservoirs of Uttar Pradesh and Bihar into neighboring communities in Nepal occurred up to 2010, occasionally sparking limited circulation within Nepal. More surprising was the longer-range exportations of Indian WPV1 to southern Africa and Central Asia in the waning years of endemicity in India. Two WPV1 importations into Angola After eradication of its indigenous WPVs in 2002, Angola experienced importation of WPV1 in 2005, and a second www.sciencedirect.com

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WPV1 importation in 2007 [25]. In both instances the source reservoir for the imported WPV1 was Uttar Pradesh, India. WPV1 spread from Angola to D.R. Congo, and from there to Burundi (Figure 2 and Table S1), and from Angola to the Republic of Congo (see below). WPV1 transmission was re-established in both Angola and D.R. Congo (Figure 2). The Tajikistan outbreak, 2010 Between 1 February and 4 July 2010, 458 cases associated with WPV1 were reported in Tajikistan (population [2010]: eight million), whose last indigenous WPV1 case was reported in 1997 [26]. This was the first outbreak in the European Region since it was declared polio-free in 2002. Genetic analysis performed by GPLN Reference Laboratories in Moscow and Mumbai showed that the outbreak virus was a recent import from Uttar Pradesh, India. The outbreak virus spread to Turkmenistan (3 cases), Kazakhstan (1 case), and the Russian Federation (14 cases in four widely separate areas) (Figure 2 and Table S1); indirect evidence also pointed to an outbreak in neighboring Uzbekistan. Many (160/458; 35%) of the cases in Tajikistan were in older age groups (>5 years of age), and the median age increased as the outbreak progressed. Four rounds of national SIAs using mOPV1, targeting persons <15 years of age, controlled the outbreak in Tajikistan. The last outbreak case was reported in Russia on 25 September 2010. Declining rates of OPV coverage in Tajikistan prompted the European Regional Commission for the Certification of Poliomyelitis Eradication to highlight the risk of WPV importation and recommend in 2009 preventive SIAs, but the required funding was not allocated [26]. The Republic of Congo outbreak, 2010–2011 The Republic of Congo (population [2011]: 4.2 million) appeared to have escaped the polio outbreaks afflicting neighboring countries, as the last case before 2010 was in 2000. Rates of OPV coverage, however, had been low for 20 years in part because of civil conflict, and no national SIAs had been conducted since 2006. In November 2010, a case of polio associated with WPV1 was confirmed in a resident of the port city of Pointe Noire; the isolate was closely related to virus circulating nearby in Angola [27,28]. An explosive outbreak spread inland from the coastal departments of Pointe Noire and Kouilou, which had 80% of the approximately 441 cases (Table S1). The precise duration and extent of the outbreak is uncertain because adequate specimens were collected from <20% of patients and only 70 AFP cases were confirmed virologically. The very high case:fatality ratio (40%) in the two coastal departments was attributable to widespread infection in older age groups (known to be at higher risk of bulbar polio than children), as the median age of cases was 20 years (range 0–63 years). An unexpectedly high proportion (68%) of AFP cases was in www.sciencedirect.com

males. Virus spread to D. R. Congo (62 cases) via multiple importations, to Gabon (1 case), and back to Angola (Table S1). The outbreak was controlled in the Republic of Congo by four national SIAs (two mOPV1 rounds followed by two bOPV rounds) targeting the entire population, synchronized with neighboring areas in D. R. Congo, Angola, and Gabon. Circulation continued, however, through 2011 in D. R. Congo (Table S2). Indian WPV3 spreads southwest

Like the earlier WPV1 importations, the WPV3 imported into Angola originated in Uttar Pradesh, India [25]. The WPV3 was associated with 24 cases in Angola between March and September 2008, and spread to D. R. Congo, where it was associated with four cases between October 2008 and June 2009 (Table S2). Pakistani WPV1 spreads north to Xinjiang, China, 2011

Xinjiang, a relatively sparsely populated semi-arid Autonomous Region (population: 22 million) in western China, had the last indigenous WPV3 case (1993) and among the last indigenous WPV1 cases (1994) in China. Between 3 July and 9 October 2011, 21 cases associated with WPV1 were reported from three southern prefectures where the rates of OPV coverage had declined (http://www.wpro.who.int/health_topics/poliomyelitis/ china/poliochn7.htm) (Figure 2). Molecular epidemiologic investigations by the GPLN Reference Laboratories in Beijing and Islamabad showed that the outbreak virus had recently been imported from Sindh, Pakistan. As in the Republic of Congo and Tajikistan, a high proportion (11/21; 52%) of virologically confirmed cases were in older age groups (19–53 years of age), with the remainder in children <3 years of age. Two patients (9.5%) died. China launched four SIAs in Xinjiang, targeting all persons <40 years of age, and intensified polio surveillance. The outbreak appears to have stopped, but the risk remains of reimportation from endemic Pakistan. Vaccine-derived poliovirus outbreaks

Among the two well-defined categories of VDPVs (Box 2), cVDPVs are of the greatest current public health concern [9,14]. Since 2000, cVDPV outbreaks have occurred in 18 countries, with the large majority (84%) of reported cases associated with cVDPV2 (Figure 4 and Table 1). By contrast, cVDPV3 outbreaks are rare, accounting for only 1.6% of known cVDPV cases, an unexpected finding because the type 3 OPV strain is a major contributor to vaccine-associated paralytic poliomyelitis in OPV recipients [29]. Because the case:infection ratio for PV2 infections is low (Box 3) [6], the number of cVDPV2 infections worldwide since 2000 is estimated at nearly one million [30]. Moreover, several recent cVDPV2 outbreaks involve either successive emergences [31] or concurrent outbreaks associated with multiple independent emergences [9,32]. Current Opinion in Virology 2012, 2:188–198

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Box 2 Polio and polio immunization.

Table 1

Poliomyelitis (polio) is caused by polioviruses, which constitute three closely related serotypes within a large group of enteroviruses designated species C [36]. Like other enteroviruses, PVs replicate in the intestinal tract, and only rarely invade the central nervous system. Accordingly, most PV infections are asymptomatic, and the paralytic case: infection ratios are low (type 1, 1:200; type 2, 1:1800; type 3, 1:1200) [6]. Humans are the only natural reservoir host for PV, and because both OPV and the inactivated poliovirus vaccine (IPV) are effective against all strains of PV, global polio eradication is feasible. OPV has several key advantages over IPV for use by the GPEI in developing countries: first, ease of administration; second, suitability for use in mass immunization campaigns; third, efficient induction of intestinal mucosal (secretory IgA) immunity; and fourth, low cost. The synchronous induction of intestinal immunity through mass OPV campaigns (SIAs) efficiently blocks person-to-person transmission of WPV, thereby protecting individual OPV recipients and the broader community. tOPV is also administered as a part of routine immunization, where several vaccines are given early in life to protect against serious infectious diseases. The disadvantages of OPV are: first, the ongoing risk of rare cases of vaccine-associated paralytic poliomyelitis among OPV recipients and their unimmunized contacts; second, the risk of emergence of highly divergent vaccinederived polioviruses (box 4). In recognition of these OPV risks, an increasing number of countries that have been polio-free for many years have shifted from OPV to IPV, a trend that is likely to continue for the foreseeable future [2,14].

Geographic distribution of circulating vaccine-derived polioviruses (cVDPVs), 2000–2011.a Country cVDPV1 Haiti/Dominican Republic Philippines China Indonesia Myanmar Mozambique cVDPV2 Madagascar Nigeria Niger b Ethiopia Somalia D. R. Congo India Chad b Afghanistan Yemen cVDPV3 Cambodia Ethiopia a b

Multiple independent cVDPV2 outbreaks, Nigeria, 2005–2011

Since 2005, a polio outbreak of 381 cases associated with cVDPV2 has occurred in 11 northern and three central states of Nigeria [9,32,33] (Figure 4 and Table 1). The outbreak peaked at 153 cases in 2009, but 27 cases were detected in 2010, and 35 cases were detected by mid-December 2011. Genetic analysis resolved the outbreak into >20 independent VDPV2 emergences that occurred during 2004–2011, at least 7 of which established circulating lineages [32]. The outbreak occurred in northern states where routine immunization coverage with tOPV is low and tOPV SIAs were infrequent [32,33]. Spread of the cVDPV2 from northern Nigeria has been very limited, with only six cases in Niger from multiple importations and one case in Chad from an importation in 2010 (Figure 4 and Table 1) (Box 4).

Other recent cVDPV outbreaks

Most of the recent outbreaks have been associated with cVDPV2 (Figure 4 and Table 1), several of which (e.g., D. R. Congo, India, and Yemen) were associated with multiple independent emergences [9]. In several settings, this reflects the continued weakness in routine immunization with tOPV and the extensive use of mOPV1 and bOPV in SIAs. However, it also reflects the greater tendency of the Sabin 2 OPV strain to revert and spread to contacts [29]. Three separate cVDPV3 emergences were detected in Ethiopia in 2009–2010, Current Opinion in Virology 2012, 2:188–198

Year(s) detected 2000–2001 2001 2004 2005 2006–2007 2011

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Data as of 03 January 2012. Importations from Nigeria.

and a single cVDPV1 emergence was detected in Mozambique in 2011 (Figure 4 and Table 1).

Differential outbreak risks for the three poliovirus serotypes The three PV serotypes differ substantially in their polio risks. WPV1 presents the highest risk: it has the highest case:infection ratio (Box 2) and the greatest capacity to spread over wide geographic areas (Figure 2) and cause explosive outbreaks [34] (Table S1). By contrast, cVDPV1 outbreaks recognized over the past decade have been of intermediate size and duration (Table 1). Although WPV2 is extinct, cVDPV2 appears to have recovered all the key biological properties of WPV2. In at least three different settings (Nigeria, D. R. Congo, and Egypt) cVDPV2 transmission continued for several years [29,30] (Table 1). Nonetheless, the geographic spread of cVDPV2 has been more restricted, possibly because of the high levels of immunity induced by tOPV and the tendency of the Sabin type 2 strain to spread to secondary contacts, thereby conferring broader population immunity even in settings of moderate rates of tOPV coverage [29]. Currently, PV3 may present the lowest public health risk. WPV3 reservoirs are the most restricted, WPV3 appears to be less transmissible than WPV1 (Figures 2 and 3), and bOPV has been especially effective in stopping WPV3 transmission [1,14] (Figure 1b,e). Finally, cVDPV3 (and iVDPV3) emergence is comparatively infrequent [9] (Figure 4 and Table 1), despite the major www.sciencedirect.com

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Circulating vaccine-derived poliovirus (cVDPV) outbreaks, 2000–2011. Map: location of cVDPV outbreaks, color-coded by serotype (red, cVDPV type 1 [cVDPV1]; yellow, cVDPV2; blue, cVDPV3). The major focus of cVDPV transmission in India is shown by the yellow ellipse, and localized, transient circulation in China is shown by a red circle. The emergence of cVDPV2 and cVDPV3 in Ethiopia is indicated by upward yellow and blue diagonal patterns. Apart from the 2000–2001 cVDPV1 outbreak on the island of Hispaniola (Haiti and the Dominican Republic) and the limited spread of the cVDPV2 from Nigeria to Niger and Chad (indicated by yellow tint across borders), all other outbreaks are independent events. Some countries had successive (e.g., Madagascar) or concurrent (e.g., Nigeria and D. R. Congo) cVDPV2 outbreaks. Table 1 cases associated with cVDPV outbreaks, 2000–2011, color-coded by serotype.

role of Sabin 3 in vaccine-associated paralytic poliomyelitis among tOPV recipients [29].

A changing global polio risk profile The underlying mechanism of polio eradication with OPV is to displace WPVs with vaccine strains whose presence in the community is transient wherever coverage rates are high. Displacement is most efficient in the www.sciencedirect.com

low season for WPV transmission, usually in the winter in temperate zones and the cool dry season in tropical areas, when WPV chains of transmission are fewest [6]. SIAs conducted in the low season reduces WPV transmission by synchronously inducing high levels of population immunity, and continued routine immunization and SIAs throughout the year block re-establishment of WPV transmission and protect the new birth cohort. Because Current Opinion in Virology 2012, 2:188–198

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Box 3 Global polio surveillance and poliovirus molecular epidemiology. Global poliovirus surveillance integrates field surveillance for cases of acute flaccid paralysis (AFP) with laboratory investigations of clinical specimens (usually stool specimens) from patients with AFP and their contacts. Because AFP has multiple etiologies (including Guillian-Barre´ syndrome, transverse myelitis, and transient [or occasionally permanent] paralyses associated with non-polio enterovirus infections), AFP surveillance must be combined with virologic studies to investigate the possible etiologic role of WPV (and VDPV; box 4) infections. Beginning in 1985, WHO has built a Global Polio Laboratory Network (GPLN) of 145 formally accredited and technically proficient poliovirus laboratories, strategically located to support global PV surveillance [37]. The GPLN supplements virus isolation with analyses by real-time reverse transcriptase PCR using poliovirus group-specific, serotype-specific, vaccine strain-specific, and WPV genotype-specific primers and probes [37,38]. All independent WPV and VDPV isolates are sequenced within the 900-nucleotide interval encoding the major poliovirus surface capsid protein, VP1. When increased sensitivity for detecting PV circulation is needed, AFP surveillance has been supplemented by sampling healthy contacts of AFP cases or through environmental surveillance [16,20,39]. The rapid evolution PV genomes, 1% per year at all sites and 3% per year at synonymous sites [40], permits the patterns of PV transmission to be followed with extraordinary precision. Evolution rates appear to be similar across serotypes and for WPV and VDPVs circulating within communities, and for immunodeficiency-associated VDPVs replicating in a single patient [41,42]. Sequence relationships among isolates are used to: first, determine the pathways of PV transmission; second, identify WPV endemic reservoirs; third, estimate the dates of WPV importation; fourth, detect gaps in surveillance from gaps in the sequence record; fifth, estimate the dates of VDPV emergence; sixth, estimate the duration of prolonged VDPV infections.

antigenic evolution of PV is restricted, and appears to play little if any role in PV spread, the many WPV genotypes found in the pre-vaccine era appear to have been firmly entrenched in their core endemic reservoirs [17]. Natural displacement of pre-existing WPV genotypes from highly endemic communities was probably infrequent, and epidemics from imported WPV introduced into other endemic areas were likely rare.

Box 4 Vaccine-derived polioviruses (VDPVs). VDPVs can cause paralytic polio in humans and have the potential for sustained circulation. VDPVs resemble WPVs biologically [43] and differ from the majority of vaccine-related poliovirus isolates by having genetic properties consistent with prolonged replication or transmission. Because poliovirus genomes evolve at a rate of approximately 1% per year (Box 3), vaccine-related viruses that differ from the corresponding OPV strain by >1% of VP1 nucleotide positions are estimated to have replicated for at least one year in one or more persons after administration of an OPV dose. This is substantially longer than the normal period of 4–6 weeks of vaccine virus replication in an OPV recipient. PV isolates are grouped into three categories, based on the extent of divergence of the VP1 nucleotide region compared to the corresponding OPV strain: first, vaccine-related polioviruses (1% divergent [types 1 and 3] or 0.6% divergent [type 2]); second, VDPVs (vaccine-related polioviruses that are >1% divergent [types 1 and 3] or >0.6% divergent [type 2] from the corresponding OPV strain); and third, WPVs (no genetic evidence of derivation from any vaccine strain) [43]. VDPVs are further categorized as: first, circulating VDPVs (cVDPVs), when evidence of person-to-person transmission in the community exists; second, immunodeficiencyassociated VDPVs (iVDPVs), which are isolated from persons with primary immunodeficiencies who have prolonged VDPV infections; and third, ambiguous VDPVs (aVDPVs), which are either clinical isolates from persons with no known immunodeficiency or sewage isolates whose ultimate source is unknown [43]. The three categories of VDPVs differ in their public health importance. cVDPVs have recovered the biological properties of WPVs, and have the potential to circulate for years in settings where poliovirus vaccination coverage to prevent that particular type is low. iVDPVs, of which 60 infections have been identified since 1961 [9], may be excreted by persons with certain primary immunodeficiencies for many (>10) years with no apparent paralytic signs [44,45]. Persons infected with iVDPVs without paralysis are at risk of developing paralytic poliomyelitis and may infect others with PV, presenting the potential risk of outbreaks in areas with low polio vaccine coverage. aVDPVs are heterogeneous: some represent the initial isolates from cVDPV outbreaks, whereas others — such as highly divergent aVDPVs detected in sewage — are probably iVDPVs from inapparent chronic infections.

only from imported WPVs but also from endogenous emergence of cVDPVs.

The imperative to reach the last 1% of children The successful eradication of WPV in all but a few parts of the world has fundamentally altered global PV ecology, as the only source of immunity to PV in nearly all countries is from immunization. Natural WPV infection no longer infects most children early in life, paralyzing a small proportion, while conferring lifelong immunity to the rest. Because the Sabin OPV strains do not normally persist and circulate in the environment, immunity gaps can quickly develop in countries with large populations and low rates of vaccine coverage, and efficient global transportation places all under-immunized populations at risk for polio outbreaks. The wider the immunity gaps and the higher the proportion of unimmunized older person, the greater the likelihood of explosive and devastating polio outbreaks. The current outbreak risks are not Current Opinion in Virology 2012, 2:188–198

The GPEI has confronted challenges far more daunting than were originally envisioned at its launch: suboptimal immunogenicity of OPV in some high-risk settings, deteriorating infrastructure in key endemic countries, intense biological risk, lack of political support in some countries, severe social conflict in core endemic areas, anti-OPV rumors, re-establishment of WPV transmission in areas previously polio-free, repeated outbreaks in Africa and Asia, and the recurring emergence of cVDPVs. Nonetheless, each of these challenges has been surmounted in all but a few locations, most notably in India where the most difficult biological challenges converge. The key in India and other polio-free countries has been translation of higher-level political commitment into effective vaccine delivery and surveillance at the local level www.sciencedirect.com

Reaching the last one per cent Kew 197

[12]. The important lessons from India (and other poliofree countries) urgently need to be replicated in the remaining endemic and re-established transmission countries. It is imperative to quickly clear the last 1% of reservoir communities to avoid continuation of the cycle of resurgence and (sometimes incomplete) retreat of polio seen over the past decade. The urgency for a timely completion of the GPEI grows as the perceived threat of polio fades in many developing countries, public health priorities shift, and routine immunization programs fail to attain sufficient coverage to protect against the emerging outbreak threats. Without a renewed commitment to polio eradication in the few locales where polio still persists, many of the hard-won gains over past quarter century could be lost [12], along with the tremendous opportunity presented in 1988 to implement the most efficient, equitable, and cost-effective [35] means of controlling this devastating disease.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.coviro. 2012.02.006.

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