THE POTENTIAL IMPACT OF EXPANDING TARGET AGE GROUPS FOR POLIO IMMUNIZATION CAMPAIGNS.

BMC Infect Dis. 2014 Jan 29;14:45. doi: 10.1186/1471-2334-14-45.

Duintjer Tebbens RJ¹, Kalkowska DA, Wassilak SG, Pallansch MA, Cochi SL, Thompson KM.

Abstract below; full text is at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918103/

BACKGROUND:

Global efforts to eradicate wild polioviruses (WPVs) continue to face challenges due to uninterrupted endemic WPV transmission in three countries and importation-related outbreaks into previously polio-free countries. We explore the potential role of including older children and adults in supplemental immunization activities (SIAs) to more rapidly increase population immunity and prevent or stop transmission.

METHODS:

We use a differential equation-based dynamic poliovirus transmission model to analyze the epidemiological impact and vaccine resource implications of expanding target age groups in SIAs. We explore the use of older age groups in SIAs for three situations: alternative responses to the 2010 outbreak in Tajikistan, retrospective examination of elimination in two high-risk states in northern India, and prospective and retrospective strategies to accelerate elimination in endemic northwestern Nigeria. Our model recognizes the ability of individuals with waned mucosal immunity (i.e., immunity from a historical live poliovirus infection) to become re-infected and contribute to transmission to a limited extent.

RESULTS:

SIAs involving expanded age groups reduce overall caseloads, decrease transmission, and generally lead to a small reduction in the time to achieve WPV elimination. Analysis of preventive expanded age group SIAs in Tajikistan or prior to type-specific surges in incidence in high-risk areas of India and Nigeria showed the greatest potential benefits of expanded age groups. Analysis of expanded age group SIAs in outbreak situations or to accelerate the interruption of endemic transmission showed relatively less benefit, largely due to the circulation of WPV reaching individuals sooner or more effectively than the SIAs. The India and Nigeria results depend strongly on how well SIAs involving expanded age groups reach relatively isolated subpopulations that sustain clusters of susceptible children, which we assume play a key role in persistent endemic WPV transmission in these areas.

CONCLUSIONS:

This study suggests the need to carefully consider the epidemiological situation in the context of decisions to use expanded age group SIAs. Subpopulations of susceptible individuals may independently sustain transmission, which will reduce the overall benefits associated with using expanded age group SIAs to increase population immunity to a sufficiently high level to stop transmission and reduce the incidence of paralytic cases.

Abstract below; full text is at http://wwwnc.cdc.gov/eid/article/19/10/13-0028_article.htm

Polioviruses isolated from 70 acute flaccid paralysis patients from the Democratic Republic of Congo (DRC) during 2004–2011 were characterized and found to be vaccine-derived type 2 polioviruses (VDPV2s). Partial genomic sequencing of the isolates revealed nucleotide sequence divergence of up to 3.5% in the viral protein 1 capsid region of the viral genome relative to the Sabin vaccine strain. Genetic analysis identified at least 7 circulating lineages localized to specific geographic regions. Multiple independent events of VDPV2 emergence occurred throughout DRC during this 7-year period. During 2010–2011, VDPV2 circulation in eastern DRC occurred in an area distinct from that of wild poliovirus circulation, whereas VDPV2 circulation in the southwestern part of DRC (in Kasai Occidental) occurred within the larger region of wild poliovirus circulation.

Indigenous wild-type poliovirus (WPV) remains endemic to 3 countries: Nigeria, Afghanistan, and Pakistan (1). Poliovirus (PV) circulation has been sustained in several African countries after importation from a PV-endemic country, resulting in reestablished virus transmission. Worldwide, the number of cases decreased by 50% from 2010 to 2011 (2). In developing countries, live attenuated oral PV vaccine (OPV) is still the vaccine of choice. However, the virus can revert to virulence during OPV replication in humans, resulting in person-to-person spread and circulation of vaccine-derived PVs in areas with low rates of vaccination coverage (3). Substantial sequence drift occurs in circulating VDPVs (>1% nt difference in types 1 and 3, >0.6% nt difference in type 2), indicating prolonged replication of the vaccine strain in human populations and consequent changes in phenotypic properties of neurovirulence and transmissibility (3,4). Poliomyelitis outbreaks associated with circulating VDPVs have been reported in several countries, including Egypt (1982–1993), Haiti (2000–2001), Dominican Republic (2000–2001), Philippines (2001), Madagascar (2002 and 2005), China (2004), Cambodia (2005–2006), Indonesia (2005), and Nigeria 2005–2010 (4–11). As a result of accumulating evidence about the emergence and spread of circulating VDPVs, there are plans to stop using OPV and synchronously implement more widespread use of inactivated polio vaccine (12–15). A better understanding of VDPV persistence and circulation is crucial for deciding when and how to stop vaccination with OPV after WPVs have been eradicated (16–18).

In early 2001, indigenous WPVs were eliminated from DRC, but starting in 2006 and continuing through 2011, WPV was imported into DRC from Angola several times. During 2010−2011 in DRC, 2 genetic clusters of the Southeast Asian PV1 genotype circulated; this genotype was imported twice from India to Angola and subsequently to DRC. Since December 2011, no cases of infection with WPV have been detected in DRC (19).

Monovalent OPV types 1 and 3 and bivalent OPV effectively induce immunity because of a lack of interference by the type 2 component (20). Reliance on monovalent OPV1, monovalent OPV3, and bivalent OPV in supplemental vaccination activities has contributed to the emergence of VDPV2. These alternative OPV formulations are more effective than trivalent OPV at inducing higher levels of population immunity to WPV1 and WPV3 because there is no interference from the type 2 OPV strain. No type 2–specific immunity is induced. To maintain population immunity to type 2 PV, the World Health Organization (WHO) recommends 2 doses of trivalent OPV each year.

We describe the genetic characterization of circulating VDPV2 associated with outbreaks in DRC. During 2004–2011, the same time that extensive circulating VDPV transmission occurred in Nigeria, VDPV2 excretion was found for 70 children with acute flaccid paralysis (10,11). The close genetic relationships among many of the viruses provide evidence for circulation in several regions of DRC.

Abstract below; full text, with figures, is at http://jvi.asm.org/content/87/9/4907.full

Since 2005, a large poliomyelitis outbreak associated with type 2 circulating vaccine-derived poliovirus (cVDPV2) has occurred in northern Nigeria, where immunization coverage with trivalent oral poliovirus vaccine (tOPV) has been low. Phylogenetic analysis of P1/capsid region sequences of isolates from each of the 403 cases reported in 2005 to 2011 resolved the outbreak into 23 independent type 2 vaccine-derived poliovirus (VDPV2) emergences, at least 7 of which established circulating lineage groups. Virus from one emergence (lineage group 2005-8; 361 isolates) was estimated to have circulated for over 6 years. The population of the major cVDPV2 lineage group expanded rapidly in early 2009, fell sharply after two tOPV rounds in mid-2009, and gradually expanded again through 2011. The two major determinants of attenuation of the Sabin 2 oral poliovirus vaccine strain (A₄₈₁ in the 5′-untranslated region [5′-UTR] and VP1-Ile₁₄₃) had been replaced in all VDPV2 isolates; most A₄₈₁ 5′-UTR replacements occurred by recombination with other enteroviruses. cVDPV2 isolates representing different lineage groups had biological properties indistinguishable from those of wild polioviruses, including efficient growth in neuron-derived HEK293 cells, the capacity to cause paralytic disease in both humans and PVR-Tg21 transgenic mice, loss of the temperature-sensitive phenotype, and the capacity for sustained person-to-person transmission. We estimate from the poliomyelitis case count and the paralytic case-to-infection ratio for type 2 wild poliovirus infections that ∼700,000 cVDPV2 infections have occurred during the outbreak. The detection of multiple concurrent cVDPV2 outbreaks in northern Nigeria highlights the risks of cVDPV emergence accompanying tOPV use at low rates of coverage in developing countries.

Clin Infect Dis. (2012) 55 (10): 1291-1298. doi: 10.1093/cid/cis714 First published online: August 21, 2012

An Outbreak of Wild Poliovirus in the Republic of Congo, 2010–2011

Minal K. Patel1, Mandy Kader Konde3, Boris Hermann Didi-Ngossaki4, Edouard Ndinga4, Riziki Yogolelo6, Mbaye Salla5, Keith Shaba5, Johannes Everts7,

Gregory L. Armstrong2, Danni Daniels1, Cara Burns2, Steve Wassilak1, Mark Pallansch2, and Katrina Kretsinger1

+ Author Affiliations

1Global Immunization Division

2Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

3Expanded Programme on Immunization, World Health Organization

4Ministry of Health

5Expanded Programme on Immunization, World Health Organization Regional Office for Africa, Brazzaville, Republic of Congo

6Institut National de Recherche Biomédicale, Ministry of Public Health, Kinshasa, Democratic Republic of the Congo

7World Health Organization, Geneva, Switzerland

Correspondence: Minal K. Patel, MD, Global Immunization Division, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS A-04, Atlanta, GA 30329 (hgo9@cdc.gov).  

Abstract below; full text, with figures, is at http://cid.oxfordjournals.org/content/55/10/1291.long

Background. The Republic of Congo has had no cases of wild poliovirus type 1 (WPV1) since 2000. In October 2010, a neurologist noted an abnormal number of cases of acute flaccid paralysis (AFP) among adults, which were later confirmed to be caused by WPV1.

Methods. Those presenting with AFP underwent clinical history, physical examination, and clinical specimen collection to determine if they had polio. AFP cases were classified as laboratory-confirmed, clinical, or nonpolio AFP. Epidemiologic features of the outbreak were analyzed.

Results. From 19 September 2010 to 22 January 2011, 445 cases of WPV1 were reported in the Republic of Congo; 390 cases were from Pointe Noire. Overall, 331 cases were among adults; 378 cases were clinically confirmed, and 64 cases were laboratory confirmed. The case-fatality ratio (CFR) was 43%. Epidemiologic characteristics differed among polio cases reported in Pointe Noire and cases reported in the rest of the Republic of Congo, including age distribution and CFR. The outbreak stopped after multiple vaccination rounds with oral poliovirus vaccine, which targeted the entire population.

Conclusions. This outbreak underscores the need to maintain high vaccination coverage to prevent outbreaks, the need to maintain timely high-quality surveillance to rapidly identify and respond to any potential cases before an outbreak escalates, and the need to perform ongoing risk assessments of immunity gaps in polio-free countries.

Randomized Trial of Type 1 and Type 3 Oral Monovalent Poliovirus Vaccines in Newborns in Africa

J Infect Dis. (2012) 205 (2): 228-236. doi: 10.1093/infdis/jir721 First published online: December 8, 2011

Zainab Waggie1, Hennie Geldenhuys2, Roland W. Sutter3, Mariana Jacks2, Humphrey Mulenga2, Hassan Mahomed2, Marwou De Kock2, Willem Hanekom2,

Mark A. Pallansch4, Anna-Lea Kahn3, Anthony H. Burton3, Meghana Sreevatsava3 and Gregory Hussey1

+ Author Affiliations

1School of Child and Adolescent Health and Institute of Infectious Disease and Molecular Medicine

2South African Tuberculosis Vaccine Initiative, School of Child and Adolescent Health and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

3Polio Eradication Department, World Health Organization, Geneva, Switzerland

4Centers for Disease Control and Prevention, Atlanta, Georgia

Correspondence: Zainab Waggie, FCPaed (SA), Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa (zainab.waggie@uct.ac.za).

Abstract below; full text is at http://jid.oxfordjournals.org/content/205/2/228.long

(See the editorial commentary by Cochi and Linkins, on pages 169–71.)

ARTICLE

Background. The Global Polio Eradication Initiative aims to eradicate wild poliovirus by the end of 2012. Therefore, more-immunogenic polio vaccines, including monovalent oral poliovirus vaccines (mOPVs), are needed for supplemental immunization activities. This trial assessed the immunogenicity of monovalent types 1 and 3, compared with that of trivalent oral poliovirus vaccine (tOPV), in South Africa.

Methods. We conducted a blinded, randomized, 4-arm controlled trial comparing the immunogenicity of a single dose of mOPV1 (from 2 manufacturers) and mOPV3 (from 1 manufacturer), given at birth, with the immunogenicity of tOPV.

Results. Eight hundred newborns were enrolled; 762 (95%) were included in the analysis. At 30 days after vaccine administration, seroconversion to poliovirus type 1 was 73.4% and 76.4% in the 2 mOPV1 arms, compared with 39.1% in the tOPV arm (P < .0000001), and seroconversion to poliovirus type 3 was 58.0% in the mOPV3 arm, compared with 21.2% in the tOPV arm (P < .0000001). The vaccines were well tolerated, and no adverse events were attributed to trial interventions.

Conclusion. A dose of mOPV1 or mOPV3 at birth was superior to that of tOPV in inducing type-specific seroconversion in this sub-Saharan African population. Our results support continued use of mOPVs in supplemental immunization activities in countries where poliovirus types 1 or 3 circulate.

Clin Infect Dis. (2011) 53 (1): 13-19. doi: 10.1093/cid/cir332

Poliomyelitis-Related Case-Fatality Ratio in India, 2002–2006

Sucheta J. Doshi1,a, Hardeep S. Sandhu2, Linda V. Venczel2,a, Karen J. Hymbaugh4, Jagadish M. Deshpande6, Mark A. Pallansch3, Sunil Bahl5, Jay D. Wenger5,a, and

Steve L. Cochi2

+ Author Affiliations

1Global Immunization Division, National Center for Immunization and Respiratory Diseases and Epidemic Intelligence Service Program

2Global Immunization Division, National Center for Immunization and Respiratory Diseases

3Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

4World Health Organization, Regional Office for South-East Asia

5National Polio Surveillance Project–India, New Delhi

6Enterovirus Research Centre, Mumbai, India

Correspondence: Hardeep S. Sandhu, MBBS, MD, Centers for Disease Control and Prevention, National Centre for Immunization and Respiratory Diseases, MS E-05, Global Immunization Division, 1600 Clifton Rd, Atlanta, GA 30333 (hsandhu@cdc.gov).

Abstract below; full text is at http://cid.oxfordjournals.org/content/53/1/13.long

Background. On the basis of studies from developed countries, the case-fatality ratio (CFR) of poliomyelitis generally ranges from 2%–5% among children <5 years of age to 10%–30% among adults. However, little information is available for poliomyelitis-related CFR in developing countries. We conducted a study to determine the CFR in India, 1 of the 4 remaining countries with endemic wild poliovirus (WPV) circulation, during outbreaks of WPV infection during 2002 and 2006 and during the inter-epidemic years of 2003–2005.

Methods. We conducted a descriptive analysis with use of data from the acute flaccid paralysis surveillance system in India. Variables analyzed included age, caregiver-reported vaccination status, date of paralysis onset, laboratory results, final case classification, and survival outcome. Our analysis also accounted for surveillance changes that occurred in 2005, impacting case definitions and final classification.

Results. In 2006, 45 deaths occurred among 676 WPV cases in India, yielding a CFR of 6.7%. By comparison, in 2002, there were 66 deaths among 1600 reported WPV cases (CFR, 4.2%) and during 2002–2005, CFR was 1.5%–5.2%. All 45 deaths were among 644 (95%) WPV cases in children aged <5 years (CFR, 7.0%). Among those who died, 33 (73%) were children aged <2 years (CFR, 7.1%).

Conclusions. The CFR among children aged <2 years in India is high compared with previously published CFRs for young children, in part because of improved case finding through enhanced surveillance techniques. Fatal cases emphasize the lethal nature of the disease and the importance of achieving polio eradication in India.

J Infect Dis. (2011) 203 (7): 898-909. doi: 10.1093/infdis/jiq140

Outbreak of Type 2 Vaccine-Derived Poliovirus in Nigeria: Emergence and Widespread Circulation in an Underimmunized Population

Steven Wassilak1, Muhammad Ali Pate2, Kathleen Wannemuehler1, Julie Jenks1, Cara Burns1, Paul Chenoweth1, Emmanuel Ade Abanida2, Festus Adu4,

Marycelin Baba5, Alex Gasasira3, Jane Iber1, Pascal Mkanda3, A. J. Williams1, Jing Shaw1, Mark Pallansch1 and Olen Kew1

+ Author Affiliations

1Centers for Disease Control and Prevention, Atlanta, Georgia

2National Primary Health Care Development Agency

3World Health Organization, Nigeria, Abuja

4Department of Virology, College of Medicine, University of Ibadan

5University of Maiduguri Teaching Hospital, Maiduguri, Nigeria

Reprints or correspondence: Steven Wassilak, MD, 1600 Clifton Rd. N.E., Mail Stop E-05, Atlanta, GA 30333 (sgw1@cdc.gov).

Abstract below; full text is at http://jid.oxfordjournals.org/content/203/7/898.long

(See the article by Nathanson et al., on pages 889–90.)

Wild poliovirus has remained endemic in northern Nigeria because of low coverage achieved in the routine immunization program and in supplementary immunization activities (SIAs). An outbreak of infection involving 315 cases of type 2 circulating vaccine-derived poliovirus (cVDPV2; >1% divergent from Sabin 2) occurred during July 2005–June 2010, a period when 23 of 34 SIAs used monovalent or bivalent oral poliovirus vaccine (OPV) lacking Sabin 2. In addition, 21 “pre-VDPV2” (0.5%–1.0% divergent) cases occurred during this period. Both cVDPV and pre-VDPV cases were clinically indistinguishable from cases due to wild poliovirus. The monthly incidence of cases increased sharply in early 2009, as more children aged without trivalent OPV SIAs. Cumulative state incidence of pre-VDPV2/cVDPV2 was correlated with low childhood immunization against poliovirus type 2 assessed by various means. Strengthened routine immunization programs in countries with suboptimal coverage and balanced use of OPV formulations in SIAs are necessary to minimize risks of VDPV emergence and circulation.

The cornerstone of the Global Polio Eradication Initiative is immunization of children with multiple doses of oral poliovirus vaccine (OPV), via both routine immunization (RI) and supplementary immunization activities (SIAs) [1]. The key advantages of OPV are ease of administration and efficient induction of mucosal immunity, thereby limiting poliovirus shedding and person-to-person transmission [2]. Through widespread implementation of this approach and with standardized virologic surveillance, indigenous wild poliovirus (WPV) transmission has stopped in all but 4 countries (Nigeria, Pakistan, Afghanistan, and India) [1]. WPV type 2 (WPV2) circulation apparently stopped in Africa in the mid-1990s (F. Adu and C. Koffi; unpublished data), and WPV2 was last detected (in India) in 1999 [3].

Despite its advantages, OPV use carries the infrequent risks of vaccine-associated paralytic poliomyelitis among OPV recipients and their direct contacts [2] and the emergence of genetically divergent vaccine-derived polioviruses (VDPVs) [4, 5], both a consequence of selection against the attenuated phenotype during intestinal replication [6]. VDPVs are operationally defined as OPV-related isolates having >1% nucleotide (nt) sequence divergence from the parental OPV strain in the ∼900-nt region encoding the major capsid surface protein, VP1 [4, 5]. This arbitrary demarcation represents ∼1 year of poliovirus (PV) replication after administration of the initiating OPV dose [7], substantially longer than the normal postvaccination excretion period of 4–6 weeks [2, 8]. VDPVs are further categorized as circulating (cVDPVs) when there is clear evidence of transmission beyond close contacts [4, 5]. cVDPV outbreaks have occurred in settings of widening susceptibility to ≥1 poliovirus serotype in association with weak RI programs and in locations where the corresponding WPVs of the same serotype have been eliminated [4, 5, 9, 10]. The risk of cVDPV emergence appears to be highest for the Sabin type 2 (Sabin 2) OPV strain [4, 5, 10], particularly in areas with high densities of nonimmune persons, poor sanitation, and tropical or subtropical climates [11].

Northern Nigeria had remained a major reservoir for WPV1 and WPV3 [12, 13], leading to extensive international spread of WPV1 in 2003–2006 [14] and 2008–2009 [13, 15] and limited WPV3 international spread in 2008–2009 [13, 15]. Low trivalent OPV (tOPV) coverage in the RI program, suspension of SIAs in some states in 2003–2004, and low coverage in SIAs have contributed to ongoing WPV transmission [14]. To more efficiently stop WPV1 and WPV3 transmission, monovalent OPV type 1 (mOPV1) was regularly used in SIAs starting in March 2006, and mOPV3 was intermittently used starting in July 2007 [12, 13]. During the period July 2005–June 2010, 11 of 34 SIA rounds in northern Nigeria used tOPV, including only 4 rounds during the period March 2006–April 2009.

In 2002, a case involving VDPV type 2 (VDPV2) was detected in Plateau state, but no related cases involving VDPV2 or any other VDPVs were detected over the next 4 years [16]. In August 2006, virologic investigations detected a cluster of acute flaccid paralysis (AFP) cases associated with Sabin 2-related isolates in northern Nigeria; sequence analysis revealed that the isolates were VDPVs [17]. Retrospective analyses found an early outbreak isolate in 2005, and continued screening through mid-2010 detected a total of 315 VDPV2 case isolates. We found an additional 21 cases with “pre-VDPV2” isolates (0.5%–1% VP1 divergent from Sabin 2), sporadically found in settings of high OPV coverage.

Here, we describe epidemiologic characteristics of the outbreak of cVDPV2 infection in Nigeria during the period from July 2005 through 30 June 2010, constituting the largest and second-longest known cVDPV-associated outbreak [5, 17-21]. Furthermore, in accord with the findings of Jenkins et al [21], we compare clinical features of both VDPV2- and pre-VDPV2–associated cases with WPV and non-polio AFP (NP-AFP) cases. We then assess risks of the emergence and spread of cVDPV2 in northern Nigeria and discuss measures needed to prevent further cVDPV outbreaks.

J Infect Dis. (2009) 199 (3): 391-397. doi: 10.1086/596052

Transmission of Imported Vaccine-Derived Poliovirus in an Undervaccinated Community in Minnesota

James P. Alexander1, Kristen Ehresmann2, Jane Seward1, Gary Wax2,a, Kathleen Harriman2,a, Susan Fuller2, Elizabeth A. Cebelinski2, Qi Chen1, Olen M. Kew1,

Mark A. Pallansch1, M. Steven Oberste1, Mark Schleiss3, Jeffrey P. Davis4, Bryna Warshasky5, Susan Squires6, Harry F. Hull2,a and for the Vaccine-Derived Poliovirus Investigations Groupb

+ Author Affiliations

1National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and PreventionAtlanta, Georgia

2Minnesota Department of Health, St. PaulMinneapolis

3University of Minnesota School of Medicine

4Division of Public Health, Wisconsin Department of Health and Family ServicesMadison

5Middlesex-London Health UnitLondon

6Public Health Agency of CanadaOttawa, Ontario, Canada

+ Author Notes

↵a Present affiliations: California Department of Public Health, Immunization Branch, Epidemiology and Surveillance Section, Richmond (K.H.); HF Hull Associates, St. Paul, Minnesota (H.F.H.); HealthEast Care System, St. Josephs Hospital, St. Paul, Minnesota (G.W.).

Reprints or correspondence: Dr. James Alexander, 1600 Clifton Rd. NE, Mail Stop E-05, Atlanta, GA 30333 (axj1@cdc.gov).

Presented in part: National Vaccine Advisory Committee, Washington, DC, 8 February 2006; National Immunization Conference, Atlanta, 7 March 2006.

Abstract below; full text is at http://jid.oxfordjournals.org/content/199/3/391.long

Background.Oral poliovirus vaccine (OPV) has not been used in the United States since 2000. Type 1 vaccinederived poliovirus (VDPV) was identified in September 2005, from an unvaccinated Amish infant hospitalized in Minnesota with severe combined immunodeficiency. An investigation was conducted to determine the source of the virus and its means of transmission.

Methods. The infant was tested serially for poliovirus excretion. Investigations were conducted to detect poliovirus infections or paralytic poliomyelitis in Amish communities in Minnesota, neighboring states, and Ontario, Canada. Genomic sequences of poliovirus isolates were determined for phylogenetic analysis.

Results. No source for the VDPV could be identified. In the index community, 8 (35%) of 23 children tested, including the infant, had evidence of type 1 poliovirus or VDPV infection. Phylogenetic analysis suggested that the VDPV circulated in the community for ∼2 months before the infants infection was detected and that the initiating OPV dose had been given before her birth. No paralytic disease was found in the community, and no poliovirus infections were found in other Amish communities investigated.

Conclusions. This is the first demonstrated transmission of VDPV in an undervaccinated community in a developed country. Continued vigilance is needed in all countries to identify poliovirus infections in communities at high risk of poliovirus transmission.

Because of successful vaccination programs, endemic poliomyelitis was eliminated from the United States by the mid-1970s. In 1979, after importation of wild poliovirus, the last US polio outbreak occurred in unvaccinated Amish communities, involving 13 cases of paralytic disease in 3 states and subclinical infections in 3 other states as well as 2 cases of paralytic disease in Ontario, Canada [1, 2]. From 1980 to 1997, a mean of 9 reported paralytic poliomyelitis cases occurred annually in the United States [3, 4]. Nearly all were vaccineassociated paralytic polio (VAPP), underscoring the ongoing risk associated with oral poliovirus vaccine (OPV), estimated to be 1 case of VAPP per 2.9 million doses distributed [4]. As the occurrence of wild poliovirus importations declined to only 5 in the 1980s and to 2 in the 1990s [3, 4], the risk-benefit equation changed in favor of using inactivated poliovirus vaccine (IPV) routinely. From 1997 to 2000, the transition in vaccination policy from an all-OPV to an all-IPV schedule eliminated VAPP in the United States; the last endemically acquired case of VAPP occurred in 1999 [4–6].

In addition to causing VAPP, OPV use is also associated with the rare occurrence of genetically drifted vaccine-derived polioviruses (VDPVs) that can circulate in undervaccinated populations (circulating VDPVs [cVDPVs]) or cause persistent infections in immunodeficient individuals (immunodeficiency- related VDPVs [iVDPVs]) [7-9]. In September 2005, a poliovirus infection in an unvaccinated Amish infant was identified by the Minnesota Department of Health and reported to the Centers for Disease Control and Prevention. The virus was identified as type 1 VDPV. The present report describes the epidemiologic and laboratory investigations and control efforts regarding the first VDPV with community transmission detected in the United States.

Monovalent Type 1 Oral Poliovirus Vaccine in Newborns

Nasr El-Sayed, M.D., M.P.H., Yehia El-Gamal, M.D., Ph.D., Ahmed-Amr Abbassy, M.D., Ph.D., Iman Seoud, M.D., Ph.D., Maha Salama, M.D., Amr Kandeel, M.D., M.P.H., Elham Hossny, M.D., Ph.D., Ahmed Shawky, M.D., Heba Abou Hussein, M.D., Ph.D., Mark A. Pallansch, Ph.D., Harrie G.A.M. van der Avoort, Ph.D., Anthony H. Burton, B.S., Meghana Sreevatsava, M.P.H., Pradeep Malankar, M.D., Mohamed H. Wahdan, M.D., Ph.D., and Roland W. Sutter, M.D., M.P.H.T.M.

N Engl J Med 2008; 359:1655-1665October 16, 2008

Abstract below; full text is at http://www.nejm.org/doi/pdf/10.1056/NEJMoa0800390

Background

In 1988, the World Health Assembly resolved to eradicate poliomyelitis. Although substantial progress toward this goal has been made, eradication remains elusive. In 2004, the World Health Organization called for the development of a potentially more immunogenic monovalent type 1 oral poliovirus vaccine.

Methods

We conducted a trial in Egypt to compare the immunogenicity of a newly licensed monovalent type 1 oral poliovirus vaccine with that of a trivalent oral poliovirus vaccine. Subjects were randomly assigned to receive one dose of monovalent type 1 oral poliovirus vaccine or trivalent oral poliovirus vaccine at birth. Thirty days after birth, a single challenge dose of monovalent type 1 oral poliovirus vaccine was administered in all subjects. Shedding of serotype 1 poliovirus was assessed through day 60.

Results

A total of 530 subjects were enrolled, and 421 fulfilled the study requirements. Thirty days after the study vaccines were administered, the rate of seroconversion to type 1 poliovirus was 55.4% in the monovalent-vaccine group, as compared with 32.1% in the trivalent-vaccine group (P<0.001). Among those with a high reciprocal titer of maternally derived antibodies against type 1 poliovirus (>64), 46.0% of the subjects in the monovalent-vaccine group underwent seroconversion, as compared with 21.3% in the trivalent-vaccine group (P<0.001). Seven days after administration of the challenge dose of monovalent type 1 vaccine, a significantly lower proportion of subjects in the monovalent-vaccine group than in the trivalent-vaccine group excreted type 1 poliovirus (25.9% vs. 41.5%, P=0.001). None of the serious adverse events reported were attributed to the trial interventions.

Conclusions

When given at birth, monovalent type 1 oral poliovirus vaccine is superior to trivalent oral poliovirus vaccine in inducing humoral antibodies against type 1 poliovirus, overcoming high preexisting levels of maternally derived antibodies, and increasing the resistance to excretion of type 1 poliovirus after administration of a challenge dose. (Current Controlled Trials number, ISRCTN76316509.)

Isolation of Sabin-Like Polioviruses from Wastewater in a Country Using Inactivated Polio Vaccine▿

Sebastian Zurbriggen1, Kurt Tobler1, Carlos Abril1,†, Sabine Diedrich2, Mathias Ackermann1, Mark A. Pallansch3 and Alfred Metzler1,*

+ Author Affiliations

1Institute of Virology, University of Zurich, CH-8057 Zurich, Switzerland

2Robert Koch Institute, Regional Reference Laboratory for Poliomyelitis, D-13302 Berlin, Germany

3Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333

Abstract below; full text, with figures, is at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2547022/

From 2001 to 2004, Switzerland switched from routine vaccination with oral polio vaccine (OPV) to inactivated polio vaccine (IPV), using both vaccines in the intervening period. Since IPV is less effective at inducing mucosal immunity than OPV, this change might allow imported poliovirus to circulate undetected more easily in an increasingly IPV-immunized population. Environmental monitoring is a recognized tool for identifying polioviruses in a community. To look for evidence of poliovirus circulation following cessation of OPV use, two sewage treatment plants located in the Zurich area were sampled from 2004 to 2006. Following virus isolation using either RD or L20B cells, enteroviruses and polioviruses were identified by reverse transcription-PCR. A total of 20 out of 174 wastewater samples were positive for 62 Sabin-like isolates. One isolate from each poliovirus-positive sample was analyzed in more detail. Sequencing the complete viral protein 1 (VP1) capsid coding region, as well as intratypic differentiation (ITD), identified 3 Sabin type 1, 13 Sabin type 2, and 4 Sabin type 3 strains. One serotype 1 strain showed a discordant result in the ITD. Three-quarters of the strains showed mutations within the 5′ untranslated region and VP1, known to be associated with reversion to virulence. Moreover, three strains showed heterotypic recombination (S2/S1 and S3/S2/S3). The low number of synonymous mutations and the partial temperature sensitivity are not consistent with extended circulation of these Sabin virus strains. Nevertheless, the continuous introduction of polioviruses into the community emphasizes the necessity for uninterrupted child vaccination to maintain high herd immunity.

The global polio eradication initiative was launched in 1988. Substantive progress has been made toward this goal, but further work is still required (11, 12, 21, 29). Successful eradication of the cause of an infectious disease, exemplified by that of Variola virus, has at least four fundamental requirements: (i) absence of an animal reservoir; (ii) effective vaccines and, in the case of live-attenuated viruses, genetically stable vaccines; (iii) absence of long-term virus carriers; and (iv) sensitive tools to detect the presence of the causal agent. In the case of poliovirus eradication, these requirements have not been completely met. The basic strategy of the polio eradication initiative involves achieving high levels of routine immunization, mass vaccination, supplementary mop-up immunization activity, and poliovirus surveillance based on virological investigation of acute flaccid paralysis (AFP) cases (51, 56). There are two effective vaccines: inactivated polio vaccine (IPV), originally developed by Jonas Salk and colleagues, and the live-attenuated oral polio vaccine (OPV) of Albert Sabin (39). Both vaccines provide effective protection from poliomyelitis. However, IPV induces less mucosal immunity in the gut than OPV, a prerequisite for reducing intestinal reinfection, virus shedding, and transmission to susceptible contacts (33, 37, 41, 44, 45). OPV, which better protects from infection, suffers from other inadequacies that complicate the ongoing initiative (11, 12, 21, 29). One inadequacy is the emergence of virulent vaccine-derived polioviruses (VDPVs) upon long-term replication in immunodeficient persons (iVDPV) or following sustained circulation in populations with immunity gaps (cVDPV). Ambiguous VDPVs, such as environmental isolates, represent a category of virulent polioviruses that cannot easily be assigned to iVDPV or cVDPV (29). Additional challenges for the initiative are poorly understood deficiencies in vaccine efficacy (24) and the low clinical attack rate following infection with virulent polioviruses (≤1:100 paralytic case/infections). This calls for specific and sensitive virus-tracking tools. AFP surveillance is presently the gold standard for meeting those requirements (56).

The three serotypes of poliovirus are members of the family Picornaviridae (20, 40, 55, 61). The viruses possess a single-stranded RNA genome of approximately 7,400 nucleotides (nt). Upon infection, the genomic RNA is translated as a polyprotein, which is then processed by proteases into functional proteins. The structural proteins are located within the N-terminal P1 region and the nonstructural proteins within the succeeding P2 and P3 regions of the polyprotein. Similar to some other RNA viruses, the virus-encoded RNA-dependent RNA polymerase is error prone and lacks proofreading activity. This results in a high mutation frequency for these viruses. The molecular evolution of polioviruses is characterized by selective propagation of virus variants that are generated through mutations and heterotypic or intragenus recombination (29). During wild-type (wt) poliovirus infection, a steady accumulation of mostly synonymous mutations is the major contribution to genetic evolution (23). In addition, an early burst of nonsynonymous mutations and recombination is characteristic of the evolution of the Sabin strains in the guts of vaccinees and their susceptible contacts. This helps the virus to regain replicative fitness (64) and to revert to the virulent phenotype with an increased possibility of causing neurologic disease. There are a number of serotype-specific nucleotide positions associated with attenuation (29). Therefore, observation of the reversion of these attenuating mutations at these positions implies an increase in virulence. Nonetheless, other factors not solely associated with these single-nucleotide changes could also play a role in virulence (28). The number of synonymous mutations within the region coding for the capsid protein viral protein 1 (VP1) is used to estimate the “age” of poliovirus strains, i.e., the duration of in vivo replication in single or successive hosts (4, 14, 15, 23, 26). VDPVs are defined as viruses with a 1 to 15% nucleotide sequence difference within the VP1 region compared to the parental Sabin vaccine strain of the same type (11, 29). Viral isolates that display <1% nucleotide sequence difference from the parental vaccine strain are defined as vaccine- or Sabin-like (SL). In principal, both VDPVs and SL viruses can cause poliomyelitis, but at different rates on average. In settings with low vaccination coverage, however, the VDPVs are of growing concern in the efforts toward global polio eradication (12).

There are a few European countries that have relied exclusively and successfully upon IPV to control both poliomyelitis and the circulation of wt polioviruses. This success has been achieved by maintaining high vaccination coverage (17, 41). Similar to other countries, Switzerland before 2001 used mainly OPV. Between 2001 and 2004, Switzerland used a combination of IPV and OPV for safety reasons, i.e., to prevent cases of vaccine-associated paralytic poliomyelitis. In 2004, there was a switch to the IPV-only vaccination schedule. The reported vaccination coverage of children less than 2 years old with three doses of IPV is 94% (9). Following the switch from OPV to IPV, the Swiss population now consists of an older age group that was immunized with OPV and a growing younger age group that is immunized only with IPV. The national AFP surveillance system is important but not optimal, because a low number of stool samples are submitted for virological examination (59).

Since IPV provides only limited protection against intestinal infection, a possible risk is the undetected circulation of imported wt or vaccine poliovirus in persons with only IPV-induced immunity. Furthermore, vaccine viruses silently circulating among individuals lacking mucosal immunity could be a potential source for generation of cVDPV. Consistent with reports of the international spread of poliovirus, such strains could provoke a poliomyelitis outbreak in a setting with inadequate immunity. This prompted the initiation of a study to investigate the prevalence of poliovirus in municipal wastewater samples in Switzerland following the cessation of routine OPV use. In this study, we characterized poliovirus-positive sewage samples collected between January 2004 and October 2006 by employing a new protocol for virus concentration and either RD or L20B cells for primary virus isolation.