Update on Vaccine-Derived Polioviruses --- Worldwide, July 2009--March 2011

In 1988, the World Health Assembly resolved to eradicate poliomyelitis worldwide (1). The live, attenuated oral poliovirus vaccine (OPV) has many advantages favoring its use in polio eradication: it is administered easily by mouth; confers intestinal immunity, making recent OPV recipients resistant to infection by wild polioviruses (WPVs); provides long-term protection against paralytic disease through durable humoral immunity; and is inexpensive. Despite its many advantages, OPV use carries the risk for occurrence of rare cases of vaccine-associated paralytic poliomyelitis among immunologically normal OPV recipients and their contacts and the additional risk for emergence of vaccine-derived polioviruses (VDPVs). Because of these risks, OPV use will be discontinued worldwide once the goal of eradicating all WPV transmission is achieved. VDPVs can cause polio outbreaks in areas with low OPV coverage and can replicate for years in immunodeficient persons; therefore, strategies to strengthen global polio immunization and surveillance are needed to limit emergence of VDPVs (2). This report updates previous surveillance summaries (3,4) and describes VDPVs detected worldwide during July 2009--March 2011 and reported as of June 20, 2011. Three new outbreaks of circulating VDPVs (cVDPVs), ranging in size from six to 16 cases, were identified in Afghanistan, Ethiopia, and India; three previously identified outbreaks in Nigeria, Democratic Republic of Congo (DRC), and Somalia continued through late 2010 or into 2011 and resulted in 355, 37, and 13 total cases, respectively; two countries experienced importations of cVDPVs from Nigeria; nine newly identified paralyzed immunodeficient persons in seven middle-income and developing countries were found to excrete VDPVs; and VDPVs were found among persons and environmental samples in 15 countries. With the use of alternate OPV formulations since 2005 (1) and with enhanced poliovirus surveillance sensitivity and laboratory screening, the number of identified cVDPV outbreaks per year has increased over time (2,3). To prevent VDPV emergence and spread, all countries should maintain high poliovirus vaccination coverage against all three poliovirus serotypes. Sensitive poliovirus surveillance to detect VDPVs will continue to increase in importance.

Properties of VDPVs

VDPVs can cause paralytic polio in humans and have the potential for sustained circulation. VDPVs resemble WPVs biologically (3) and differ from the majority of vaccine-related poliovirus (VRPV) isolates by having genetic properties consistent with prolonged replication or transmission. Because poliovirus genomes evolve at a rate of approximately 1% per year, VRPVs that differ from the corresponding OPV strain by >1% of nucleotide positions (usually determined by sequencing the genomic region that encodes the major viral surface protein [VP1]) are presumed to have replicated for at least 1 year in one or more persons after administration of an OPV dose. This is substantially longer than the normal period of vaccine virus replication of 4--6 weeks in an OPV recipient.

Three poliovirus serotypes exist: types 1, 2, and 3. Poliovirus isolates are grouped into three categories, based on the extent of divergence of the VP1 nucleotide region compared with the corresponding OPV strain: 1) VRPVs (<1% divergent [types 1 and 3] or <0.6% divergent [type 2]); 2) VDPVs (VRPVs that are >1% divergent [types 1 and 3] or >0.6% divergent [type 2] from the corresponding OPV strain); and 3) WPVs (no genetic evidence of derivation from any vaccine strain) (3). VDPVs are further categorized as 1) cVDPVs, when evidence of person-to-person transmission in the community exists; 2) immunodeficiency-associated VDPVs (iVDPVs), which are isolated from persons with primary immunodeficiencies who have prolonged VDPV infections; and 3) ambiguous VDPVs (aVDPVs), which are either clinical isolates from persons with no known immunodeficiency or sewage isolates whose source is unknown (3).

Virologic Testing for VDPVs

All poliovirus isolates are characterized by laboratories of the Global Polio Laboratory Network (4). The original protocol to screen for VDPVs, using a combination of molecular and antigenic methods, largely has been replaced by a real-time reverse transcription--polymerase chain reaction (rRT-PCR) nucleic acid amplification targeted to nucleotide substitutions that occur early in VDPV emergence (3). Candidate VDPVs are sequenced in the VP1 region for routine analysis; the complete genome is sequenced if higher epidemiologic resolution is required.

cVDPVs

The number of countries with indigenous cVDPV emergence increased from three to six since the last reporting period (3), and VDPVs were imported from Nigeria into two countries. In all but one country the emerging cVDPVs were type 2 (Figure).

Afghanistan. Six type 2 cVDPV (cVDPV2) isolates (1.0%--1.2% divergent) were isolated during June 2010--January 2011 in the southern province of Helmand, where routine trivalent OPV (tOPV) coverage is low, and where WPV1 has circulated throughout the reporting period and WPV3 was isolated until April 2010. After introduction of bivalent OPV (bOPV) type 1 and 3 in December 2009, two of 12 subsequent supplementary immunization activities (SIAs)* through March 2011 used tOPV.

Chad. One cVDPV2 (5.3% divergent) was isolated from a patient in Ndjamena with onset of acute flaccid paralysis (AFP) in November 2010. The isolate was closely related to virus circulating in northeastern Nigerian states in 2010.

DRC. The cVDPV2 outbreak in DRC continued through 2010, with a total of 37 cases detected. Since July 2009, a total of 17 cVDPV2 isolates (0.7%--3.5% divergent) from AFP cases have been detected in five provinces. Five additional aVDPV2 isolates (0.7%--1.4% divergent) from AFP patients were detected in three of these provinces. Multiple independent cVDPV2 and aVDPV2 emergences occurred in DRC.

Ethiopia. Seven cVDPV3 isolates (1.3%--3.1% divergent) were isolated from AFP patients in three overlapping VDPV3 outbreaks that emerged independently in three central regions.

India. Sixteen cVDPV2 isolates (1.0%--1.6% divergent), representing four independent emergences, were isolated from AFP patients in Uttar Pradesh. The cVDPV2 cases clustered in districts of western Uttar Pradesh that previously had been at high risk for WPV1 and WPV3 circulation (5). Although all patients had received >7 mOPV1 doses in SIAs, <50% had received a tOPV dose.

Niger. One cVDPV2 (2.5% divergent) was isolated from a patient in southwestern Niger with onset of AFP in June 2010. The isolate was closely related to a cVDPV circulating in neighboring Sokoto State, Nigeria. As with the four previous cVDPV2 importations from Nigeria detected since May 2006 (3), no secondary cases were found in Niger.

Nigeria. Since 2005, a total of 355 AFP cases associated with an outbreak of cVDPV2 (0.7%--6.2% divergent) have been reported in 11 northern and three central states of Nigeria (3,6,7). The outbreak peaked at 153 cases in 2009, but 27 cases were detected in 2010, and five cases (representing three transmission chains) were detected through March 2011. Genetic analysis indicated that detected cases represent at least seven concurrent outbreaks arising from multiple cVDPV2 emergences during 2004--2006 (3,7). The outbreak occurred in northern states, where coverage attained through routine vaccination with tOPV was low and tOPV SIAs were infrequent (3,6,7).

Somalia. VDPV2 has been detected in Somalia since 2005. During July 2009--March 2011, cVDPV2 (1.0%--2.4% divergent) were isolated from five AFP cases and six contacts in the regions surrounding Mogadishu; all were derived from a single emergence. An independent aVDPV2 (0.7% divergent) was isolated in 2010 from an AFP patient.

iVDPVs

Since the introduction of OPV in 1961, approximately 50 persons with B-cell immunodeficiencies have been found worldwide to be excreting iVDPVs (indicating prolonged infections), most of which were detected only after the onset of AFP. Intensified surveillance for VDPVs and special studies of iVDPV excretion among persons with primary immunodeficiencies in developing and middle-income countries have resulted in an increase in recognized iVDPV infections, from two in the previous reporting period (3) to nine currently, seven of which were associated with iVDPV2. New iVDPV infections will occur as long as OPV is used and no effective therapies to clear iVDPV infections are available.

Algeria. A girl aged 1.5 years with HLA-DR--associated immunodeficiency, who had received 2 OPV doses, developed AFP in April 2010, and died in November 2010 from complications of immunodeficiency; iVDPV2 (1.0%--1.8% divergent) was isolated from four consecutive stool specimens.

China. An iVDPV2 (1.9% divergent) was isolated from a girl aged 9 years with primary immunodeficiency, and an iVDPV3 (2.0% divergent) was isolated from a boy aged 2 years with primary immunodeficiency. Both patients had received 3 OPV doses, and both developed AFP in February 2011.

Colombia. A boy aged 15 months with agammaglobulinemia who had received 4 OPV doses in his first months of life, developed AFP in July 2009, 15 months after receipt of the first OPV dose; iVDPV2 (1.5% divergent) was isolated from two consecutive stool specimens.

India. A boy aged 11 years with common variable immunodeficiency who had received 4 OPV doses, developed AFP in September 2009, 5 years after receipt of the most recent OPV dose; iVDPV1 (4.1% divergent) was isolated from two consecutive stool specimens. A child aged 10 years with primary immunodeficiency who had received 19 OPV doses developed AFP in January 2010; iVDPV2 (1.2% divergent) was isolated from two consecutive stool specimens.

Iraq. A boy aged 8 months who showed signs of primary immunodeficiency (multiple infections) and had received 6 OPV doses developed AFP in December 2010; iVDPV2 (1.2% divergent) was isolated from stool specimens taken within a week of AFP onset. The child had no residual paralysis when examined 60 days after AFP onset but died 2 weeks later from acute severe bronchiolitis.

Sri Lanka. An iVDPV2 (1.3% divergent) was isolated in 2010 from a boy aged 8 months diagnosed with severe combined immunodeficiency who had received 3 OPV doses but had not developed AFP.

Turkey. An iVDPV2 (1.8% divergent) was isolated in 2011 from a boy aged 1 year with primary immunodeficiency who had received 1 OPV dose but had not developed AFP.

aVDPVs

During July 2009--March 2011, aVDPVs were isolated in 15 countries (Table). Descriptions of the most divergent aVDPVs, all from sewage samples in countries with high rates of polio vaccination coverage, follow. Despite follow-up investigations in all three countries, the persons infected with the corresponding aVDPVs have not been identified. In settings of low poliovirus vaccine coverage, aVDPVs might signal cVDPV emergence and potential gaps in surveillance.

Estonia. Highly divergent (13.5%--15.8%) aVDPV2s were isolated through late 2010 and are related to sewage isolates detected previously in Estonia (3).

Finland. Highly divergent (12.4%--14.6%) aVDPV1s, aVDPV2s, and aVDPV3s were isolated from sewage samples collected during July 2009--October 2010 (8). The isolates were related to aVDPVs detected previously and unrelated to the Estonian aVDPVs (3). Of 13 samples collected, 11 contained heterotypic VDPV mixtures sharing similar degrees of divergence from the parental OPV strains, consistent with the source being a person chronically infected with iVDPVs of all three serotypes.

Israel. Sewage samples from the Tel Aviv area (sampling populations of approximately 350,000 and 10,000) yielded two genetically distinct groups of type 2 aVDPVs (9). Group 1 aVDPV2s (15.0%--16.7% divergent), first detected in 1998, were found in samples collected during July 2009--March 2011. Group 2 aVDPV2s (10.7%--11.2% divergent), first detected in 2006, were found in samples collected during the same period.

Reported by

Polio Eradication Dept, World Health Organization, Geneva, Switzerland. Global Polio Laboratory Network. Div of Viral Diseases and Global Immunization Div, National Center for Immunization and Respiratory Diseases, CDC. Corresponding contributor: Olen M. Kew, Div of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, okew@cdc.gov, 404-639-3940.

Editorial Note

The three categories of VDPVs differ in their public health importance. First, cVDPVs have recovered the biologic properties of WPVs and have the potential to circulate for years in settings where polio vaccination coverage to prevent that particular type is low. In addition, for each case detected, another 100--1,000 asymptomatic infections occur among susceptible children, as is the case for WPVs (10). Second, iVDPVs can be excreted for many years by persons with certain primary immunodeficiencies, and some chronic infections are latent. Many persons with prolonged iVDPV infections either spontaneously clear the infections or die from the complications of immunodeficiency. Nonetheless, in the absence of effective antiviral therapy, persons infected with iVDPVs without paralysis are at risk for developing paralytic poliomyelitis and might infect others with poliovirus, posing a risk for outbreaks in areas with low polio vaccination coverage. Third, aVDPVs are heterogeneous; some represent the initial isolates from cVDPV outbreaks, especially in areas with type-specific immunity gaps, and aVDPVs isolated during cVDPV outbreaks of the same serotype might be cVDPVs whose progenitors or progeny were not detected. Other aVDPVs, such as those detected in sewage in Estonia, Finland, and Israel, probably are iVDPVs from latent chronic infections. Still other aVDPVs, especially those with limited divergence, might represent limited spread of OPV virus or the upper limit of OPV divergence in a single normal vaccine recipient or contact.

The detection in Nigeria of numerous isolates with <1% divergence that were ancestral to cVDPV2 lineages (7) prompted a redefinition of VDPV2 for purposes of reporting by the Global Polio Laboratory Network to include isolates with >0.6% divergence and was applied beginning in 2010.

The increased frequency of VDPV detection compared with the previous reporting period (3) is attributable partly to increased surveillance sensitivity and improved laboratory methods. However, for cVDPVs, the most important factor is the growth of type-specific immunity gaps in areas with low routine vaccination, arising from the intensive use of mOPV1 and bOPV in SIAs. These alternative OPV formulations, by eliminating interference from the type 2 OPV strain, are more effective than tOPV in inducing higher levels of population immunity to WPV1 and WPV3. Their use in endemic and outbreak countries has facilitated WPV control. In settings of inadequate routine vaccination coverage with tOPV, conditions develop that favor multiple independent VDPV2 emergences, as occurred in DRC, India, Nigeria, and Somalia. Emergence of cVDPV3 appears to be rare but occurred in areas of low tOPV coverage in Ethiopia after a cVDPV2 emergence in 2008 (3).

Current and past experiences underscore the importance of robust routine vaccination with tOPV (or, alternatively, inactivated poliovirus vaccine) to prevent VDPV emergence and spread as well as to prevent WPV transmission. In countries with low routine vaccination coverage, closing the immunity gaps to all three poliovirus serotypes by periodic but regular use of tOPV in SIAs is essential to prevent cVDPV emergence (3). Maintenance of sensitive AFP surveillance also is crucial; any temporal and geographic clustering of vaccine-related isolates of the same serotype should prompt further investigation.

References

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