Olen Kew

Oral poliovirus vaccine evolution and insights relevant to modeling the risks of circulating vaccine-derived polioviruses (cVDPVs).

The live, attenuated oral poliovirus vaccine (OPV) provides a powerful tool for controlling and stopping the transmission of wild polioviruses (WPVs), although the risks of vaccine-associated paralytic polio (VAPP) and circulating vaccine-derived poliovirus (cVDPV) outbreaks exist as long as OPV remains in use. Understanding the dynamics of cVDPV emergence and outbreaks as a function of population immunity and other risk factors may help to improve risk management and the development of strategies to respond to possible outbreaks. We performed a comprehensive review of the literature related to the process of OPV evolution and information available from actual experiences with cVDPV outbreaks. Only a relatively small fraction of poliovirus infections cause symptoms, which makes direct observation of the trajectory of OPV evolution within a population impractical and leads to significant uncertainty. Despite a large global surveillance system, the existing genetic sequence data largely provide information about transmitted virulent polioviruses that caused acute flaccid paralysis, and essentially no data track the changes that occur in OPV sequences as the viruses transmit largely asymptomatically through real populations with suboptimal immunity. We updated estimates of cVDPV risks based on actual experiences and identified the many limitations in the existing data on poliovirus transmission and immunity and OPV virus evolution that complicate modeling. Modelers should explore the space of potential model formulations and inputs consistent with the available evidence and future studies should seek to improve our understanding of the OPV virus evolution process to provide better information for policymakers working to manage cVDPV risks.

Isolation of a type 3 vaccine-derived poliovirus (VDPV) from an Iranian child with X-linked agammaglobulinemia.

Type 3 immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) were isolated from a 15-month-old Iranian boy with acute flaccid paralysis (AFP) who was subsequently diagnosed with X-linked agammaglobulinemia (XLA). VP1 nucleotide sequences of the two isolates differed from Sabin 3 by 2.0% and 2.1% and from each other by 0.6%. Although the key determinant of attenuation and temperature sensitivity in the 5-untranslated region (U(472)-->C) had reverted, a second capsid-region determinant (VP3:Phe(091)) was unchanged, but a presumptive suppressor (VP1:Ala(054)-->Val) was found. The isolates were Sabin 3/Sabin 1 recombinants, sharing a single recombination breakpoint in the 2C region. Although the two isolates were antigenically distinct from Sabin 3, only one amino acid replacement was found in the neutralizing antigenic sites (VP3:Ser(059)-->Asn in site 3). The patient was placed on intravenous immunoglobulin (IVIG) therapy within 9 days of onset of AFP, and iVDPV excretion ceased thereafter, but the patient remained severely paralyzed until his death approximately 11 months after paralysis. No secondary AFP cases were found, and none of the seven tested contacts of the patient were found to be infected with poliovirus.

Identification of vaccine-derived polioviruses using dual-stage real-time RT-PCR

Vaccine-derived polioviruses (VDPVs) are associated with polio outbreaks and prolonged infections in individuals with primary immunodeficiencies. VDPV-specific PCR assays for each of the three Sabin oral poliovirus vaccine (OPV) strains were developed, targeting sequences within the VP1 capsid region that are selected for during replication of OPV in the human intestine. Over 2400 Sabin-related isolates and identified 755 VDPVs were screened. Sensitivity of all assays was 100%, while specificity was 100% for serotypes 1 and 3, and 76% for serotype 2. The assays permit rapid, sensitive identification of OPV-related viruses and flag programmatically important isolates for further characterization by genomic sequencing.

Natural Type 3/Type 2 Intertypic Vaccine-Related Poliovirus Recombinants with the First Crossover Sites within the VP1 Capsid Coding Region

Background Ten uncommon natural type 3/type 2 intertypic poliovirus recombinants were isolated from stool specimens from nine acute flaccid paralysis case patients and one healthy vaccinee in China from 2001 to 2008. Principal Findings Complete genomic sequences revealed their vaccine-related genomic features and showed that their first crossover sites were randomly distributed in the 3′ end of the VP1 coding region. The length of donor Sabin 2 sequences ranged from 55 to 136 nucleotides, which is the longest donor sequence reported in the literature for this type of poliovirus recombination. The recombination resulted in the introduction of Sabin 2 neutralizing antigenic site 3a (NAg3a) into a Sabin 3 genomic background in the VP1 coding region, which may have been altered by some of the type 3-specific antigenic properties, but had not acquired any type 2-specific characterizations. NAg3a of the Sabin 3 strain seems atypical; other wild-type poliovirus isolates that have circulated in recent years have sequences of NAg3a more like the Sabin 2 strain. Conclusions 10 natural type 3/type 2 intertypic VP1 capsid-recombinant polioviruses, in which the first crossover sites were found to be in the VP1 coding region, were isolated and characterized. In spite of the complete replacement of NAg3a by type 2-specific amino acids, the serotypes of the recombinants were not altered, and they were totally neutralized by polyclonal type 3 antisera but not at all by type 2 antisera. It is possible that recent type 3 wild poliovirus isolates may be a recombinant having NAg3a sequences derived from another strain during between 1967 and 1980, and the type 3/type 2 recombination events in the 3′ end of the VP1 coding region may result in a higher fitness.

Comparing Israeli and Palestinian polio vaccination policies and the challenges of silent entry of wild poliovirus in 2013–14: a ‘natural experiment’

Eradication of poliomyelitis has been a long time global challenge and is currently reaching the final end stages (Moturi et al. 2014). The potential for reappearance of both wild poliovirus (WPV) and other vaccine-related polioviruses has impacted policy development and influenced strategies implemented worldwide (World Health Organization 2013; Mundel and Orenstein 2013). This commentary views the use of a combined oral polio vaccine (OPV) and inactivated polio vaccine (IPV) schedule in comparison to IPV-alone polio immunization programs in limiting the spread of imported WPV. In 2013, type 1 wild poliovirus (WPV1) entered highly immunized Israel and Palestinian Territories from Egypt and circulated for more than a year (Anis et al. 2013; Manor et al. 2014). During the 1970s, Gaza and the West Bank experienced high levels of clinical poliomyelitis with many cases occurring among children who had received multiple doses of OPV. In the early 1980s, polio was eliminated in both areas using a combination of OPV and IPV (Goldblum et al. 1994). Israel used OPV nationwide, except for in two districts in which an IPV-only schedule was used. Following a 1988 outbreak of poliomyelitis in one of these areas (Hadera) in which 15 cases of polio occurred, Israel adopted a combined OPV/IPV schedule. No further cases were found and a routine sewage monitoring system for polioviruses was initiated in Israel, the West Bank and Gaza (Slater et al. 1990). In 2004, Israel adopted an IPV-only policy in keeping with practices adopted in European and North American countries. Having achieved polio-free status, these countries sought to prevent vaccine-associated poliomyelitis (VAPP), a more pressing national priority at that time than prevention of WPV transmission, which was no longer endemic. In 2013, routine monitoring tests showed WPV1 in sewage in southern and later central Israel. Increased surveillance, developed in consultation with international experts, indicated widespread WPV1 isolates in Southern and Central Israel continuing into early 2014. The positive sewage findings were primarily in Israel, initially among Bedouin communities, but later spreading to mixed communities in Central Israel. A mass campaign of OPV was conducted for children up to age 10 in early 2014. Increased sampling in the West Bank and Gaza showed This commentary is part of the special issue ‘‘Driving the Best Science to Meet Global Health Challenges’’ edited on the occasion of the 9th European Congress on Tropical Medicine and International Health 2015.

Complete Genome Sequence of the Last Representative Genotype of Wild Indigenous Poliovirus Type 1, Which Circulated in Brazil

ABSTRACT Polioviruses are the major etiological agents associated with acute flaccid paralysis (AFP). The complete genome sequence of a representative of the last wild poliovirus type 1 genotype isolated in Brazil from a paralytic poliomyelitis case is reported here.