Eugene Gavrilin

Molecular epidemiology of silent introduction and sustained transmission of wild poliovirus type 1, Israel, 2013.

Poliovirus vaccine coverage in Israel is over 90%. The last nine birth cohorts have been vaccinated exclusively with inactivated polio vaccine (IPV). However, between February and July 2013 type 1 wild poliovirus (WPV1) was detected persistently in 10 and intermittently in 8 of 47 environmental surveillance sites in southern and central Israel and in 30 stool samples collected during July from healthy individuals in southern Israel. We report results of sequence and phylogenetic analyses of genes encoding capsid proteins to determine the source and transmission mode of the virus. WPV1 capsid protein 1 nucleotide sequences were most closely related to South Asia (SOAS) cluster R3A polioviruses circulating in Pakistan in 2012 and isolated from Egyptian sewage in December 2012. There was no noticeable geographical clustering within WPV1-positive sites. Uniform codon usage among isolates from Pakistan, Egypt and Israel showed no signs of optimisation or deoptimisation. Bayesian phylogenetic time clock analysis of the entire capsid coding region (2,643 nt) with a 1.1% evolutionary rate indicated that Israeli and Egyptian WPV1-SOAS lineages diverged in September 2012, while Israeli isolates split into two sub-branches after January 2013. This suggests one or more introduction events into Israel with subsequent silent circulation despite high population immunity.

Expansion of the Global Measles and Rubella Laboratory Network 2005–09

Enhancing measles surveillance with integration of epidemiologic and laboratory information is one of the key strategies for accelerated measles control and elimination. The World Health Organization (WHO) Global Measles and Rubella Laboratory Network (LabNet) has been developed since 2000 to currently include 690 laboratories serving 183 countries. The LabNet testing strategy follows well-validated, standardized procedures for confirming suspected cases and for monitoring measles and rubella virus transmission patterns. The strength of the LabNet is a strong quality assurance program that monitors the performance of all laboratories through annual proficiency testing and continuous assessment. In the 5-year period 2005-2009, the results of >1 million measles immunoglobulin M (IgM) tests have been reported by the LabNet and, in addition, sequence information on >7000 measles and 600 rubella viruses has been shared. Progress with the development of the LabNet during 2005-2009 is discussed.

Molecular Genotyping and Epidemiology of Measles Virus Transmission in the World Health Organization European Region, 2007–2009

BACKGROUND In 2002, the World Health Organization (WHO) adopted a goal to eliminate measles in the European Region by 2010. Measles elimination is defined as the interruption of indigenous measles virus (MV) transmission. The molecular epidemiology of MV transmission in the WHO European Region was studied through the investigation of reported cases and outbreaks to monitor the regions progress toward its measles elimination goal. METHODS National and regional laboratories performed molecular characterization of MV detected between 2007 and 2009 in the WHO European Region. To document indigenous transmission and importations into the region, we analyzed genotyping results and epidemiological data on measles outbreaks reported by the member states. RESULTS Since 2007, MV genotype D6 has not been reported in the WHO European Region, suggesting that its chains of transmission have been interrupted, whereas several other MV genotypes are still circulating. Although several European countries have already interrupted indigenous MV transmission, genotyping showed that 3 endemic MV transmission chains have been reestablished in other countries. CONCLUSIONS The WHO European Region 2010 goal will not be met, as indigenous transmission of MV has not been interrupted. As the region begins to document its process of elimination verification to monitor progress toward the goal, countries will need to ensure that genotyping is performed in all measles outbreaks.

Importation and circulation of poliovirus in Bulgaria in 2001

OBJECTIVE To characterize the circumstances in which poliomyelitis occurred among three children in Bulgaria during 2001 and to describe the public health response. METHODS Bulgarian authorities investigated the three cases of polio and their contacts, conducted faecal and serological screening of children from high-risk groups, implemented enhanced surveillance for acute flaccid paralysis, and conducted supplemental immunization activities. FINDINGS The three cases of polio studied had not been vaccinated and lived in socioeconomically deprived areas of two cities. Four Roma children from the Bourgas district had antibody titres to serotype 1 poliovirus only, and wild type 1 virus was isolated from the faeces of two asymptomatic Roma children in the Bourgas and Sofia districts. Poliovirus isolates were related genetically and represented a single evolutionary lineage; genomic sequences were less than 90% identical to poliovirus strains isolated previously in Europe, but 98.3% similar to a strain isolated in India in 2000. No cases or wild virus isolates were found after supplemental immunization activities were launched in May 2001. CONCLUSIONS In Bulgaria, an imported poliovirus was able to circulate for two to five months among minority populations. Surveillance data strongly suggest that wild poliovirus circulation ceased shortly after supplemental immunization activities with oral poliovirus vaccine were conducted.

Genetic Analysis and Characterization of Wild Poliovirus Type 1 During Sustained Transmission in a Population With >95% Vaccine Coverage, Israel 2013

BACKGROUND Israel has >95% polio vaccine coverage with the last 9 birth cohorts immunized exclusively with inactivated polio vaccine (IPV). Using acute flaccid paralysis and routine, monthly countrywide environmental surveillance, no wild poliovirus circulation was detected between 1989 and February 2013, after which wild type 1 polioviruses South Asia genotype (WPV1-SOAS) have persistently circulated in southern Israel and intermittently in other areas without any paralytic cases as determined by intensified surveillance of environmental and human samples. We aimed to characterize antigenic and neurovirulence properties of WPV1-SOAS silently circulating in a highly vaccinated population. METHODS WPV1-SOAS capsid genes from environmental and stool surveillance isolates were sequenced, their neurovirulence was determined using transgenic mouse expressing the human poliovirus receptor (Tg21-PVR) mice, and their antigenicity was characterized by in vitro neutralization using human sera, epitope-specific monoclonal murine anti-oral poliovirus vaccine (OPV) antibodies, and sera from IPV-immunized rats and mice. RESULTS WPV1 amino acid sequences in neutralizing epitopes varied from Sabin 1 and Mahoney, with little variation among WPV1 isolates. Neutralization by monoclonal antibodies against 3 of 4 OPV epitopes was lost. Three-fold lower geometric mean titers (Z = -4.018; P < .001, Wilcoxon signed-rank test) against WPV1 than against Mahoney in human serum correlated with 4- to 6-fold lower neutralization titers in serum from IPV-immunized rats and mice. WPV1-SOAS isolates were neurovirulent (50% intramuscular paralytic dose in Tg21-PVR mice: log10(7.0)). IPV-immunized mice were protected against WPV1-induced paralysis. CONCLUSIONS Phenotypic and antigenic profile changes of WPV1-SOAS may have contributed to the intense silent transmission, whereas the reduced neurovirulence may have contributed to the absence of paralytic cases in the background of high population immunity.

Characteristics of an Environmentally Monitored Prolonged Type 2 Vaccine Derived Poliovirus Shedding Episode that Stopped without Intervention

Vaccine derived poliovirus (VDPV) type 2 strains strongly divergent from the corresponding vaccine strain, Sabin 2, were repeatedly isolated from sewage in Slovakia over a period of 22 months in 2003–2005. Cell cultures of stool specimens from known immune deficient patients and from an identified putative source population of 500 people failed to identify the potential excretor(s) of the virus. The occurrence of VDPV in sewage stopped without any intervention. No paralytic cases were reported in Slovakia during the episode. According to a GenBank search and similarity plotting-analysis, the closest known relative of the first isolate PV2/03/SVK/E783 through all main sections of the genome was the type 2 poliovirus Sabin strain, with nucleotide identities in 5′UTR, P1, P2, P3, and 3′UTR parts of the genome of 88.6, 85.9, 87.3, 88.5, and 94.0 percent, respectively. Phenotypic properties of selected Slovakian aVDPV strains resembled those of VDPV strains isolated from immune deficient individuals with prolonged PV infection (iVDPV), including antigenic changes and moderate neurovirulence in the transgenic mouse model. One hundred and two unique VP1 coding sequences were determined from VDPV strains isolated from 34 sewage specimens. Nucleotide differences from Sabin 2 in the VP1 coding region ranged from 12.5 to 15.6 percent, and reached a maximum of 9.6 percent between the VDPV strains under study. Most of the nucleotide substitutions were synonymous but as many as 93 amino acid positions out of 301 in VP1 showed substitutions. We conclude that (1) individuals with prolonged poliovirus infection are not as rare as suggested by the studies on immune deficient patients known to the health care systems and (2) genetic divergence of VDPV strains may remain extensive during years long replication in humans.

Prolonged Excretion of Poliovirus among Individuals with Primary Immunodeficiency Disorder: An Analysis of the World Health Organization Registry

Individuals with primary immunodeficiency disorder may excrete poliovirus for extended periods and will constitute the only remaining reservoir of virus after eradication and withdrawal of oral poliovirus vaccine. Here, we analyzed the epidemiology of prolonged and chronic immunodeficiency-related vaccine-derived poliovirus cases in a registry maintained by the World Health Organization, to identify risk factors and determine the length of excretion. Between 1962 and 2016, there were 101 cases, with 94/101 (93%) prolonged excretors and 7/101 (7%) chronic excretors. We documented an increase in incidence in recent decades, with a shift toward middle-income countries, and a predominance of poliovirus type 2 in 73/101 (72%) cases. The median length of excretion was 1.3 years (95% confidence interval: 1.0, 1.4) and 90% of individuals stopped excreting after 3.7 years. Common variable immunodeficiency syndrome and residence in high-income countries were risk factors for long-term excretion. The changing epidemiology of cases, manifested by the greater incidence in recent decades and a shift to from high- to middle-income countries, highlights the expanding risk of poliovirus transmission after oral poliovirus vaccine cessation. To better quantify and reduce this risk, more sensitive surveillance and effective antiviral therapies are needed.

Challenges of Maintaining Polio-free Status of the European Region

BACKGROUND The European region, certified as polio free in 2002, had recent wild poliovirus (WPV) introductions, resulting in a major outbreak in Central Asian countries and Russia in 2010 and in current widespread WPV type 1 circulation in Israel, which endangered the polio-free status of the region. METHODS We assessed the data on the major determinants of poliovirus transmission risk (population immunity, surveillance, and outbreak preparedness) and reviewed current threats and measures implemented in response to recent WPV introductions. RESULTS Despite high regional vaccination coverage and functioning surveillance, several countries in the region are at high or intermediate risk of poliovirus transmission. Coverage remains suboptimal in some countries, subnational geographic areas, and population groups, and surveillance (acute flaccid paralysis, enterovirus, and environmental) needs further strengthening. Supplementary immunization activities, which were instrumental in the rapid interruption of WPV1 circulation in 2010, should be implemented in high-risk countries to close population immunity gaps. National polio outbreak preparedness plans need strengthening. Immunization efforts to interrupt WPV transmission in Israel should continue. CONCLUSIONS The European region has successfully maintained its polio-free status since 2002, but numerous challenges remain. Staying polio free will require continued coordinated efforts, political commitment and financial support from all countries.

Responding to a cVDPV1 outbreak in Ukraine: Implications, challenges and opportunities

BACKGROUND The European Region, certified polio-free in 2002, remains at risk of wild poliovirus reintroduction and emergence of circulating vaccine-derived polioviruses (cVDPV) until global polio eradication is achieved, as demonstrated by the cVDPV1 outbreak in Ukraine in 2015. METHODS We reviewed epidemiologic, clinical and virology data on cVDPV cases, surveillance and immunization coverage data, and reports of outbreak-related surveys, country missions, and expert group meetings. RESULTS In Ukraine, 3-dose polio vaccine coverage declined from 91% in 2008 to 15% by mid-2015. In summer, 2015, two unrelated children from Zakarpattya province were paralyzed by a highly divergent cVDPV1. The isolates were 20 and 26 nucleotide divergent from prototype Sabin strain (with 18 identical mutations) consistent with their common origin and ∼2-year evolution. Outbreak response recommendations developed with international partner support included conducting three nationwide supplementary immunization activities (SIAs) with tOPV, strengthening surveillance and implementing communication interventions. SIAs were conducted during October 2015-February 2016 (officially reported coverage, round 1-64.4%, round 2-71.7%, and round 3-80.7%). Substantial challenges to outbreak response included lack of high-level support, resistance to OPV use, low perceived risk of polio, widespread vaccine hesitancy, anti-vaccine media environment, economic crisis and military conflict. Communication activities improved caregiver awareness of polio and confidence in vaccination. Surveillance was enhanced but did not consistently meet applicable performance standards. Post-outbreak assessments concluded that cVDPV1 transmission in Ukraine has likely stopped following the response, but significant gaps in population immunity and surveillance remained. CONCLUSIONS Chronic under-vaccination in Ukraine resulted in the accumulation of children susceptible to polioviruses and created favorable conditions for VDPV1 emergence and circulation, leading to the outbreak. Until programmatic gaps in immunization and surveillance are addressed, Ukraine will remain at high-risk for VDPV emergence and circulation, as well as at risk for other vaccine-preventable diseases.