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Complete genomic sequences of a non-redundant set of 70 recombinants between three serotypes of attenuated Sabin polioviruses as well as location (based on partial sequencing) of crossover sites of 28 additional recombinants were determined and compared with the previously published data. It is demonstrated that the genomes of Sabin viruses contain distinct strain-specific segments that are eliminated by recombination. The presumed low fitness of these segments could be linked to mutations acquired upon derivation of the vaccine strains and/or may have been present in wild-type parents of Sabin viruses. These "weak" segments contribute to the propensity of these viruses to recombine with each other and with other enteroviruses as well as determine the choice of crossover sites. The knowledge of location of such segments opens additional possibilities for the design of more genetically stable and/or more attenuated variants, i.e., candidates for new oral polio vaccines. The results also suggest that the genome of wild polioviruses, and, by generalization, of other RNA viruses, may harbor hidden low-fitness segments that can be readily eliminated only by recombination., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Unlabelled: Four cases of acute flaccid paralysis caused by slightly evolved (Sabin-like) vaccine polioviruses of serotype 2 were registered in July to August 2010 in an orphanage of Biysk (Altai Region, Russia). The Biysk cluster of vaccine-associated paralytic poliomyelitis (VAPP) had several uncommon, if not unique, features. (i) Until this outbreak, Sabin-like viruses (in distinction to more markedly evolved vaccine-derived polioviruses [VDPVs]) were reported to cause only sporadic cases of VAPP. Consequently, VAPP cases were not considered to require outbreak-type responses. However, the Biysk outbreak completely blurred the borderline between Sabin-like viruses and VDPVs in epidemiological terms. (ii) The outbreak demonstrated a very high disease/infection ratio, apparently exceeding even that reported for wild polioviruses. The viral genome structures did not provide any substantial hints as to the underlying reason(s) for such pathogenicity. (iii) The replacement of intestinal poliovirus lineages by other Sabin-like lineages during short intervals after the disease onsets was observed in two patients. Again, the sequences of the respective genomes provided no clues to explain these events. (iv) The polioviruses isolated from the patients and their contacts demonstrated a striking heterogeneity as well as rapid and uneven evolution of the whole genomes and their parts, apparently due to extensive interpersonal contacts in a relatively small closed community, multiple bottlenecking, and recombination. Altogether, the results demonstrate several new aspects of pathogenicity, epidemiology, and evolution of vaccine-related polioviruses and underscore several serious gaps in understanding these problems., Importance: The oral poliovirus vaccine largely contributed to the nearly complete disappearance of poliovirus-caused poliomyelitis. Being generally safe, it can, in some cases, result in a paralytic disease. Two types of such outcomes are distinguished: those caused by slightly diverged (Sabin-like) viruses on the one hand and those caused by significantly diverged VDPVs on the other. This classification is based on the number of mutations in the viral genome region encoding a viral structural protein. Until now, only sporadic poliomyelitis cases due to Sabin-like polioviruses had been described, and in distinction from the VDPV-triggered outbreaks, they did not require broad-scale epidemiological responses. Here, an unusual outbreak of poliomyelitis caused by a Sabin-like virus is reported, which had an exceptionally high disease/infection ratio. This outbreak blurred the borderline between Sabin-like polioviruses and VDPVs both in pathogenicity and in the kind of responses required, as well as underscoring important gaps in understanding the pathogenicity, epidemiology, and evolution of vaccine-derived polioviruses., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

A large outbreak of poliomyelitis, with 463 laboratory-confirmed and 47 polio-compatible cases, took place in 2010 in Tajikistan. Phylogenetic analysis of the viral VP1 gene suggested a single importation of wild poliovirus type 1 from India in late 2009, its further circulation in Tajikistan and expansion into neighbouring countries, namely Kazakhstan, Russia, Turkmenistan and Uzbekistan. Whole-genome sequencing of 14 isolates revealed recombination events with enterovirus C with cross-overs within the P2 region. Viruses with one class of recombinant genomes co-circulated with the parental virus, and representatives of both caused paralytic poliomyelitis. Serological analysis of 327 sera from acute flaccid paralysis cases as well as from patients with other diagnoses and from healthy people demonstrated inadequate immunity against polio in the years preceding the outbreak. Evidence was obtained suggesting that vaccination against poliomyelitis, in rare cases, may not prevent the disease. Factors contributing to the peculiarities of this outbreak are discussed. The outbreak emphasises the necessity of continued vaccination against polio and the need, at least in risk areas, of quality control of this vaccination through well planned serological surveillance.

Historical records of patients with vaccine-associated paralytic poliomyelitis (VAPP) in Hungary during 1961-1981 were reviewed to assess the risk of VAPP after oral polio vaccine (OPV) administration. A confirmed VAPP case was defined as a diagnosis of paralytic poliomyelitis and residual paralysis at 60 days in a patient with an epidemiologic link to the vaccine. Archived poliovirus isolates were retested using polymerase chain reaction and sequencing of the viral protein 1 capsid region. This review confirmed 46 of 47 cases previously reported as VAPP. Three cases originally linked to monovalent OPV (mOPV) 3 and one case linked to mOPV1 presented after administration of bivalent OPV 1 + 3 (bOPV). The adjusted VAPP risk per million doses administered was 0.18 for mOPV1 (2 cases/11.13 million doses), 2.96 for mOPV3 (32 cases/10.81 million doses), and 12.82 for bOPV (5 cases/390,000 doses). Absence of protection from immunization with inactivated poliovirus vaccine or exposure to OPV virus from routine immunization and recent injections could explain the higher relative risk of VAPP in Hungarian children. In polio-endemic areas in which mOPV3 and bOPV are needed to achieve eradication, the higher risk of VAPP would be offset by the high risk of paralysis due to wild poliovirus and higher per-dose efficacy of mOPV3 and bOPV compared with trivalent OPV.

Genetic characterization of wild-type measles viruses (MVs) is an important component of laboratory surveillance of measles. In this study, a phylogenetic analysis was performed of the nucleoprotein gene sequences of 228 MVs isolated in the Russian Federation between 2003 and 2007. Five genotypes, D4, D5, D6, D8, and H1, were detected. From 1999 through the first 6 months of 2003, the most prevalent genotype in the European part of Russia was D4. All genotype D4-type viruses were closely related to each other (with overall sequence diversity of

The global eradication of poliomyelitis will require substantial changes in immunization practices. One of the proposed scenarios includes cessation of vaccination with live oral poliovirus vaccine (OPV) and the creation of an OPV stockpile for emergency response in case of the reintroduction of poliovirus into circulation. We describe here a retrospective analysis of the cessation of OPV usage in a region of the Byelorussian Republic of the former Soviet Union in 1963 to 1966. During this period, a widespread circulation and evolution of independent lineages of vaccine-derived polioviruses took place in the region. Some of these lineages appeared to originate from OPV given to 40 children in the community during this period of essentially no vaccinations. The data demonstrate very high risks associated with both the local cessation of OPV vaccination and the proposed use of OPV to control a possible reemergence of poliovirus in the postvaccination period. The high transmissibility of OPV-derived viruses in nonimmune population, documented here, and the known existence of long-term OPV excretors should be also considered in assessing risks of the synchronized global cessation of OPV usage.

After introducing surveillance for poliomyelitis and AFP cases in the Russian Federation in 1998, 740 AFP cases have been registered in 1998-1999, and 18 of that number were considered as vaccine-associated paralytic poliomyelitis (VAPP). Of 18 cases 11 were classified as VAPP of vaccine recipients and confirmed by virus isolation; from two of the vaccine recipients virus was not isolated, and five were poliomyelitis cases in contact non-vaccinated children. In all the cases the disease was characterised with the typical clinical picture with residual pareses and paralyses. One case was fatal. Vaccine virus type 3 has been isolated from all the vaccine recipients. The MAPREC test has shown that the quality of monovaccine type 3 bulks used for vaccinating these children did not differ from the quality of other bulk vaccines produced by the Chumakov Institute of Poliomyelitis. Patients surveyed for gammaglobulin were positive. Polioviruses type 1 isolated from two of the contact cases had changed antigenic properties and were recombinants of types 1 and 2.

An outbreak of poliomyelitis with 146 cases among children of whom six died occurred in the Chechen Republic in 1995. Sporadic cases of poliomyelitis have been reported in the neighbouring Ingush Republic. The outbreak lasted for five months (from May to September) and the maximum number of cases was registered in July. The age of the patients did not exceed 11 years, and more than 90% of the patients were children aged from one month to four years. The overwhelming majority of the patients had not been vaccinated in the routine OPV immunization programme. The outbreak was due to wild poliovirus type 1 belonging to genotype T previously known to circulate in the territory of the former Soviet Union (FSU). Chechen and Ingush isolates were very closely related to each other and to isolates from Central Asia, Tajikistan, 1994. Only a very distant relatedness of the Chechen and Ingush isolates was found with the strains isolated at about the same time outside the FSU (China 1994, Pakistan 1995). The presence of high numbers of non-vaccinated/poorly vaccinated persons and the poor sanitary and hygienic conditions for civilians due to the military conflict were factors that had a role in the outbreak.

We determined nucleotide sequences of the VP1 and 2AB genes and portions of the 2C and 3D genes of two evolving poliovirus lineages: circulating wild viruses of T geotype and Sabin vaccine-derived isolates from an immunodeficient patient. Different regions of the viral RNA were found to evolve nonsynchronously, and the rate of evolution of the 2AB region in the vaccine-derived population was not constant throughout its history. Synonymous replacements occurred not completely randomly, suggesting the need for conservation of certain rare codons (possibly to control translation elongation) and the existence of unidentified constraints in the viral RNA structure. Nevertheless the major contribution to the evolution of the two lineages came from linear accumulation of synonymous substitutions. Therefore, in agreement with current theories of viral evolution, we suggest that the majority of the mutations in both lineages were fixed as a result of successive sampling, from the heterogeneous populations, of random portions containing predominantly neutral and possibly adverse mutations. As a result of such a mode of evolution, the virus fitness may be maintained at a more or less constant level or may decrease unless more-fit variants are stochastically generated. The proposed unifying model of natural poliovirus evolution has important implications for the epidemiology of poliomyelitis.

The genomic relationships of wild poliovirus type 1 strains recently isolated in Europe, the Middle East, and the Indian subcontinent was analyzed by automated amplicon sequencing of the VP1/2A junction region of the genome. Four major genotypes of poliovirus type 1 were found to circulate. Two genotypes were found predominantly in Eastern Europe, one of these in the Caucasian Region and the other in countries bordering the Black Sea. A third genotype circulated mainly in Egypt. The fourth and largest genotype circulated in the largest geographic area. Strains belonging to this genotype could be found in countries as far apart as Malaysia and Ukraine. Considerable genetic variation was observed among strains isolated in Egypt, Pakistan, and India, where poliovirus is endemic. Strains belonging to all four genotypes circulated in Pakistan. Data confirm the extent of poliovirus circulation in certain regions, stressing the need for intensification of vaccination in these regions.

Five representatives from a collection of 21 Sabin type 2-like poliovirus strains isolated from paralytic poliomyelitis cases in two regions of the USSR have been subjected to limited nucleotide sequencing. All proved to be intertypic recombinants having the genes encoding capsid proteins of Sabin 2 origin and a 3'-end portion of the genome derived from either type 1 (3 isolates) or type 3 (2 isolates) Sabin strains. The crossover points in all the 5 genomes have been mapped to different loci of the P3 region. At least 6 additional isolates from the same collection (and 2 isolates from healthy contacts), appeared to have a type 2/type 1 recombinant genome, as judged by oligonucleotide mapping. The biological significance of frequent occurrence of recombinants among field isolates of vaccine-related strains is discussed.

When the osmotic pressure of the maintenance medium is decreased, poliovirus reproduction is inhibited. Poliovirus strains may vary in their sensitivity to the effect of hypotonic solutions. Mutants have been selected (designated as osm mutants) the reproduction of which is characterized by particularly high resistance to media with reduced osmotic pressure. Initial stages of the virus-cell interaction proceed at similar rates in physiologic and hypotonic solutions. Reactions sensitive to hypotonic solutions take place in the second half of the latent period and during the stage of virus maturation. The multiplication of viruses in moderately hypotonic solutions exhibits a marked dependence upon the temperature and the presence of cystine in the medium, even though these factors have relatively small influence upon the reproduction of the viruses in isotonic solutions. Despite complete cessation of the production of infectious virus in certain hypotonic media, there is a considerable synthesis of virus-induced RNA. At least some of the RNA produced under these conditions is infectious. With a further decrease of the osmotic pressure of the medium the synthesis of the viral RNA is inhibited. Some possible explanations of the observed facts are briefly discussed.