Poliovirus Virus Research Articles

Genetic stabilization of attenuated oral vaccines against poliovirus types 1 and 3

Vaccination with Sabin, a live attenuated oral polio vaccine (OPV), results in robust intestinal and humoral immunity and has been key to controlling poliomyelitis. As with any RNA virus, OPV evolves rapidly to lose attenuating determinants critical to the reacquisition of virulence1–3 resulting in vaccine-derived, virulent poliovirus variants. Circulation of these variants within underimmunized populations leads to further evolution of circulating, vaccine-derived poliovirus with higher transmission capacity, representing a significant risk of polio re-emergence. A new type 2 OPV (nOPV2), with promising clinical data on genetic stability and immunogenicity, recently received authorization from the World Health Organization for use in response to circulating, vaccine-derived poliovirus outbreaks. Here we report the development of two additional live attenuated vaccine candidates against type 1 and 3 polioviruses. The candidates were generated by replacing the capsid coding region of nOPV2 with that from Sabin 1 or 3. These chimeric viruses show growth phenotypes similar to nOPV2 and immunogenicity comparable to their parental Sabin strains, but are more attenuated. Our experiments in mice and deep sequencing analysis confirmed that the candidates remain attenuated and preserve all the documented nOPV2 characteristics concerning genetic stability following accelerated virus evolution. Importantly, these vaccine candidates are highly immunogenic in mice as monovalent and multivalent formulations and may contribute to poliovirus eradication.

Immunogenicity of Catch-Up Immunization with Conventional Inactivated Polio Vaccine among Japanese Adults.

Most Japanese adults are vaccinated twice with the Sabin trivalent oral polio vaccine. Booster vaccination is recommended for Japanese travelers to polio-endemic/high-risk countries. We assessed the catch-up immunization of healthy Japanese adults aged ≥20 years with two doses of standalone conventional inactivated polio vaccine (cIPV). Immunogenicity was evaluated by serum neutralization titers (pre-booster vaccination, 4-6 weeks after each vaccination) against type 1, 2, and 3 poliovirus strains. The participants were 61 healthy Japanese adults (26 men/35 women; mean age ± standard deviation age 35.8 ± 8.0 years). Seropositivity rates (percentage of participants with anti-poliovirus antibody titers ≥1:8) pre-vaccination were 88.5%, 95.1%, and 52.5% for Sabin strains (type 1, 2, and 3); 72.1%, 93.4%, and 31.1% for virulent poliovirus strains (type 1: Mahoney; type 2: MEF-1; and type 3: Saukett); and 93.4%, 93.4%, 93.4%, and 88.5% for type 2 vaccine-derived poliovirus strains (SV3128, SV3130, 11,196, and 11,198). After one cIPV dose, all seropositivity rates increased to 98.4-100.0%. After two cIPV doses, the seropositivity rates reached 100% for all strains. cIPV was well tolerated, with no safety concerns. Catch-up immunization with standalone cIPV induced robust immune responses in Japanese adults, indicating that one booster dose boosted serum-neutralizing antibodies to many strains.

Polio Environmental Surveillance and Its Application to SARS-CoV-2 Detection

The polio eradication program, launched in 1988, has successfully decreased the number of poliomyelitis patients worldwide. However, in areas with immunization gaps where oral polio vaccine coverage has dropped, outbreaks of more virulent vaccine-derived polioviruses (VDPVs) have become a threat to public health. In Japan, inactivated polio vaccine replaced oral polio vaccine as the routine immunization in 2012. Polio environmental surveillance (ES) has been conducted nationwide since 2013 to efficiently monitor the wild type poliovirus or VDPV, which may be imported from overseas. ES may also be utilized to detect other viruses in stool samples. We propose a method of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection based on the polio ES network, and establish a procedure to detect fragments of SARS-CoV-2 genome in wastewater solids. Our findings suggest that polio ES can be used to simultaneously monitor SARS-CoV-2 RNA fragments in sewage waters.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Physicochemical Characterization of Sabin Inactivated Poliovirus Vaccine for Process Development.

Upscaling the production capacity of inactivated poliovirus vaccines (IPV) is urgently needed to eradicate polio worldwide. For the development of a robust manufacturing process for IPV, the impact of stresses on the properties of the poliovirus during manufacturing needs to be carefully evaluated. In this study, the physicochemical properties of Sabin poliovirus after low pH exposure were analyzed by asymmetrical flow field-flow fractionation coupled to multi-angle laser light scattering (AF4-MALS), sedimentation velocity analytical ultracentrifugation (SV-AUC), transmission electron microscopy (TEM), dynamic light scattering (DLS) and surface plasmon resonance (SPR). Low pH stress caused structural changes and aggregation of inactivated poliovirus virions, whereas degraded virion particles would not revert to native virions even after neutralization. Importantly, a complete loss of the D-antigenicity of IPV by low pH stress, followed by neutralization, was observed in SPR. These results suggest that the exposure of poliovirus particle to low pH stress would induce irreversible denaturation and aggregation of virus particles and lead to the loss of D-antigenicity; thus, low pH stress during the manufacturing of poliovirus vaccine should be minimized. The analytical methods above can be efficiently utilized in the development of high-integrity manufacturing processes and high-quality vaccines.

Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus

Enteroviruses support cell-to-cell viral transmission prior to their canonical lytic spread of virus. Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, and picornaviruses in general, transport multiple virions en bloc via infectious extracellular vesicles, 100~1000 nm in diameter, secreted from host cells. Using biochemical and biophysical methods we identify multiple components in secreted microvesicles, including mature PV virions; positive-sense genomic and negative-sense replicative, template viral RNA; essential viral replication proteins; and cellular proteins. Using cryo-electron tomography, we visualize the near-native three-dimensional architecture of secreted infectious microvesicles containing both virions and a unique morphological component that we describe as a mat-like structure. While the composition of these mat-like structures is not yet known, based on our biochemical data they are expected to be comprised of unencapsidated RNA and proteins. In addition to infectious microvesicles, CD9-positive exosomes released from PV-infected cells are also infectious and transport virions. Thus, our data show that, prior to cell lysis, non-enveloped viruses are secreted within infectious vesicles that also transport viral unencapsidated RNAs, viral and host proteins. Understanding the structure and function of these infectious particles helps elucidate the mechanism by which extracellular vesicles contribute to the spread of non-enveloped virus infection.

Use of a Glycan Library Reveals a New Model for Enteric Virus Oligosaccharide Binding and Virion Stabilization.

Enteric viruses infect the gastrointestinal tract, and bacteria can promote replication and transmission of several enteric viruses. Viruses can be inactivated by exposure to heat or bleach, but poliovirus, coxsackievirus B3, and reovirus can be stabilized by bacteria or bacterial polysaccharides, limiting inactivation and aiding transmission. We previously demonstrated that certain N-acetylglucosamine (GlcNAc)-containing polysaccharides can stabilize poliovirus. However, the detailed virus-glycan binding specificity and glycan chain length requirements, and thus the mechanism of virion stabilization, have been unclear. A previous limitation was our lack of defined-length glycans to probe mechanisms and consequences of virus-glycan interactions. Here, we generated a panel of polysaccharides and oligosaccharides to determine the properties required for binding and stabilization of poliovirus. Poliovirus virions are nonenveloped icosahedral 30-nm particles with 60 copies of each of four capsid proteins, VP1 to VP4. VP1 surrounds the 5-fold axis, and our past work indicates that this region likely contains the glycan binding site. We found that relatively short GlcNAc oligosaccharides, such as a six-unit GlcNAc oligomer, can bind poliovirus but fail to enhance virion stability. Virion stabilization required binding of long GlcNAc polymers of greater than 20 units. Our data suggest a model where GlcNAc polymers of greater than 20 units bind and bridge adjacent 5-fold axes, thus aiding capsid rigidity and stability. This study provides a deeper understanding of enteric virus-bacterial glycan interactions, which are important for virion environmental stability and transmission.IMPORTANCE Enteric viruses are transmitted through the fecal-oral route, but how enteric viruses survive in the environment is unclear. Previously, we found that bacterial polysaccharides enhance poliovirus stability against heat or bleach inactivation, but the specific molecular requirements have been unknown. Here, we showed that certain short-chain oligosaccharides can bind to poliovirus but do not increase virion stability. Long-chain polysaccharides bind and may bridge adjacent sites on the viral surface, thus increasing capsid rigidity and stability. This work defines the unique interactions of poliovirus and glycans, which provides insight into virion environmental stability and transmission.

Identification and Characterization of a Poliovirus Capsid Mutant with Enhanced Thermal Stability.

Enteric viruses, including poliovirus, are spread by the fecal-oral route. In order to persist and transmit to a new host, enteric virus particles must remain stable once they are in the environment. Environmental stressors such as heat and disinfectants can inactivate virus particles and prevent viral transmission. It has been previously demonstrated that bacteria or bacterial surface glycans can enhance poliovirus virion stability and limit inactivation from heat or bleach. While investigating the mechanisms underlying bacterially enhanced virion thermal stability, we identified and characterized a poliovirus (PV) mutant with increased resistance to heat inactivation. The M132V mutant harbors a single amino acid change in the VP1 capsid coding that is sufficient to confer heat resistance but not bleach resistance. Although the M132V virus was stable in the absence of bacteria or feces at most temperatures, M132V virus was stabilized by feces at very high temperatures. M132V PV had reduced specific infectivity and RNA uncoating compared with those of wild-type (WT) PV, but viral yields in HeLa cells were similar. In orally inoculated mice, M132V had a slight fitness cost since fecal titers were lower and 12.5% of fecal viruses reverted to the WT. Overall, this work sheds light on factors that influence virion stability and fitness.IMPORTANCE Viruses spread by the fecal-oral route need to maintain viability in the environment to ensure transmission. Previous work indicated that bacteria and bacterial surface polysaccharides can stabilize viral particles and enhance transmission. To explore factors that influence viral particle stability, we isolated a mutant poliovirus that is heat resistant. This mutant virus does not require feces for stability at most temperatures but can be stabilized by feces at very high temperatures. Even though the mutant virus is heat resistant, it is susceptible to inactivation by treatment with bleach. This work provides insight into how viral particles maintain infectivity in the environment.

Cold-Adapted Viral Attenuation (CAVA): Highly Temperature Sensitive Polioviruses as Novel Vaccine Strains for a Next Generation Inactivated Poliovirus Vaccine.

The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV) is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA) poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4–9.9 Log10TCID50/ml) on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature) anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the highly productive PER.C6 cell culture platform, the stably attenuated CAVA strains may serve as an attractive low-cost and (bio)safe option for the production of a novel next generation IPV.

New Strains Intended for the Production of Inactivated Polio Vaccine at Low-Containment After Eradication.

Poliomyelitis has nearly been eradicated through the efforts of the World Health Organization’s Global Eradication Initiative raising questions on containment of the virus after it has been eliminated in the wild. Most manufacture of inactivated polio vaccines currently requires the growth of large amounts of highly virulent poliovirus, and release from a production facility after eradication could be disastrous; WHO have therefore recommended the use of the attenuated Sabin strains for production as a safer option although it is recognised that they can revert to a transmissible paralytic form. We have exploited the understanding of the molecular virology of the Sabin vaccine strains to design viruses that are extremely genetically stable and hyperattenuated. The viruses are based on the type 3 Sabin vaccine strain and have been genetically modified in domain V of the 5’ non-coding region by changing base pairs to produce a cassette into which capsid regions of other serotypes have been introduced. The viruses give satisfactory yields of antigenically and immunogenically correct viruses in culture, are without measurable neurovirulence and fail to infect non-human primates under conditions where the Sabin strains will do so.

Circulating vaccine-derived polioviruses in the Extreme North region of Cameroon

BackgroundThe World Health Organization (WHO) poliovirus eradication program includes careful surveillance of acute-flaccid paralysis (AFP) and mass and routine immunization with oral polio vaccine (OPV). In populations with low vaccine coverage, the live-attenuated Sabin strains, OPV types 1, 2 and 3, can evolve into virulent vaccine-derived polioviruses (VDPVs) and circulate in the community. Until recently, circulating VDPVs (cVDPVs) had not been reported in Cameroon despite the fact that VDPV2 outbreaks have occurred in nearby countries. ObjectivesThis study aimed to characterize virus isolates from four AFP patients infected with cVDPV2 in the Extreme North region of Cameroon in 2013. Study designThe complete VP1 region of the four VDPV strains was sequenced and the relationships with cVDPVs from neighboring countries were investigated. ResultsAll four patients were infected by cVDPV2 strains showing 1.2–2.0% nucleotide difference compared to the reference Sabin 2 VP1 sequence. Phylogenetic analysis indicated that the VDPV strains were genetically linked to cVDPV2 lineages of the recent Chad cVDPV2 outbreak. ConclusionsThe circulation of pathogenic VDPVs suggests that there are localized immunization gaps in some districts like Makary, Mada and Kolofata in Cameroon. To avoid poliomyelitis outbreaks in Cameroon, especially in the districts close to neighboring countries with ongoing cVDPV outbreaks, high polio vaccine coverage is essential.

Inactivated polio vaccine launch in Nepal: a public health milestone.

Inactivated polio vaccine launch in Nepal: a public health milestone.

Different roles of the three loops forming the adhesive interface of nectin-4 in measles virus binding and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1.

Many viruses utilize cell adhesion molecules of the immunoglobulin superfamily as receptors. In particular, viruses of different classes exploit nectins. The large DNA viruses, herpes simplex and pseudorabies viruses, use ubiquitous nectins 1 and 2. The negative-strand RNA virus measles virus (MeV) uses tissue-specific nectin-4, and the positive-strand RNA virus poliovirus uses nectin-like 5 (necl-5), also known as poliovirus receptor. These viruses contact the BC, C'C", and FG loops on the upper tip of their receptor's most membrane-distal domain. This location corresponds to the newly defined canonical adhesive interface of nectins, but how viruses utilize this interface has remained unclear. Here we show that the same key residues in the BC and FG loops of nectin-4 govern binding to the MeV attachment protein hemagglutinin (H) and cell entry, nectin-4 homodimerization, and heterodimerization with nectin-1. On the other hand, residues in the C'C" loop necessary for homo- and heterotypic interactions are dispensable for MeV-induced fusion and cell entry. Remarkably, the C'C" loop governs dissociation of the nectin-4 and H ectodomains. We provide formal proof that H can interfere with the formation of stable nectin-1/nectin-4 heterodimers. Finally, while developing an alternative model to study MeV spread, we observed that polarized primary pig airway epithelial sheets cannot be infected. We show that a single amino acid variant in the BC loop of pig nectin-4 fully accounts for restricted MeV entry. Thus, the three loops forming the adhesive interface of nectin-4 have different roles in supporting MeV H association and dissociation and MeV-induced fusion. Different viruses utilize nectins as receptors. Nectins are immunoglobulin superfamily glycoproteins that mediate cell-cell adhesion in vertebrate tissues. They interact through an adhesive interface located at the top of their membrane-distal domain. How viruses utilize the three loops forming this interface has remained unclear. We demonstrate that while nectin-nectin interactions require residues in all three loops, the association of nectin-4 with the measles virus hemagglutinin requires only the BC and FG loops. However, we discovered that residues in the C'C" loop modulate the dissociation of nectin-4 from the viral hemagglutinin. Analogous mechanisms may support cell entry of other viruses that utilize nectins or other cell adhesion molecules of the immunoglobulin superfamily as receptors.

Inactivation of an enterovirus by airborne disinfectants

BackgroundThe activity of airborne disinfectants on bacteria, fungi and spores has been reported. However, the issue of the virucidal effect of disinfectants spread by fogging has not been studied thoroughly.MethodsA procedure has been developed to determine the virucidal activity of peracetic acid-based airborne disinfectants on a resistant non-enveloped virus poliovirus type 1. This virus was laid on a stainless carrier. The products were spread into the room by hot fogging at 55°C for 30 minutes at a concentration of 7.5 mL.m-3. Poliovirus inoculum, supplemented with 5%, heat inactivated non fat dry organic milk, were applied into the middle of the stainless steel disc and were dried under the air flow of a class II biological safety cabinet at room temperature. The Viral preparations were recovered by using flocked swabs and were titered on Vero cells using the classical Spearman-Kärber CPE reading method, the results were expressed as TCID50.ml-1.ResultsThe infectious titer of dried poliovirus inocula was kept at 105 TCID50.mL-1 up to 150 minutes at room temperature. Dried inocula exposed to airborne peracetic acid containing disinfectants were recovered at 60 and 120 minutes post-exposition and suspended in culture medium again. The cytotoxicity of disinfectant containing medium was eliminated through gel filtration columns. A 4 log reduction of infectious titer of dried poliovirus inocula exposed to peracetic-based airborne disinfectant was obtained.ConclusionThis study demonstrates that the virucidal activity of airborne disinfectants can be tested on dried poliovirus.

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.

Antibody responses of Macaca fascicularis against a new inactivated polio vaccine derived from Sabin strains (sIPV) in DTaP-sIPV vaccine

Antibody responses of Macaca fascicularis against a new tetravalent vaccine composed of diphtheria toxoid, tetanus toxoid, acellular pertussis antigens, and inactivated poliovirus derived from Sabin strains (sIPV) was investigated to predict an optimal dose of sIPV in a new tetravalent vaccine (DTaP-sIPV) prior to conducting a dose-defined clinical study. Monkeys were inoculated with DTaP-sIPVs containing three different antigen units of sIPVs: Vaccine A (types 1:2:3 = 3:100:100 DU), Vaccine B (types 1:2:3 = 1.5:50:50 DU), and Vaccine C (types 1:2:3 = 0.75:25:25 DU). There was no difference in the average titers of neutralizing antibody against the attenuated or virulent polioviruses between Vaccines A and B. The average neutralizing antibody titers of Vaccine C tended to be lower than those of Vaccines A and B. The sIPV antigens did not affect the anti-diphtheria or anti-tetanus antibody titers of DTaP-sIPV. Furthermore, the average neutralizing antibody titers of Vaccine A against the attenuated and virulent polioviruses were comparable between M. fascicularis and humans. These results suggest that M. fascicularis may be a useful animal model for predicting the antibody responses to sIPVs in humans, and that it may be likely to reduce the amount of sIPVs contained in DTaP-sIPVs, even for humans.

PER.C6® cells as a serum-free suspension cell platform for the production of high titer poliovirus: A potential low cost of goods option for world supply of inactivated poliovirus vaccine

There are two highly efficacious poliovirus vaccines: Sabin's live-attenuated oral polio vaccine (OPV) and Salk's inactivated polio vaccine (IPV). OPV can be made at low costs per dose and is easily administrated. However, the major drawback is the frequent reversion of the OPV vaccine strains to virulent poliovirus strains which can result in Vaccine Associated Paralytic Poliomyelitis (VAPP) in vaccinees. Furthermore, some OPV revertants with high transmissibility can circulate in the population as circulating Vaccine Derived Polioviruses (cVDPVs). IPV does not convey VAPP and cVDPVs but the high costs per dose and insufficient supply have rendered IPV an unfavorable option for low and middle-income countries.Here, we explored whether the human PER.C6® cell-line, which has the unique capability to grow at high density in suspension, under serum-free conditions, could be used as a platform for high yield production of poliovirus. PER.C6® cells supported replication of all three poliovirus serotypes with virus titers ranging from 9.4log10 to 11.1log10TCID50/ml irrespective of the volume scale (10ml in shaker flasks to 2L in bioreactors). This production yield was 10–30 fold higher than in Vero cell cultures performed here, and even 100-fold higher than what has been reported for Vero cell cultures in literature [38]. In agreement, the D-antigen content per volume PER.C6®-derived poliovirus was on average 30-fold higher than Vero-derived poliovirus. Interestingly, PER.C6® cells produced on average 2.5-fold more D-antigen units per cell than Vero cells.Based on our findings, we are exploring PER.C6® as an interesting platform for large-scale production of poliovirus at low costs, potentially providing the basis for global supply of an affordable IPV.

Estimating the risk of re-emergence after stopping polio vaccination.

Live vaccination against polio has effectively prevented outbreaks in most developed countries for more than 40 years, and there remain only a few countries where outbreaks of poliomyelitis by the wild strain still threaten the community. It is expected that worldwide eradication will be eventually achieved through careful surveillance and a well-managed immunization program. The present paper argues, however, that based on a simple stochastic model the risk of outbreak by a vaccine-derived strain after the cessation of vaccination is quite high, even if many years have passed since the last confirmed case. As vaccinated hosts are natural reservoirs for virulent poliovirus, the source of the risk is the vaccination itself, employed to prevent the outbreaks. The crisis after stopping vaccination will emerge when the following two conditions are met: the susceptible host density exceeds the threshold for epidemics and the vaccinated host density remains large enough to ensure the occurrence of virulent mutants in the population. Our estimates for transmission, recovery, and mutation rates, show that the probability of an outbreak of vaccine-derived virulent viruses easily exceeds 90%. Moreover, if a small fraction of hosts have a longer infectious period, as observed in individuals with innate immunodeficiency, the risk of an outbreak rises significantly. Under such conditions, successful global eradication of polio is restricted to a certain range of parameters even if inactivated polio vaccine (IPV) is extensively used after the termination of live vaccination.

Inactivated polio vaccine and global polio eradication

2012 will mark the 24th year of WHO's Global Poliomyelitis Eradication Initiative. 1 WHOGlobal eradication of poliomyelitis by the year 2000. Week Epidemiol Rec. 1988; 63: 161-162 Google Scholar Eradication has proven more difficult than originally envisioned because of geopolitical events, such as war, social disruption, and political indifference; social and cultural issues, such as distrust of poliovirus vaccines and vaccinators; and the unanticipated emergence of virulent vaccine-derived polioviruses in many locations. Few of these obstacles have bewildered the scientific community as much as the low efficacy of the major weapon in the arsenal, trivalent oral polio vaccine (OPV) in regions with dense populations, high birthrates, and poor sanitation resulting from diarrhoea due to enteric pathogens, particularly rotaviruses, and perhaps nutritional deficiencies and other factors. 2 Patriarca PA Wright PF John TJ Factors affecting the immunogenicity of oral poliovirus vaccine in developing countries. Rev Infect Dis. 1991; 13: 926-939 Crossref PubMed Scopus (358) Google Scholar , 3 Myaux JA Unicomb L Besser RE et al. Effect of diarrhea on the humoral response to oral polio vaccination. Pediatr Infect Dis J. 1996; 15: 204-209 Crossref PubMed Scopus (38) Google Scholar This dilemma has been most frustrating in northern India where, in some crowded, resource-poor areas, the overall effectiveness of each trivalent OPV dose is estimated to be 10% and some children have developed paralytic polio after as many as ten doses. 4 Grassly NC Fraser C Wenger J et al. New strategies for the elimination of polio from India. Science. 2006; 314: 1150-1153 Crossref PubMed Scopus (216) Google Scholar Immunogenicity of supplemental doses of poliovirus vaccine for children aged 6–9 months in Moradabad, India: a community-based, randomised controlled trialSupplemental mOPV1 resulted in almost total seroprevalence against poliovirus type 1, which is consistent with recent absence of poliomyelitis cases; whereas seroprevalence against types 2 and 3 was expected for routine vaccination histories. The immunogenicity of IPV produced in India (Panacea) was similar to that of an internationally manufactured IPV (GSK). Intradermal IPV was less immunogenic. Full-Text PDF

Virology: molecular biology and pathogenesis

Table of Contents Part I. Introduction 1. A Selective History on the Nature of Viruses Introduction The Early Years: Discoverers and Pioneers The First Stirrings of the Molecular Era The Phage Group Phage Growth: Eclipse and Replication Defining Viruses Are Viruses Alive? Origin of Viruses The Modern Era of Animal Virology 2. Biosynthesis of Viruses: An Introduction to Virus Classification T-Even Bacteriophages as a Model System T-Even Phage Structure and Entry Sequence of Phage Biosynthetic Events Phage Protein Synthesis RNA Metabolism in Infected Cells Assembly of Progeny Phages Packaging DNA within the Phage Particle Unique Features of T-Even Phages Modified Bases Regulated Gene Expression Phage Release: Lysozyme and the rII Region Bacteriophage Lambda: Lysogeny and Transduction Some Final Comments on Bacteriophages Introduction to the Animal Viruses Animal Virus Structure Entry of Animal Viruses The Families of Animal Viruses: Principles of Classification Viral Genetic Systems: The Baltimore Classification Scheme 3. Modes of Virus Infection and Disease Introduction Portals of Entry Routes of Dissemination Hematogenous and Neural Dissemination The Placenta and the Fetus Acute versus Persistent Infections Acute Infections Persistent Infections Slow Infections Chronic Infections Latent Infections Transmissible Spongiform Encephalopathies: Prions 4. Host Defenses and Viral Countermeasures Introduction Overview of Defenses Physical Barriers against Infection The Innate Immune System Cytokines: the Interferons Cytokines: TNF-[alpha], Some Other Cytokines, and Inflammation Macrophages, Neutrophils, and NK Cells and ADCC The Complement System Viral Evasion of Innate Immunity Evasion of Interferons Evasion of Cytokines Evasion of NK Cells and ADCC Evasion of Complement APOBEC3G and the HIV Vif Protein The Adaptive Immune System Antibodies and B Cells Antibody Diversity Viral Evasion of Antibodies Cell-Mediated Immunity Antigen Presentation by MHC Class I Molecules Antigen Presentation by MHC Class II Molecules The Rationale for MHC Restriction Activation of Helper T Cells: Dendritic Cells and B Cells Activation of B Cells Activation of CTLs Mechanism of Action of CTLs T Cells and Antiviral Cytokines Viral Evasion of Cell-Mediated Immunity Inhibition of Antigen Presentation to CTLs Inhibition of Antigen Presentation to Helper T Cells Inhibition of Apoptosis Immunological Memory Self Tolerance The Immune System in Disease Immunopathology Autoimmune Disease Part II. Virus Replication and Pathogenesis subpart RNA Viruses: Double-Stranded 5. Reoviruses Introduction Structure, Binding, Entry, and Uncoating Reovirus Binding and Entry into the Cell Structure, Uncoating, and Entry into the Cytoplasm The Reovirus Genome: Transcription and Translation The Particle-Associated RNA Polymerase The Segmented Reovirus Genome Conversion of ISVPs to Cores Replication and Encapsidation of the Reovirus Genome Synthesis of Double-Stranded RNA Assembly of Progeny Subviral Particles Encapsidation of RNA Segments Reoviruses and Interferon Primary versus Secondary Transcription Final Virus Assembly Pathogenesis Orthoreoviruses Rotaviruses Coltiviruses subpart RNA Viruses: Single-Stranded 6. Picornaviruses Introduction Structure, Binding, and Entry Picornavirus Structure Rhinovirus Receptor and Binding: the Canyon Hypothesis The Poliovirus Receptor Receptors for Coxsackieviruses and Other Enteroviruses Receptors for Foot and Mouth Disease Viruses Poliovirus and Rhinovirus Entry: Some General Points Poliovirus Entry Human Rhinovirus Entry Poliovirus and Rhinovirus Entry: Why the Differences? Translation Translation: Part I Translation: a Digression The RNA Phages Picornaviruses versus RNA Phages: Why the Differences? Translation: Part II Transcription and Genome Replication Assembly and Maturation Medical Aspects Poliovirus Rhinoviruses: the Common Cold Coxsackievirus and Echovirus Viral Hepatitis: Hepatitis A Virus 7. Flaviviruses Introduction Structure and Entry Replication Assembly and Release Historic Interlude: Identification of Hepatitis C Virus West Nile Virus: an Emerging Virus Epidemiology and Pathogenesis General Principles of Arthropod Transmission Infection, Dissemination, and Determinants of Pathogenesis Hemorrhagic Fever Viruses: Yellow Fever and Dengue Encephalitis Viruses: Japanese Encephalitis, St. Louis Encephalitis, and West Nile Viruses Japanese Encephalitis and St. Louis Encephalitis Viruses West Nile Virus Hepatitis C Virus 8. Togaviruses Introduction Structure and Entry Transcription, Translation, and Genome Replication Assembly and Maturation Epidemiology and Pathogenesis Alphaviruses That Cause Encephalitis: Eastern, Western, and Venezuelan Equine Encephalitis Viruses Alphaviruses That Cause Arthritis: Chikungunya, Ross River, and Sindbis Viruses Rubella Virus 9. Coronaviruses Introduction Structure Entry Genome Organization and Expression Coronavirus mRNAs and Their Translation Coronavirus Transcription Coronavirus Recombination Coronavirus Reverse Genetics Assembly and Release Medical Aspects SARS 10. Rhabdoviruses Introduction Structure Entry Genome Organization, Expression, and Replication The General Transcriptional Strategy of Viruses That Contain Negative-Sense RNA Genomes Gene Organization and Transcription Replication Assembly and Release Medical Aspects Cytopathic Effects Vesicular Stomatitis Virus Rabies Virus 11. Paramyxoviruses Introduction Structure Entry Syncytium Formation Genome Organization, Expression, and Replication Genome Organization and Transcription Replication Assembly and Release Medical Aspects Measles Clinical Conditions Sclerosing Panencephalitis (SSPE) Where Did It Come From?