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Cell Host & Microbe May 2020The live-attenuated oral poliovirus vaccine (OPV or Sabin vaccine) replicates in gut-associated tissues, eliciting mucosa and systemic immunity. OPV protects from...
The live-attenuated oral poliovirus vaccine (OPV or Sabin vaccine) replicates in gut-associated tissues, eliciting mucosa and systemic immunity. OPV protects from disease and limits poliovirus spread. Accordingly, vaccination with OPV is the primary strategy used to end the circulation of all polioviruses. However, the ability of OPV to regain replication fitness and establish new epidemics represents a significant risk of polio re-emergence should immunization cease. Here, we report the development of a poliovirus type 2 vaccine strain (nOPV2) that is genetically more stable and less likely to regain virulence than the original Sabin2 strain. We introduced modifications within at the 5' untranslated region of the Sabin2 genome to stabilize attenuation determinants, 2C coding region to prevent recombination, and 3D polymerase to limit viral adaptability. Prior work established that nOPV2 is immunogenic in preclinical and clinical studies, and thus may enable complete poliovirus eradication.
Topics: Adult; Animals; Chlorocebus aethiops; Disease Models, Animal; Female; Genetic Engineering; HeLa Cells; Humans; Immunogenicity, Vaccine; Male; Mice; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; RNA, Viral; RNA-Dependent RNA Polymerase; Recombination, Genetic; Vaccination; Vaccines, Attenuated; Vero Cells; Virulence
PubMed: 32330425
DOI: 10.1016/j.chom.2020.04.003 -
Bulletin of the World Health... Dec 2023A decrease in vaccine coverage in conflict-affected areas has placed Yemen at higher risk of polio outbreaks caused by vaccine-derived poliovirus strains.
PROBLEM
A decrease in vaccine coverage in conflict-affected areas has placed Yemen at higher risk of polio outbreaks caused by vaccine-derived poliovirus strains.
APPROACH
In response to polio outbreaks, the Yemeni health ministry and partners initiated multiple vaccination campaigns to deliver vaccines to children. We also implemented several measures to enhance communication, education, health promotion and hygiene, especially in camps for internally displaced people.
LOCAL SETTING
In 2009, Yemen achieved polio-free status and maintained it until 2019. However, the ongoing political conflict since 2015, coupled with challenges in delivering the polio vaccine to conflict-affected areas, resulted in two polio outbreaks: 35 cases caused by vaccine-derived poliovirus strain 1 between 2019 and 2021, and 230 cases due to vaccine-derived poliovirus strain 2 between November 2021 and December 2022.
RELEVANT CHANGES
In response to the first outbreak, by the end of 2020, we vaccinated 7.2 million children through nationwide vaccination campaigns, except in Sa'ada governorate due to a ban by the authorities. By the end of 2021, 3 800 313 children younger than 5 years had received polio vaccines. For the second outbreak, by the end of 2022, 4 463 389 vaccines had been given to children younger than 10 years, and 1 217 423 to those younger than 5 years.
LESSONS LEARNT
Vaccination campaigns in conflict-affected areas with low vaccine coverage remain crucial in eradicating polio. Efforts are needed to reach vulnerable groups such as displaced populations. Advocacy, communication and social mobilization actions help ensure broader public inclusion and participation in vaccination efforts to prevent polio outbreaks.
Topics: Child; Humans; Yemen; Poliomyelitis; Poliovirus; Poliovirus Vaccines; Disease Outbreaks
PubMed: 38024246
DOI: 10.2471/BLT.23.290122 -
Nucleic Acids Research Sep 2023The genomes of positive-strand RNA viruses serve as a template for both protein translation and genome replication. In enteroviruses, a cloverleaf RNA structure at the...
The genomes of positive-strand RNA viruses serve as a template for both protein translation and genome replication. In enteroviruses, a cloverleaf RNA structure at the 5' end of the genome functions as a switch to transition from viral translation to replication by interacting with host poly(C)-binding protein 2 (PCBP2) and the viral 3CDpro protein. We determined the structures of cloverleaf RNA from coxsackievirus and poliovirus. Cloverleaf RNA folds into an H-type four-way junction and is stabilized by a unique adenosine-cytidine-uridine (A•C-U) base triple involving the conserved pyrimidine mismatch region. The two PCBP2 binding sites are spatially proximal and are located on the opposite end from the 3CDpro binding site on cloverleaf. We determined that the A•C-U base triple restricts the flexibility of the cloverleaf stem-loops resulting in partial occlusion of the PCBP2 binding site, and elimination of the A•C-U base triple increases the binding affinity of PCBP2 to the cloverleaf RNA. Based on the cloverleaf structures and biophysical assays, we propose a new mechanistic model by which enteroviruses use the cloverleaf structure as a molecular switch to transition from viral protein translation to genome replication.
Topics: Humans; Enterovirus; Genome, Viral; HeLa Cells; Nucleic Acid Conformation; Poliovirus; Protein Biosynthesis; RNA, Viral; RNA-Binding Proteins; Viral Proteins; Virus Replication
PubMed: 37486760
DOI: 10.1093/nar/gkad618 -
PloS One 2022Eradication of poliovirus (PV) is a global public health priority, and as clinical cases decrease, the role of environmental surveillance becomes more important....
Eradication of poliovirus (PV) is a global public health priority, and as clinical cases decrease, the role of environmental surveillance becomes more important. Persistence of PV and the environmental factors that influence it (such as temperature and sample type) are an important part of understanding and interpreting positive environmental surveillance samples. The objective of this study was to evaluate the persistence of poliovirus type 2 (PV2) and type 3 (PV3) in wastewater and sediment. Microcosms containing either 1) influent wastewater or 2) influent wastewater with a sediment matrix were seeded with either PV2 or PV3, and stored for up to 126 days at three temperatures (4°C, room temperature [RT], and 30°C). Active PV in the liquid of (1), and the sediment and liquid portions of (2) were sampled and quantified at up to 10 time points via plaque assay and RT-qPCR. A suite of 17 models were tested for best fit to characterize decay of PV2 and PV3 over time and determine the time points at which >90% (T90) and >99% (T99) reduction was reached. Linear models assessed the influence of experimental factors (matrix, temperature, virus type and method of detection) on the predicted T90 and T99 values. Results showed that when T90 was the dependent variable, virus type, matrix, and temperature significantly affected decay, and there was a clear interaction between the sediment matrix and temperature. When T99 was the dependent variable, only temperature and matrix type significantly influenced the decay metric. This study characterizes the persistence of both active and molecular PV2 and PV3 in relevant environmental conditions, and demonstrates that temperature and sediment both play important roles in PV viability. As eradication nears and clinical cases decrease, environmental surveillance and knowledge of PV persistence will play a key role in understanding the silent circulation in endemic countries.
Topics: Environmental Monitoring; Geologic Sediments; Poliovirus; Wastewater
PubMed: 35081146
DOI: 10.1371/journal.pone.0262761 -
Cell Dec 2021RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we...
RNA viruses generate defective viral genomes (DVGs) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication, and protects mice from several RNA viruses, including enteroviruses, influenza, and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.
Topics: Administration, Intranasal; Animals; Antiviral Agents; Broadly Neutralizing Antibodies; COVID-19; Capsid Proteins; Cell Line; Defective Interfering Viruses; Disease Models, Animal; Genome, Viral; Humans; Influenza, Human; Interferons; Male; Mice; Mice, Inbred C57BL; Poliovirus; Respiratory Tract Infections; SARS-CoV-2; Virus Replication
PubMed: 34852237
DOI: 10.1016/j.cell.2021.11.023 -
Epidemiology and Infection Feb 2017Polio cases due to wild virus are reported by only three countries in the world. Poliovirus type 2 has been globally eradicated and the last detection of poliovirus type... (Review)
Review
Polio cases due to wild virus are reported by only three countries in the world. Poliovirus type 2 has been globally eradicated and the last detection of poliovirus type 3 dates to November 2012. Poliovirus type 1 remains the only circulating wild strain; between January and September 2016 it caused 26 cases (nine in Afghanistan, 14 in Pakistan, three in Nigeria). The use of oral polio vaccine (OPV) has been the key to success in the eradication effort. However, paradoxically, moving towards global polio eradication, the burden caused by vaccine-derived polioviruses (VDPVs) becomes increasingly important. In this paper circulation of both wild virus and VDPVs is reviewed and implications for the polio eradication endgame are discussed. Between April and May 2016 OPV2 cessation has been implemented globally, in a coordinated switch from trivalent OPV to bivalent OPV. In order to decrease the risk for cVDPV2 re-emergence inactivated polio vaccine (IPV) has been introduced in the routine vaccine schedule of all countries. The likelihood of re-emergence of cVDPVs should markedly decrease with time after OPV cessation, but silent circulation of polioviruses cannot be ruled out even a long time after cessation. For this reason, immunity levels against polioviruses should be kept as high as possible in the population by the use of IPV, and both clinical and environmental surveillance should be maintained at a high level.
Topics: Afghanistan; Antibodies, Viral; Disease Eradication; Health Policy; Humans; Nigeria; Pakistan; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Inactivated; Poliovirus Vaccine, Oral
PubMed: 27866483
DOI: 10.1017/S0950268816002569 -
The American Journal of Tropical... Dec 2019Poliovirus (PV) environmental surveillance was established in Haiti in three sites each in Port-au-Prince and Gonaïves, where sewage and fecal-influenced environmental... (Comparative Study)
Comparative Study
Poliovirus (PV) environmental surveillance was established in Haiti in three sites each in Port-au-Prince and Gonaïves, where sewage and fecal-influenced environmental open water channel samples were collected monthly from March 2016 to February 2017. The primary objective was to monitor for the emergence of vaccine-derived polioviruses (VDPVs) and the importation and transmission of wild polioviruses (WPVs). A secondary objective was to compare two environmental sample processing methods, the gold standard two-phase separation method and a filter method (bag-mediated filtration system [BMFS]). In addition, non-polio enteroviruses (NPEVs) were characterized by next-generation sequencing using Illumina MiSeq to provide insight on surrogates for PVs. No WPVs or VDPVs were detected at any site with either concentration method. Sabin (vaccine) strain PV type 2 and Sabin strain PV type 1 were found in Port-au-Prince, in March and April samples, respectively. Non-polio enteroviruses were isolated in 75-100% and 0-58% of samples, by either processing method during the reporting period in Port-au-Prince and Gonaïves, respectively. Further analysis of 24 paired Port-au-Prince samples confirmed the detection of a human NPEV and echovirus types E-3, E-6, E-7, E-11, E-19, E-20, and E-29. The comparison of the BMFS filtration method to the two-phase separation method found no significant difference in sensitivity between the two methods (mid--value = 0.55). The experience of one calendar year of sampling has informed the appropriateness of the initially chosen sampling sites, importance of an adequate PV surrogate, and robustness of two processing methods.
Topics: Disease Eradication; Environmental Monitoring; Feces; Filtration; Haiti; High-Throughput Nucleotide Sequencing; Humans; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Sewage; Water Microbiology
PubMed: 31701857
DOI: 10.4269/ajtmh.19-0469 -
Nature Communications Oct 2022Enteroviruses are non-enveloped positive-sense RNA viruses that cause diverse diseases in humans. Their rapid multiplication depends on remodeling of cytoplasmic...
Enteroviruses are non-enveloped positive-sense RNA viruses that cause diverse diseases in humans. Their rapid multiplication depends on remodeling of cytoplasmic membranes for viral genome replication. It is unknown how virions assemble around these newly synthesized genomes and how they are then loaded into autophagic membranes for release through secretory autophagy. Here, we use cryo-electron tomography of infected cells to show that poliovirus assembles directly on replication membranes. Pharmacological untethering of capsids from membranes abrogates RNA encapsidation. Our data directly visualize a membrane-bound half-capsid as a prominent virion assembly intermediate. Assembly progression past this intermediate depends on the class III phosphatidylinositol 3-kinase VPS34, a key host-cell autophagy factor. On the other hand, the canonical autophagy initiator ULK1 is shown to restrict virion production since its inhibition leads to increased accumulation of virions in vast intracellular arrays, followed by an increased vesicular release at later time points. Finally, we identify multiple layers of selectivity in virus-induced autophagy, with a strong selection for RNA-loaded virions over empty capsids and the segregation of virions from other types of autophagosome contents. These findings provide an integrated structural framework for multiple stages of the poliovirus life cycle.
Topics: Autophagy; Capsid; Class III Phosphatidylinositol 3-Kinases; Enterovirus Infections; Humans; Poliovirus; RNA; Virion; Virus Assembly
PubMed: 36216808
DOI: 10.1038/s41467-022-33483-7 -
Nature Jul 2023Vaccination with Sabin, a live attenuated oral polio vaccine (OPV), results in robust intestinal and humoral immunity and has been key to controlling poliomyelitis. As...
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 virulence 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.
Topics: Animals; Mice; Disease Models, Animal; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Vaccines, Attenuated; Disease Eradication
PubMed: 37316671
DOI: 10.1038/s41586-023-06212-3 -
Nature Microbiology Sep 2023Timely detection of outbreaks is needed for poliovirus eradication, but gold standard detection in the Democratic Republic of the Congo takes 30 days (median). Direct...
Timely detection of outbreaks is needed for poliovirus eradication, but gold standard detection in the Democratic Republic of the Congo takes 30 days (median). Direct molecular detection and nanopore sequencing (DDNS) of poliovirus in stool samples is a promising fast method. Here we report prospective testing of stool samples from suspected polio cases, and their contacts, in the Democratic Republic of the Congo between 10 August 2021 and 4 February 2022. DDNS detected polioviruses in 62/2,339 (2.7%) of samples, while gold standard combination of cell culture, quantitative PCR and Sanger sequencing detected polioviruses in 51/2,339 (2.2%) of the same samples. DDNS provided case confirmation in 7 days (median) in routine surveillance conditions. DDNS enabled confirmation of three serotype 2 circulating vaccine-derived poliovirus outbreaks 23 days (mean) earlier (range 6-30 days) than the gold standard method. The mean sequence similarity between sequences obtained by the two methods was 99.98%. Our data confirm the feasibility of implementing DDNS in a national poliovirus laboratory.
Topics: Poliovirus; Nanopore Sequencing; Polymerase Chain Reaction; Dansyl Compounds
PubMed: 37591995
DOI: 10.1038/s41564-023-01453-4