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Proceedings of the National Academy of... Aug 2023RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions...
RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions (indels) in viral genomes are major contributors to both deleterious mutational load and evolutionary novelty, but remain understudied. To characterize the mechanistic details of their formation and evolutionary dynamics during infection, we developed a hybrid experimental-bioinformatic approach. This approach, called MultiMatch, extracts insertions and deletions from ultradeep sequencing experiments, including those occurring at extremely low frequencies, allowing us to map their genomic distribution and quantify the rates at which they occur. Mapping indel mutations in adapting poliovirus and dengue virus populations, we determine the rates of indel generation and identify mechanistic and functional constraints shaping indel diversity. Using poliovirus RdRp variants of distinct fidelity and genome recombination rates, we demonstrate tradeoffs between fidelity and Indel generation. Additionally, we show that maintaining translation frame and viral RNA structures constrain the Indel landscape and that, due to these significant fitness effects, Indels exert a significant deleterious load on adapting viral populations. Conversely, we uncover positively selected Indels that modulate RNA structure, generate protein variants, and produce defective interfering genomes in viral populations. Together, our analyses establish the kinetic and mechanistic tradeoffs between misincorporation, recombination, and Indel rates and reveal functional principles defining the central role of Indels in virus evolution, emergence, and the regulation of viral infection.
Topics: Evolution, Molecular; Genome; Mutation Rate; INDEL Mutation; RNA, Viral; RNA Viruses
PubMed: 37487061
DOI: 10.1073/pnas.2304667120 -
MBio Nov 2023Enterovirus D68 (EV-D68) contributes significantly to pathogen-induced respiratory illnesses and severe neurological disorders like acute flaccid myelitis. We lack...
Enterovirus D68 (EV-D68) contributes significantly to pathogen-induced respiratory illnesses and severe neurological disorders like acute flaccid myelitis. We lack EV-D68 preventive measures, and knowledge of its molecular and cellular biology is incomplete. Multiple studies have highlighted the role of membrane compartments and autophagy during picornavirus multiplication. Galitska et al. found that EV-D68 also exploits cellular autophagic compartments and relies on autophagic machinery as pro-viral factors (G. Galitska, A. Jassey, M. A. Wagner, N. Pollack, et al., mBio e02141-23, 2023, https://doi.org/10.1128/mbio.02141-23). Surprisingly, failure of the autophagic compartment to acidify early during EV-D68 infection causes a delay in RNA synthesis that has not been reported for other enteroviruses. This delay appears to reflect the inability of viral proteins 2B and 3A to engage membranes stably, leading to their degradation in the cytoplasm. Observations like this underscore the importance of studying individual members of the virus genus. It will be interesting to understand how this phenomenon connects to EV-D68 pathogenesis, if at all.
PubMed: 37909766
DOI: 10.1128/mbio.02281-23 -
Medical Decision Making : An... 2023Polio antiviral drugs (PAVDs) may provide a critical tool in the eradication endgame by stopping poliovirus infections in immunodeficient individuals who may not clear...
BACKGROUND
Polio antiviral drugs (PAVDs) may provide a critical tool in the eradication endgame by stopping poliovirus infections in immunodeficient individuals who may not clear the virus without therapeutic intervention. Although prolonged/chronic poliovirus excreters are rare, they represent a source of poliovirus reintroduction into the general population. Prior studies that assumed the successful cessation of all oral poliovirus vaccine (OPV) use estimated the potential upper bound of the incremental net benefits (INBs) of resource investments in research and development of PAVDs. However, delays in polio eradication, OPV cessation, and the development of PAVDs necessitate an updated economic analysis to reevaluate the costs and benefits of further investments in PAVDs.
METHODS
Using a global integrated model of polio transmission, immunity, vaccine dynamics, risks, and economics, we explore the risks of reintroduction of polio transmission due to immunodeficiency-related vaccine-derived poliovirus (iVDPV) excreters and reevaluate the upper bound of the INBs of PAVDs.
RESULTS
Under the current conditions, for which the use of OPV will likely continue for the foreseeable future, even with successful eradication of type 1 wild poliovirus by the end of 2023 and continued use of Sabin OPV for outbreak response, we estimate an upper bound INB of 60 million US$2019. With >100 million US$2019 already invested in PAVD development and with the introduction of novel OPVs that are less likely to revert to neurovirulence, our analysis suggests the expected INBs of PAVDs would not offset their costs.
CONCLUSIONS
While PAVDs could play an important role in the polio endgame, their expected economic benefits drop with ongoing OPV use and poliovirus transmissions. However, stakeholders may pursue the development of PAVDs as a desired product regardless of their economic benefits.HighlightsWhile polio antiviral drugs could play an important role in the polio endgame, their expected economic benefits continue to drop with delays in polio eradication and the continued use of oral poliovirus vaccines.The incremental net benefits of investments in polio antiviral drug development and screening for immunodeficiency-related circulating polioviruses are small.Limited global resources are better spent on increasing global population immunity to polioviruses to stop and prevent poliovirus transmission.
Topics: Humans; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Disease Outbreaks; Antiviral Agents
PubMed: 37577803
DOI: 10.1177/0272989X231191127 -
Frontiers in Public Health 2023Over the past two centuries, vaccines have been critical for the prevention of infectious diseases and are considered milestones in the medical and public health... (Review)
Review
Over the past two centuries, vaccines have been critical for the prevention of infectious diseases and are considered milestones in the medical and public health history. The World Health Organization estimates that vaccination currently prevents approximately 3.5-5 million deaths annually, attributed to diseases such as diphtheria, tetanus, pertussis, influenza, and measles. Vaccination has been instrumental in eradicating important pathogens, including the smallpox virus and wild poliovirus types 2 and 3. This narrative review offers a detailed journey through the history and advancements in vaccinology, tailored for healthcare workers. It traces pivotal milestones, beginning with the variolation practices in the early 17th century, the development of the first smallpox vaccine, and the continuous evolution and innovation in vaccine development up to the present day. We also briefly review immunological principles underlying vaccination, as well as the main vaccine types, with a special mention of the recently introduced mRNA vaccine technology. Additionally, we discuss the broad benefits of vaccines, including their role in reducing morbidity and mortality, and in fostering socioeconomic development in communities. Finally, we address the issue of vaccine hesitancy and discuss effective strategies to promote vaccine acceptance. Research, collaboration, and the widespread acceptance and use of vaccines are imperative for the continued success of vaccination programs in controlling and ultimately eradicating infectious diseases.
Topics: Humans; Vaccination; Immunization; Antigens, Viral; Influenza Vaccines; Communicable Diseases
PubMed: 38264254
DOI: 10.3389/fpubh.2023.1326154 -
Journal of Virology Aug 2023Viruses have evolved diverse strategies to evade the host innate immune response and promote infection. The retinoic acid-inducible gene I (RIG-I)-like receptors RIG-I...
Viruses have evolved diverse strategies to evade the host innate immune response and promote infection. The retinoic acid-inducible gene I (RIG-I)-like receptors RIG-I and MDA5 are antiviral factors that sense viral RNA and trigger downstream signal via mitochondrial antiviral-signaling protein (MAVS) to activate type I interferon expression. 14-3-3ε is a key component of the RIG-I translocon complex that interacts with MAVS at the mitochondrial membrane; however, the exact role of 14-3-3ε in this pathway is not well understood. In this study, we demonstrate that 14-3-3ε is a direct substrate of both the poliovirus and coxsackievirus B3 (CVB3) 3C proteases (3C) and that it is cleaved at Q236↓G237, resulting in the generation of N- and C-terminal fragments of 27.0 and 2.1 kDa, respectively. While the exogenous expression of wild-type 14-3-3ε enhances mRNA production during poly(I:C) stimulation, expression of the truncated N-terminal fragment does not. The N-terminal 14-3-3ε fragment does not interact with RIG-I in co-immunoprecipitation assays, nor can it facilitate RIG-I translocation to the mitochondria. Probing the intrinsically disordered C-terminal region identifies key residues responsible for the interaction between 14-3-3ε and RIG-I. Finally, overexpression of the N-terminal fragment promotes CVB3 infection in mammalian cells. The strategic enterovirus 3C-mediated cleavage of 14-3-3ε antagonizes RIG-I signaling by disrupting critical interactions within the RIG-I translocon complex, thus contributing to evasion of the host antiviral response. IMPORTANCE Host antiviral factors work to sense virus infection through various mechanisms, including a complex signaling pathway known as the retinoic acid-inducible gene I (RIG-I)-like receptor pathway. This pathway drives the production of antiviral molecules known as interferons, which are necessary to establish an antiviral state in the cellular environment. Key to this antiviral signaling pathway is the small chaperone protein 14-3-3ε, which facilitates the delivery of a viral sensor protein, RIG-I, to the mitochondria. In this study, we show that the enteroviral 3C protease cleaves 14-3-3ε during infection, rendering it incapable of facilitating this antiviral response. We also find that the resulting N-terminal cleavage fragment dampens RIG-I signaling and promotes virus infection. Our findings reveal a novel viral strategy that restricts the antiviral host response and provides insights into the mechanisms underlying 14-3-3ε function in RIG-I antiviral signaling.
Topics: Animals; Cysteine Endopeptidases; DEAD Box Protein 58; Immunity, Innate; Mammals; Peptide Hydrolases; Picornaviridae; Signal Transduction; Tretinoin; Viral Proteins; Picornaviridae Infections; 3C Viral Proteases
PubMed: 37555661
DOI: 10.1128/jvi.00604-23 -
International Journal of Infectious... Dec 2023During the COVID-19 pandemic, there was a decline in vaccine coverage, and the implementation of combined vaccines and co-administration strategies emerged as potential... (Randomized Controlled Trial)
Randomized Controlled Trial
Immunogenicity and safety of concomitant administration of the sabin-strain-based inactivated poliovirus vaccine, the diphtheria-tetanus-acellular pertussis vaccine, and measles-mumps-rubella vaccine to healthy infants aged 18 months in China.
OBJECTIVES
During the COVID-19 pandemic, there was a decline in vaccine coverage, and the implementation of combined vaccines and co-administration strategies emerged as potential solutions to alleviate this predicament. Our objective is to delve into the concurrent administration of the sabin-strain-based inactivated poliovirus vaccine (sIPV), the diphtheria-tetanus-acellular pertussis vaccine (DTaP), and measles-mumps-rubella vaccine (MMR), with the intention of bridging the evidentiary gap pertaining to vaccine co-administration in Chinese infants, and to ensure a safe and effective vaccination strategy, ultimately leading to an augmentation in immunization coverage.
METHODS
This study was a follow-up trial of the "Immunogenicity and safety of concomitant administration of the sIPV with the DTaP vaccine in children: a multicenter, randomized, non-inferiority, controlled trial." Blood samples were collected on day 0 and day 30, and serum antibody levels were detected to measure antibody responses to each of the antigens. Local and systemic adverse events were monitored and compared among groups. This study is the first to fill the knowledge gap in China regarding the safe and effective combined vaccination of sIPV, DTaP, and MMR vaccines.
RESULTS
The geometric mean titer of the poliovirus types I, II, and III neutralizing antibodies were 1060.22 (95% CI: 865.73-1298.39), 1537.06 (95% CI: 1324.27-1784.05), and 1539.10 (95% CI: 1296.37-1827.29) in group I on day 30; geometric mean titer of antibodies against DTaP and MMR in the simultaneous vaccination group was non-inferior to those in the DTaP alone and MMR alone group. Reporting rates of local and systemic adverse reactions were similar between groups and no serious adverse events were reported throughout the clinical study period.
CONCLUSION
Co-administration of the sIPV, DTaP, and MMR was safe and did not impact immunogenicity, which would help to mitigate administrative costs and enhance vaccine coverage rates.
Topics: Child; Humans; Infant; Diphtheria-Tetanus-acellular Pertussis Vaccines; Measles-Mumps-Rubella Vaccine; Poliovirus Vaccine, Inactivated; Pandemics; Vaccines, Combined; Poliovirus; Diphtheria-Tetanus-Pertussis Vaccine; Haemophilus Vaccines; Antibodies, Bacterial; Immunization Schedule
PubMed: 37832931
DOI: 10.1016/j.ijid.2023.10.006 -
Expert Review of Vaccines 2024Despite multiple revisions of targets and timelines in polio eradication plans since 1988, including changes in supplemental immunization activities (SIAs) that increase... (Review)
Review
BACKGROUND
Despite multiple revisions of targets and timelines in polio eradication plans since 1988, including changes in supplemental immunization activities (SIAs) that increase immunity above routine immunization (RI) coverage, poliovirus transmission continues as of 2024.
METHODS
We reviewed polio eradication plans and Global Polio Eradication Initiative (GPEI) annual reports and budgets to characterize key phases of polio eradication, the evolution of poliovirus vaccines, and the role of SIAs. We used polio epidemiology to provide context for successes and failures and updated prior modeling to show the contribution of SIAs in achieving and maintaining low polio incidence compared to expected incidence for the counterfactual of RI only.
RESULTS
We identified multiple phases of polio eradication that included shifts in targets and timelines and the introduction of different poliovirus vaccines, which influenced polio epidemiology. Notable shifts occurred in GPEI investments in SIAs since 2001, particularly since 2016. Modeling results suggest that SIAs play(ed) a key role in increasing (and maintaining) high population immunity to levels required to eradicate poliovirus transmission globally.
CONCLUSIONS
Shifts in polio eradication strategy and poliovirus vaccine usage in SIAs provide important context for understanding polio epidemiology, delayed achievement of polio eradication milestones, and complexity of the polio endgame.
Topics: Poliomyelitis; Humans; Disease Eradication; Global Health; Poliovirus Vaccines; Immunization Programs; Incidence; Poliovirus
PubMed: 38813792
DOI: 10.1080/14760584.2024.2361060 -
The Lancet. Microbe Feb 2024Laboratory-acquired infections (LAIs) and accidental pathogen escape from laboratory settings (APELS) are major concerns for the community. A risk-based approach for... (Review)
Review
Laboratory-acquired infections (LAIs) and accidental pathogen escape from laboratory settings (APELS) are major concerns for the community. A risk-based approach for pathogen research management within a standard biosafety management framework is recommended but is challenging due to reasons such as inconsistency in risk tolerance and perception. Here, we performed a scoping review using publicly available, peer-reviewed journal and media reports of LAIs and instances of APELS between 2000 and 2021. We identified LAIs in 309 individuals in 94 reports for 51 pathogens. Eight fatalities (2·6% of all LAIs) were caused by infection with Neisseria meningitidis (n=3, 37·5%), Yersinia pestis (n=2, 25%), Salmonella enterica serotype Typhimurium (S Typhimurium; n=1, 12·5%), or Ebola virus (n=1, 12·5%) or were due to bovine spongiform encephalopathy (n=1, 12·5%). The top five LAI pathogens were S Typhimurium (n=154, 49·8%), Salmonella enteritidis (n=21, 6·8%), vaccinia virus (n=13, 4·2%), Brucella spp (n=12, 3·9%), and Brucella melitensis (n=11, 3·6%). 16 APELS were reported, including those for Bacillus anthracis, SARS-CoV, and poliovirus (n=3 each, 18·8%); Brucella spp and foot and mouth disease virus (n=2 each, 12·5%); and variola virus, Burkholderia pseudomallei, and influenza virus H5N1 (n=1 each, 6·3%). Continual improvement in LAI and APELS management via their root cause analysis and thorough investigation of such incidents is essential to prevent future occurrences. The results are biased due to the reliance on publicly available information, which emphasises the need for formalised global LAIs and APELS reporting to better understand the frequency of and circumstances surrounding these incidents.
Topics: Animals; Cattle; Humans; Influenza A Virus, H5N1 Subtype; Laboratory Infection; Yersinia pestis; Salmonella enteritidis; Salmonella typhimurium
PubMed: 38101440
DOI: 10.1016/S2666-5247(23)00319-1 -
The Pan African Medical Journal 2023Nigeria made a coordinated effort to be certified by the World Health Organization's African Region for interrupting endemic transmission of wild poliovirus type-1... (Review)
Review
Nigeria made a coordinated effort to be certified by the World Health Organization's African Region for interrupting endemic transmission of wild poliovirus type-1 (WPV1) in August 2020 as a response to the resurgence of WPV1 cases in August 2016 after going two years without a case. The NEOC Data Working Group (DWG) was instrumental in providing quality and timely surveillance and campaign information for decision-making in order to interrupt WPV1 transmission and provide data toward documentation of its elimination for regional certification. The polio pre-campaign dashboard was used to assess the level of preparedness for Oral Poliovirus Vaccine (OPV) polio supplementary immunization activities (SIA) at three weeks, two weeks, one week, and three days to the start of each campaign implemented during 2016-2020. The administrative tally sheet, independent monitoring survey, and Lot Quality Assurance Sampling (LQAS) survey data collected and shared from the implementation level were analyzed by the EOC DWG to provide information by person, place, and time. Using a 90% threshold in LQAS surveys defining quality SIAs, the proportion of Local Government Areas (LGAs) in Nigeria's states in which post-SIA LQAS surveys were conducted that met this threshold were assessed over time. The highest level of preparedness attained by 3 days to a polio campaign during August 2016-February 2020 was 95% and the lowest attained was 77%. The admin, independent monitoring, and LQAS data analysis results were given to EOC working groups for assessing the performance and quality of each campaign. Twenty-twenty five percent of LGAs that failed LQAS were identified for repeat vaccination. Further, acute flaccid paralysis and environmental surveillance data and laboratory results were analyzed and shared with NEOC and partners. The government and partners used the information generated by the Data Working Group to take evidence-based action including determining the scope of the polio campaign, intensification of surveillance and routine immunization activities, and special intervention activities. On average, 12% of the 774 LGAs were identified as polio high risk LGAs for intervention using selected surveillance, routine immunization (RI), SIAs, and other relevant data sets. National Emergency Operation Centre Data Working Group provided quality and timely information that supported decision-making processes for the polio program in Nigeria. The quality and timely information enabled the NEOC to make evidence-based and timely decisions that contributed to gap identification and decision-making.
Topics: Humans; Lot Quality Assurance Sampling; Disease Eradication; Poliomyelitis; Poliovirus; Poliovirus Vaccine, Oral; Nigeria; Immunization Programs
PubMed: 38370106
DOI: 10.11604/pamj.supp.2023.45.2.39489