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IScience Feb 2024Despite effective vaccines, measles virus (MeV) outbreaks occur sporadically. Therefore, developing anti-MeV agents remains important for suppressing MeV infections. We...
Despite effective vaccines, measles virus (MeV) outbreaks occur sporadically. Therefore, developing anti-MeV agents remains important for suppressing MeV infections. We previously designed peptide-based MeV fusion inhibitors, M1 and M2, that target MeV class I fusion protein (F protein). Here, we developed a novel fusion inhibitor, MEK35, that exerts potent activity against M1/M2-resistant MeV variants. Comparing MEK35 to M1 derivatives revealed that combining disordered and helical elements was essential for overcoming M1/M2 resistance. Moreover, we propose a three-step antiviral process for peptide-based fusion inhibitors: (i) disordered peptides interact with F protein; (ii) the peptides adopt a partial helical conformation and bind to F protein through hydrophobic interactions; and (iii) subsequent interactions involving the disordered region of the peptides afford a peptide-F protein with a high-affinity peptide-F protein interaction. An M1-resistant substitution blocks the second step. These results should aid the development of novel viral fusion inhibitors targeting class I F protein.
PubMed: 38333694
DOI: 10.1016/j.isci.2024.108961 -
Nature Communications Feb 2024Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of...
Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.
Topics: Animals; Female; Ferrets; Influenza A Virus, H1N1 Subtype; Measles; Measles virus; Distemper Virus, Canine; Antiviral Agents
PubMed: 38331906
DOI: 10.1038/s41467-024-45418-5 -
Journal of Virology Mar 2024Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the...
Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient's brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV . We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease.
Topics: Child, Preschool; Humans; Adenosine Monophosphate; Alanine; Autopsy; Brain; Disease Progression; Fatal Outcome; Genome, Viral; High-Throughput Nucleotide Sequencing; Measles; Measles virus; Mutant Proteins; Quality of Life; RNA, Viral; Subacute Sclerosing Panencephalitis; Viral Proteins
PubMed: 38329336
DOI: 10.1128/jvi.01874-23 -
Vaccine Mar 2024Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research...
Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates.
Topics: Humans; Advisory Committees; World Health Organization; Vaccines; Vaccination; Immunization; Measles
PubMed: 38326131
DOI: 10.1016/j.vaccine.2024.02.014 -
Journal of Biotechnology Mar 2024Measuring infectious titer is the most time-consuming method during the production and process development of live viruses. Conventionally, it is done by measuring the...
Measuring infectious titer is the most time-consuming method during the production and process development of live viruses. Conventionally, it is done by measuring the tissue culture infectious dose (TCID50) or plaque forming units (pfu) in cell-based assays. Such assays require a time span of more than a week to the readout and significantly slow down process development. In this study, we utilized the pro-inflammatory cytokine response of a Vero production cell line to a recombinant measles vaccine virus (MVV) as model system for rapidly determining infectious virus titer within several hours after infection instead of one week. Cytokines are immunostimulatory proteins contributing to the first line of defence against virus infection. The probed cytokines in this study were MCP-1 and RANTES, which are secreted in a virus dose as well as time dependent manner and correlate to TCID50 over a concentration range of several logarithmic levels with R = 0.86 and R = 0.83, respectively. Furthermore, the pro-inflammatory cytokine response of the cells was specific for infectious virus particles and not evoked with filtered virus seed. We also discovered that individual cytokine candidates may be more suitable for off- or at-line analysis, depending on the secretion profile as well as their sensitivity towards changing process conditions. Furthermore, the method can be applied to follow a purification procedure and is therefore suited for process development and control.
Topics: Cytokines; Viral Load; Immunologic Factors; Biological Assay; Biological Transport
PubMed: 38325657
DOI: 10.1016/j.jbiotec.2024.01.016 -
Euro Surveillance : Bulletin Europeen... Feb 2024Real-time PCR is one of the most widely used techniques to diagnose measles cases. Here we report measles virus variants with three genetic mutations in the reverse...
Real-time PCR is one of the most widely used techniques to diagnose measles cases. Here we report measles virus variants with three genetic mutations in the reverse primer annealing site of a widely used PCR. The mutations result in a slight loss of the PCR sensitivity. Variants bearing the three mutations presently circulate in different countries since at least the end of 2021. Our findings highlight the usefulness of molecular surveillance in monitoring if oligonucleotides in diagnostic tests remain adequate.
Topics: Humans; Switzerland; Pathology, Molecular; RNA, Viral; Measles; Measles virus; Mutation; Sensitivity and Specificity; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 38304951
DOI: 10.2807/1560-7917.ES.2024.29.5.2400034 -
Medical Science Monitor : International... Feb 2024In December 2023, the US Centers for Disease Control and Prevention (CDC) published the updated 2024 Advisory Committee on Immunization Practices (ACIP) Adult...
Editorial: Global Health Concerns as Vaccine-Preventable Infections Including SARS-CoV-2 (JN.1), Influenza, Respiratory Syncytial Virus (RSV), and Measles Continue to Rise.
In December 2023, the US Centers for Disease Control and Prevention (CDC) published the updated 2024 Advisory Committee on Immunization Practices (ACIP) Adult Immunization Schedule, which is available online for access by the public and healthcare professionals. These new guidelines come at a time when the incidence of vaccine-preventable viral infections from SARS-CoV-2 (JN.1), respiratory syncytial virus (RSV), influenza, and measles are increasing in adults and children due to vaccine hesitancy, or non-compliance. This editorial aims to highlight the ongoing global health concerns for the consequences of increasing reports of vaccine-preventable infections, including SARS-CoV-2 (JN.1), influenza, RSV, and measles, to understand the causes of vaccine hesitancy, and introduce some public health measures that could improve vaccine uptake.
Topics: Child; Adult; Humans; Influenza, Human; SARS-CoV-2; Respiratory Syncytial Viruses; Global Health; COVID-19; Influenza Vaccines; Measles; Communicable Diseases
PubMed: 38298093
DOI: 10.12659/MSM.943911 -
Journal of Clinical Microbiology Feb 2024Measles and rubella serological diagnoses are done by IgM detection. The World Health Organization Global Measles and Rubella Laboratory Network previously endorsed... (Meta-Analysis)
Meta-Analysis
Measles and rubella serological diagnoses are done by IgM detection. The World Health Organization Global Measles and Rubella Laboratory Network previously endorsed Siemens Enzygnost enzyme-linked immunosorbant assay kits, which have been discontinued. A recommended replacement has not been determined. We aimed to search for suitable replacements by conducting a systematic review and meta-analysis of IgM detection methods that are currently available for measles and rubella. A systematic literature search was performed in Medline, Embase, Global Health, Cochrane Central, and Scopus on March 22 and on 27 September 2023. Studies reporting measles and/or rubella IgM detection with terms around diagnostic accuracy were included. Risk of bias was assessed using QUADAS tools. Meta-DiSc and R were used for statistical analysis. Clinical samples totalling 5,579 from 28 index tests were included in the measles meta-analysis. Sensitivity and specificity of the individual measles studies ranged from 0.50 to 1.00 and 0.53 to 1.00, respectively. Pooled sensitivity and specificity of all measles IgM detection methods were 0.94 (CI: 0.90-0.97) and 0.94 (CI: 0.91-0.97), respectively. Clinical samples totalling 4,983 from 15 index tests were included in the rubella meta-analysis. Sensitivity and specificity of the individual rubella studies ranged from 0.78 to 1.00 and 0.52 to 1.00, respectively. Pooled sensitivity and specificity of all rubella IgM detection methods were 0.97 (CI: 0.93-0.98) and 0.96 (CI: 0.93-0.98), respectively. Although more studies would be ideal, our results may provide valuable information when selecting IgM detection methods for measles and/or rubella.
Topics: Humans; Rubella virus; Antibodies, Viral; Immunoglobulin M; Measles; Rubella; Serologic Tests
PubMed: 38275299
DOI: 10.1128/jcm.01339-23 -
Medicina 2024Adult smokers, those with comorbidities, and the elderly, are at greater risk of contracting infections and their complications. Community acquired respiratory... (Review)
Review
Adult smokers, those with comorbidities, and the elderly, are at greater risk of contracting infections and their complications. Community acquired respiratory infections due to viruses, pneumococcus and other bacteria, affect both healthy and sick adults. There are vaccines that the pulmonologist must know and prescribe. The target strains of the influenza vaccine are defined by the WHO for the Southern hemisphere considering those involved in the previous influenza season in the Northern hemisphere. Its effectiveness depends on virulence, concordance between circulating and vaccine strains, and population coverage. The anti-pneumococcal polysaccharide vaccine available since 1983 is being replaced by more effective conjugate vaccines to prevent infections related to serotypes present in them. Immunization against SARS-CoV-2 reduced the contagion, severity, and lethality of COVID-19. The acellular vaccine against Bordetella pertussis for adults is present for specific situations in the adult calendar; vaccinating them strengthens the control of childhood contagion. The double (diphtheria + tetanus), and triple (double + pertussis) bacterial vaccines, and the vaccines against measles, chickenpox, rubella, human papillomavirus, Haemophilus influenzae, meningococcus, herpes zoster, Argentine hemorrhagic fever and yellow fever, are of a more limited use. Soon we will have new vaccines such as the one recently approved by the FDA against respiratory syncytial virus. Through a consensus of experts in respiratory infections, we review the new evidence regarding the immunization of adults who consult a pulmonologist, and thus update the recommendations on vaccination made eight years ago.
Topics: Adult; Humans; Infant; Aged; Pulmonary Medicine; Vaccination; Pneumococcal Vaccines; Influenza Vaccines; COVID-19
PubMed: 38271938
DOI: No ID Found -
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