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Journal of Virology May 2024In the early COVID-19 pandemic with urgent need for countermeasures, we aimed at developing a replicating viral vaccine using the highly efficacious measles vaccine as...
A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: candidate selection in a preclinical murine model.
In the early COVID-19 pandemic with urgent need for countermeasures, we aimed at developing a replicating viral vaccine using the highly efficacious measles vaccine as vector, a promising technology with prior clinical proof of concept. Building on our successful pre-clinical development of a measles virus (MV)-based vaccine candidate against the related SARS-CoV, we evaluated several recombinant MV expressing codon-optimized SARS-CoV-2 spike glycoprotein. Candidate V591 expressing a prefusion-stabilized spike through introduction of two proline residues in HR1 hinge loop, together with deleted S1/S2 furin cleavage site and additional inactivation of the endoplasmic reticulum retrieval signal, was the most potent in eliciting neutralizing antibodies in mice. After single immunization, V591 induced similar neutralization titers as observed in sera of convalescent patients. The cellular immune response was confirmed to be Th1 skewed. V591 conferred long-lasting protection against SARS-CoV-2 challenge in a murine model with marked decrease in viral RNA load, absence of detectable infectious virus loads, and reduced lesions in the lungs. V591 was furthermore efficacious in an established non-human primate model of disease (see companion article [S. Nambulli, N. Escriou, L. J. Rennick, M. J. Demers, N. L. Tilston-Lunel et al., J Virol 98:e01762-23, 2024, https://doi.org/10.1128/jvi.01762-23]). Thus, V591 was taken forward into phase I/II clinical trials in August 2020. Unexpected low immunogenicity in humans (O. Launay, C. Artaud, M. Lachâtre, M. Ait-Ahmed, J. Klein et al., eBioMedicine 75:103810, 2022, https://doi.org/10.1016/j.ebiom.2021.103810) revealed that the underlying mechanisms for resistance or sensitivity to pre-existing anti-measles immunity are not yet understood. Different hypotheses are discussed here, which will be important to investigate for further development of the measles-vectored vaccine platform.IMPORTANCESARS-CoV-2 emerged at the end of 2019 and rapidly spread worldwide causing the COVID-19 pandemic that urgently called for vaccines. We developed a vaccine candidate using the highly efficacious measles vaccine as vector, a technology which has proved highly promising in clinical trials for other pathogens. We report here and in the companion article by Nambulli et al. (J Virol 98:e01762-23, 2024, https://doi.org/10.1128/jvi.01762-23) the design, selection, and preclinical efficacy of the V591 vaccine candidate that was moved into clinical development in August 2020, 7 months after the identification of SARS-CoV-2 in Wuhan. These unique in-human trials of a measles vector-based COVID-19 vaccine revealed insufficient immunogenicity, which may be the consequence of previous exposure to the pediatric measles vaccine. The three studies together in mice, primates, and humans provide a unique insight into the measles-vectored vaccine platform, raising potential limitations of surrogate preclinical models and calling for further refinement of the platform.
Topics: Animals; Female; Humans; Mice; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Disease Models, Animal; Genetic Vectors; Measles Vaccine; Measles virus; Mice, Inbred BALB C; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 38563763
DOI: 10.1128/jvi.01693-23 -
Journal of Virology May 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four...
A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: protection of African green monkeys from COVID-19 disease.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four vaccines are currently approved for use worldwide, and approximately 67% of the world population has received a complete primary series of one, yet countries are dealing with new waves of infections, variant viruses continue to emerge, and breakthrough infections are frequent secondary to waning immunity. Here, we evaluate a measles virus (MV)-vectored vaccine expressing a stabilized prefusion SARS-CoV-2 spike (S) protein (MV-ATU3-S2PΔF2A; V591) with demonstrated immunogenicity in mouse models (see companion article [J. Brunet, Z. Choucha, M. Gransagne, H. Tabbal, M.-W. Ku et al., J Virol 98:e01693-23, 2024, https://doi.org/10.1128/jvi.01693-23]) in an established African green monkey model of disease. Animals were vaccinated with V591 or the control vaccine (an equivalent MV-vectored vaccine with an irrelevant antigen) intramuscularly using a prime/boost schedule, followed by challenge with an early pandemic isolate of SARS-CoV-2 at 56 days post-vaccination. Pre-challenge, only V591-vaccinated animals developed S-specific antibodies that had virus-neutralizing activity as well as S-specific T cells. Following the challenge, V591-vaccinated animals had lower infectious virus and viral (v) RNA loads in mucosal secretions and stopped shedding virus in these secretions earlier. vRNA loads were lower in these animals in respiratory and gastrointestinal tract tissues at necropsy. This correlated with a lower disease burden in the lungs as quantified by PET/CT at early and late time points post-challenge and by pathological analysis at necropsy.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the largest human pandemic in 100 years. Even though vaccines are currently available, countries are dealing with new waves of infections, variant viruses continue to emerge, breakthrough infections are frequent, and vaccine hesitancy persists. This study uses a safe and effective measles vaccine as a platform for vaccination against SARS-CoV-2. The candidate vaccine was used to vaccinate African green monkeys (AGMs). All vaccinated AGMs developed robust antigen-specific immune responses. After challenge, these AGMs produced less virus in mucosal secretions, for a shorter period, and had a reduced disease burden in the lungs compared to control animals. At necropsy, lower levels of viral RNA were detected in tissue samples from vaccinated animals, and the lungs of these animals lacked the histologic hallmarks of SARS-CoV-2 disease observed exclusively in the control AGMs.
Topics: Animals; Spike Glycoprotein, Coronavirus; Chlorocebus aethiops; SARS-CoV-2; COVID-19; Measles virus; COVID-19 Vaccines; Humans; Antibodies, Viral; Antibodies, Neutralizing; Genetic Vectors; Vero Cells; Pandemics; Female; Betacoronavirus; Pneumonia, Viral; Coronavirus Infections; Viral Vaccines; Disease Models, Animal
PubMed: 38563762
DOI: 10.1128/jvi.01762-23 -
Virology Jul 2024The Peste des petits ruminant virus (PPRV) is a member of the Paramyxoviridae family and is classified into the genus Measles virus. PPRV predominantly infects small...
The Peste des petits ruminant virus (PPRV) is a member of the Paramyxoviridae family and is classified into the genus Measles virus. PPRV predominantly infects small ruminants, leading to mortality rates of nearly 100%, which have caused significant economic losses in developing countries. Host proteins are important in virus replication, but the PPRV nucleocapsid (N) protein-host interacting partners for regulating PPRV replication remain unclear. The present study confirmed the interaction between PPRV-N and the host protein vimentin by co-immunoprecipitation and co-localization experiments. Overexpression of vimentin suppressed PPRV replication, whereas vimentin knockdown had the opposite effect. Mechanistically, N was subjected to degradation via the ubiquitin/proteasome pathway, where vimentin recruits the E3 ubiquitin ligase NEDD4L to fulfill N-ubiquitination, resulting in the degradation of the N protein. These findings suggest that the host protein vimentin and E3 ubiquitin ligase NEDD4L have an anti-PPRV effect.
Topics: Nucleocapsid Proteins; Vimentin; Virus Replication; Animals; Peste-des-petits-ruminants virus; Humans; Ubiquitination; Host-Pathogen Interactions; HEK293 Cells; Nedd4 Ubiquitin Protein Ligases; Cell Line; Peste-des-Petits-Ruminants; Protein Binding
PubMed: 38552409
DOI: 10.1016/j.virol.2024.110056 -
Annals of Neurology Jun 2024Specific human leucocyte antigen (HLA) alleles are not only associated with higher risk to develop multiple sclerosis (MS) and other autoimmune diseases, but also with...
OBJECTIVE
Specific human leucocyte antigen (HLA) alleles are not only associated with higher risk to develop multiple sclerosis (MS) and other autoimmune diseases, but also with the severity of various viral and bacterial infections. Here, we analyzed the most specific biomarker for MS, that is, the polyspecific intrathecal IgG antibody production against measles, rubella, and varicella zoster virus (MRZ reaction), for possible HLA associations in MS.
METHODS
We assessed MRZ reaction from 184 Swiss patients with MS and clinically isolated syndrome (CIS) and 89 Swiss non-MS/non-CIS control patients, and performed HLA sequence-based typing, to check for associations of positive MRZ reaction with the most prevalent HLA alleles. We used a cohort of 176 Swedish MS/CIS patients to replicate significant findings.
RESULTS
Whereas positive MRZ reaction showed a prevalence of 38.0% in MS/CIS patients, it was highly specific (97.7%) for MS/CIS. We identified HLA-DRB1*15:01 and other tightly linked alleles of the HLA-DR15 haplotype as the strongest HLA-encoded risk factors for a positive MRZ reaction in Swiss MS/CIS (odds ratio [OR], 3.90, 95% confidence interval [CI] 2.05-7.46, p = 0.0004) and replicated these findings in Swedish MS/CIS patients (OR 2.18, 95%-CI 1.16-4.02, p = 0.028). In addition, female MS/CIS patients had a significantly higher probability for a positive MRZ reaction than male patients in both cohorts combined (p <0.005).
INTERPRETATION
HLA-DRB1*15:01, the strongest genetic risk factor for MS, and female sex, 1 of the most prominent demographic risk factors for developing MS, predispose in MS/CIS patients for a positive MRZ reaction, the most specific CSF biomarker for MS. ANN NEUROL 2024;95:1112-1126.
Topics: Humans; Female; Male; Multiple Sclerosis; Immunoglobulin G; Adult; Middle Aged; Herpesvirus 3, Human; HLA-DRB1 Chains; Sweden; Cohort Studies; Young Adult; Rubella virus; HLA Antigens; Antibodies, Viral; Alleles; Switzerland
PubMed: 38551149
DOI: 10.1002/ana.26921 -
MMWR. Morbidity and Mortality Weekly... Mar 2024Syndromic polymerase chain reaction (PCR) panels are used to test for pathogens that can cause rash illnesses, including measles. Rash illnesses have infectious and...
Syndromic polymerase chain reaction (PCR) panels are used to test for pathogens that can cause rash illnesses, including measles. Rash illnesses have infectious and noninfectious causes, and approximately 5% of persons experience a rash 7-10 days after receipt of a measles, mumps, and rubella (MMR) vaccine. MMR vaccine includes live attenuated measles virus, which is detectable by PCR tests. No evidence exists of person-to-person transmission of measles vaccine virus, and illness does not typically result among immunocompetent persons. During September 2022-January 2023, the Tennessee Department of Health received two reports of measles detected by syndromic PCR panels. Both reports involved children (aged 1 and 6 years) without known risk factors for measles, who were evaluated for rash that occurred 11-13 days after routine MMR vaccination. After public health responses in Tennessee determined that both PCR panels had detected measles vaccine virus, six state health departments collaborated to assess the frequency and characteristics of persons receiving a positive measles PCR panel test result in the United States. Information was retrospectively collected from a commercial laboratory testing for measles in syndromic multiplex PCR panels. During May 2022-April 2023, among 1,548 syndromic PCR panels, 17 (1.1%) returned positive test results for measles virus. Among 14 persons who received a positive test result and for whom vaccination and case investigation information were available, all had received MMR vaccine a median of 12 days before specimen collection, and none had known risk factors for acquiring measles. All positive PCR results were attributed to detection of measles vaccine virus. Increased awareness among health care providers about potential measles detection by PCR after vaccination is needed. Any detection of measles virus by syndromic PCR testing should be immediately reported to public health agencies, which can use measles vaccination history and assessment of risk factors to determine the appropriate public health response. If a person recently received MMR vaccine and has no risk factors for acquiring measles, additional public health response is likely unnecessary.
Topics: Child; Humans; United States; Infant; Measles-Mumps-Rubella Vaccine; Retrospective Studies; Measles; Measles virus; Mumps; Vaccination; Tennessee; Exanthema; Polymerase Chain Reaction; Rubella; Antibodies, Viral
PubMed: 38547036
DOI: 10.15585/mmwr.mm7312a3 -
FEMS Microbes 2024Wastewater-based epidemiology is now widely used in many countries for the routine monitoring of SARS-CoV-2 and other viruses at a community level. However, efficient...
Wastewater-based epidemiology is now widely used in many countries for the routine monitoring of SARS-CoV-2 and other viruses at a community level. However, efficient sample processing technologies are still under investigation. In this study, we compared the performance of the novel Nanotrap® Microbiome Particles (NMP) concentration method to the commonly used polyethylene glycol (PEG) precipitation method for concentrating viruses from wastewater and their subsequent quantification and sequencing. For this, we first spiked wastewater with SARS-CoV-2, influenza and measles viruses and norovirus and found that the NMP method recovered 0.4%-21% of them depending on virus type, providing consistent and reproducible results. Using the NMP and PEG methods, we monitored SARS-CoV-2, influenza A and B viruses, RSV, enteroviruses and norovirus GI and GII and crAssphage in wastewater using quantitative PCR (qPCR)-based methods and next-generation sequencing. Good viral recoveries were observed for highly abundant viruses using both methods; however, PEG precipitation was more successful in the recovery of low-abundance viruses present in wastewater. Furthermore, samples processed with PEG precipitation were more successfully sequenced for SARS-CoV-2 than those processed with the NMP method. Virus recoveries were enhanced by high sample volumes when PEG precipitation was applied. Overall, our results suggest that the NMP concentration method is a rapid and easy virus concentration method for viral targets that are abundant in wastewater, whereas PEG precipitation may be more suited to the recovery and analysis of low-abundance viruses and for next generation sequencing.
PubMed: 38544682
DOI: 10.1093/femsmc/xtae007 -
International Journal of Molecular... Mar 2024In response to the pressing need for continuous monitoring of emergence and circulation of pathogens through genomics, it is imperative to keep developing bioinformatics...
In response to the pressing need for continuous monitoring of emergence and circulation of pathogens through genomics, it is imperative to keep developing bioinformatics tools that can help in their rapid characterization and classification. Here, we introduce ReporType, a versatile bioinformatics pipeline designed for targeted loci screening and typing of infectious agents. Developed using the snakemake workflow manager, ReporType integrates multiple software for read quality control and de novo assembly, and then applies ABRicate for locus screening, culminating in the production of easily interpretable reports for the identification of pathogen genotypes and/or screening of specific genomic loci. The pipeline accommodates a range of input formats, from Illumina or Oxford Nanopore Technology (ONT) reads (FASTQ) to Sanger sequencing files (AB1), or FASTA files, making it flexible for application in multiple pathogens and with different purposes. ReporType is released with pre-prepared databases for some viruses and bacteria, yet it remains easily configurable to handle custom databases. ReporType performance and functionality were validated through proof-of-concept exercises, encompassing diverse pathogenic species, including viruses such as measles, Newcastle disease virus (NDV), Dengue virus (DENV), influenza, hepatitis C virus (HCV) and Human T-Cell Lymphotropic virus type 1 (HTLV-1), as well as bacteria like and . In summary, ReporType emerges as a simple, dynamic and pan-pathogen tool, poised to evolve in tandem with the ever-changing needs of the fields of pathogen genomics, infectious disease epidemiology, and one health bioinformatics. ReporType is freely available at GitHub.
Topics: Humans; Sequence Analysis, DNA; Computational Biology; Genomics; Software; Bacteria; High-Throughput Nucleotide Sequencing
PubMed: 38542144
DOI: 10.3390/ijms25063172 -
Pathogens (Basel, Switzerland) Mar 2024An interesting article recently published in Medicine reports a variable risk of persistent COVID-19 among patients affected by different immunodeficiency conditions...
An interesting article recently published in Medicine reports a variable risk of persistent COVID-19 among patients affected by different immunodeficiency conditions [...].
PubMed: 38535569
DOI: 10.3390/pathogens13030226 -
Medical Science Monitor : International... Mar 2024On 22 February 2024, the World Health Organization (WHO) stated that, following the recent resurgence of measles cases in Europe, more than half the world's countries... (Review)
Review
On 22 February 2024, the World Health Organization (WHO) stated that, following the recent resurgence of measles cases in Europe, more than half the world's countries could expect significant measles outbreaks this year. Measles is a highly infectious virus with a primary case reproduction number (R0) of 12-18. Measles infection can be severe, resulting in pneumonia, and also more rarely in subacute sclerosing panencephalitis (SSPE), which occurs in 1 child out of every 1,000 and can be fatal. Until the 1990s, the hope of eliminating measles seemed possible following the successful development of effective vaccines, given individually or in the combined measles, mumps, and rubella (MMR) vaccine. Vaccine hesitancy due to misinformation about possible vaccine side effects, reduced vaccine uptake during and after the COVID-19 pandemic, and lack of awareness of the severe consequences of measles infection have contributed to low vaccine uptake, resulting in vulnerable communities. This article aims to review the recent resurgence of measles cases in the US, Europe, and the UK, to provide a reminder of the potential severity of measles, and to consider the causes of the failure to eliminate this vaccine-preventable viral infection.
Topics: Child; Humans; Measles-Mumps-Rubella Vaccine; Vaccine-Preventable Diseases; Pandemics; Vaccination; Measles
PubMed: 38525549
DOI: 10.12659/MSM.944436 -
Heliyon Mar 2024Thrombocytopenia, characterized by a decrease in platelet count, is a multifaceted clinical manifestation that can arise from various underlying causes. This review... (Review)
Review
Thrombocytopenia, characterized by a decrease in platelet count, is a multifaceted clinical manifestation that can arise from various underlying causes. This review delves into the intriguing nexus between viruses and thrombocytopenia, shedding light on intricate pathophysiological mechanisms and highlighting the pivotal role of platelets in viral infections. The review further navigates the landscape of thrombocytopenia in relation to specific viruses, and sheds light on the diverse mechanisms through which hepatitis C virus (HCV), measles virus, parvovirus B19, and other viral agents contribute to platelet depletion. As we gain deeper insights into these interactions, we move closer to elucidating potential therapeutic avenues and preventive strategies for managing thrombocytopenia in the context of viral infections.
PubMed: 38524607
DOI: 10.1016/j.heliyon.2024.e27844