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1.
Nat Commun ; 14(1): 3274, 2023 06 06.
Article in English | MEDLINE | ID: covidwho-20240984

ABSTRACT

SARS-CoV-2 has resulted in high levels of morbidity and mortality world-wide, and severe complications can occur in older populations. Humoral immunity induced by authorized vaccines wanes within 6 months, and frequent boosts may only offer transient protection. GRT-R910 is an investigational self-amplifying mRNA (samRNA)-based SARS-CoV-2 vaccine delivering full-length Spike and selected conserved non-Spike T cell epitopes. This study reports interim analyses for a phase I open-label dose-escalation trial evaluating GRT-R910 in previously vaccinated healthy older adults (NCT05148962). Primary endpoints of safety and tolerability were assessed. Most solicited local and systemic adverse events (AEs) following GRT-R910 dosing were mild to moderate and transient, and no treatment-related serious AEs were observed. The secondary endpoint of immunogenicity was assessed via IgG binding assays, neutralization assays, interferon-gamma ELISpot, and intracellular cytokine staining. Neutralizing antibody titers against ancestral Spike and variants of concern were boosted or induced by GRT-R910 and, contrasting to authorized vaccines, persisted through at least 6 months after the booster dose. GRT-R910 increased and/or broadened functional Spike-specific T cell responses and primed functional T cell responses to conserved non-Spike epitopes. This study is limited due to small sample size, and additional data from ongoing studies will be required to corroborate these interim findings.


Subject(s)
COVID-19 , RNA, Messenger/genetics , COVID-19/prevention & control , Humans , Aged , Male , Female , Middle Aged , Aged, 80 and over , Clinical Trials as Topic , Antibodies, Viral/immunology , Antibodies, Neutralizing/immunology , T-Lymphocytes/immunology
2.
Sci Rep ; 13(1): 9607, 2023 06 13.
Article in English | MEDLINE | ID: covidwho-20237193

ABSTRACT

Several clinical trials have shown that the humoral response produced by anti-spike antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines gradually declines. The kinetics, durability and influence of epidemiological and clinical factors on cellular immunity have not been fully elucidated. We analyzed cellular immune responses elicited by BNT162b2 mRNA vaccines in 321 health care workers using whole blood interferon-gamma (IFN-γ) release assays. IFN-γ, induced by CD4 + and CD8 + T cells stimulated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike epitopes (Ag2), levels were highest at 3 weeks after the second vaccination (6 W) and decreased by 37.4% at 3 months (4 M) and 60.0% at 6 months (7 M), the decline of which seemed slower than that of anti-spike antibody levels. Multiple regression analysis revealed that the levels of IFN-γ induced by Ag2 at 7 M were significantly correlated with age, dyslipidemia, focal adverse reactions to full vaccination, lymphocyte and monocyte counts in whole blood, Ag2 levels before the second vaccination, and Ag2 levels at 6 W. We clarified the dynamics and predictive factors for the long-lasting effects of cellular immune responses. The results emphasize the need for a booster vaccine from the perspective of SARS-CoV-2 vaccine-elicited cellular immunity.


Subject(s)
BNT162 Vaccine , COVID-19 , Humans , COVID-19 Vaccines , SARS-CoV-2 , COVID-19/prevention & control , Immunity, Cellular , Interferon-gamma , RNA, Messenger/genetics
3.
Sci Rep ; 13(1): 9038, 2023 06 03.
Article in English | MEDLINE | ID: covidwho-20235861

ABSTRACT

Oligonucleotide mapping via liquid chromatography with UV detection coupled to tandem mass spectrometry (LC-UV-MS/MS) was recently developed to support development of Comirnaty, the world's first commercial mRNA vaccine which immunizes against the SARS-CoV-2 virus. Analogous to peptide mapping of therapeutic protein modalities, oligonucleotide mapping described here provides direct primary structure characterization of mRNA, through enzymatic digestion, accurate mass determinations, and optimized collisionally-induced fragmentation. Sample preparation for oligonucleotide mapping is a rapid, one-pot, one-enzyme digestion. The digest is analyzed via LC-MS/MS with an extended gradient and resulting data analysis employs semi-automated software. In a single method, oligonucleotide mapping readouts include a highly reproducible and completely annotated UV chromatogram with 100% maximum sequence coverage, and a microheterogeneity assessment of 5' terminus capping and 3' terminus poly(A)-tail length. Oligonucleotide mapping was pivotal to ensure the quality, safety, and efficacy of mRNA vaccines by providing: confirmation of construct identity and primary structure and assessment of product comparability following manufacturing process changes. More broadly, this technique may be used to directly interrogate the primary structure of RNA molecules in general.


Subject(s)
COVID-19 , Tandem Mass Spectrometry , Humans , Tandem Mass Spectrometry/methods , Chromatography, Liquid/methods , SARS-CoV-2/genetics , COVID-19 Vaccines , Oligonucleotides/genetics , COVID-19/prevention & control , mRNA Vaccines , Peptide Mapping/methods , RNA, Messenger/genetics
4.
Viruses ; 15(5)2023 05 16.
Article in English | MEDLINE | ID: covidwho-20235842

ABSTRACT

miRNAs, small non-coding RNAs that regulate gene expression, are involved in various pathological processes, including viral infections. Virus infections may interfere with the miRNA pathway through the inhibition of genes involved in miRNA biogenesis. A reduction in the number and the levels of miRNAs expressed in nasopharyngeal swabs of patients with severe COVID-19 was lately observed by us, pointing towards the potential of miRNAs as possible diagnostic or prognostic biomarkers for predicting outcomes among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The objective of the present study was to investigate whether SARS-CoV-2 infection influences the expression levels of messenger RNAs (mRNAs) of key genes involved in miRNA biogenesis. mRNA levels of AGO2, DICER1, DGCR8, DROSHA, and Exportin-5 (XPO5) were measured by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal swab specimens from patients with COVID-19 and controls, as well as in cells infected with SARS-CoV-2 in vitro. Our data showed that the mRNA expression levels of AGO2, DICER1, DGCR8, DROSHA, and XPO5 were not significantly different in patients with severe COVID-19 when compared to patients with non-severe COVID-19 and controls. Similarly, the mRNA expression of these genes was not affected by SARS-CoV-2 infection in NHBE and Calu-3 cells. However, in Vero E6 cells, AGO2, DICER1, DGCR8, and XPO5 mRNA levels were slightly upregulated 24 h after infection with SARS-CoV-2. In conclusion, we did not find evidence for downregulation of mRNA levels of miRNA biogenesis genes during SARS-CoV-2 infection, neither ex vivo nor in vitro.


Subject(s)
COVID-19 , MicroRNAs , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , COVID-19/genetics , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , RNA-Binding Proteins/metabolism , RNA, Messenger/genetics , Ribonuclease III/genetics , Ribonuclease III/metabolism , DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , Karyopherins/genetics
5.
Expert Opin Drug Discov ; 18(7): 769-780, 2023 07.
Article in English | MEDLINE | ID: covidwho-20244932

ABSTRACT

INTRODUCTION: COVID-19 pandemic is one of the most serious public health events of this century. There have been more than 670 million confirmed cases and more than 6 million deaths worldwide. From the emergence of the Alpha variant to the later rampant Omicron variant, the high transmissibility and pathogenicity of SARS-CoV-2 accelerate the research and development of effective vaccines. Against this background, mRNA vaccines stepped onto the historical stage and became an important tool for COVID-19 prevention. AREAS COVERED: This article introduces the characteristics of different mRNA vaccines in the prevention of COVID-19, including antigen selection, therapeutic mRNA design and modification, and different delivery systems of mRNA molecules. It also summarizes and discusses the mechanisms, safety, effectiveness, side effects, and limitations of current COVID-19 mRNA vaccines. EXPERT OPINION: Therapeutic mRNA molecules have plenty of advantages, including flexible design, rapid production, sufficient immune activation, safety without the risk of genome insertion in the host cells, and no viral vectors or particles involved, making them an important tool to fight diseases in the future. However, the application of COVID-19 mRNA vaccines also faces many challenges, such as storage and transportation, mass production, and nonspecific immunity.


Subject(s)
COVID-19 , Viral Vaccines , Humans , COVID-19/prevention & control , SARS-CoV-2/genetics , Pandemics , RNA, Messenger/genetics , mRNA Vaccines
6.
Sci Rep ; 13(1): 8851, 2023 05 31.
Article in English | MEDLINE | ID: covidwho-20244154

ABSTRACT

Nebulization of mRNA therapeutics can be used to directly target the respiratory tract. A promising prospect is that mucosal administration of lipid nanoparticle (LNP)-based mRNA vaccines may lead to a more efficient protection against respiratory viruses. However, the nebulization process can rupture the LNP vehicles and degrade the mRNA molecules inside. Here we present a novel nebulization method able to preserve substantially the integrity of vaccines, as tested with two SARS-CoV-2 mRNA vaccines. We compare the new method with well-known nebulization methods used for medical respiratory applications. We find that a lower energy level in generating LNP droplets using the new nebulization method helps safeguard the integrity of the LNP and vaccine. By comparing nebulization techniques with different energy dissipation levels we find that LNPs and mRNAs can be kept largely intact if the energy dissipation remains below a threshold value, for LNP integrity 5-10 J/g and for mRNA integrity 10-20 J/g for both vaccines.


Subject(s)
COVID-19 , Nanoparticles , Humans , COVID-19 Vaccines , SARS-CoV-2/genetics , COVID-19/prevention & control , RNA, Messenger/genetics , mRNA Vaccines
7.
Int J Mol Sci ; 24(11)2023 Jun 05.
Article in English | MEDLINE | ID: covidwho-20242666

ABSTRACT

Waning vaccine-induced immunity, coupled with the emergence of SARS-CoV-2 variants, has inspired the widespread implementation of COVID-19 booster vaccinations. Here, we evaluated the potential of the GX-19N DNA vaccine as a heterologous booster to enhance the protective immune response to SARS-CoV-2 in mice primed with either an inactivated virus particle (VP) or an mRNA vaccine. We found that in the VP-primed condition, GX-19N enhanced the response of both vaccine-specific antibodies and cross-reactive T Cells to the SARS-CoV-2 variant of concern (VOC), compared to the homologous VP vaccine prime-boost. Under the mRNA-primed condition, GX-19N induced higher vaccine-induced T Cell responses but lower antibody responses than the homologous mRNA vaccine prime-boost. Furthermore, the heterologous GX-19N boost induced higher S-specific polyfunctional CD4+ and CD8+ T cell responses than the homologous VP or mRNA prime-boost vaccinations. Our results provide new insights into booster vaccination strategies for the management of novel COVID-19 variants.


Subject(s)
COVID-19 Vaccines , COVID-19 , T-Lymphocytes , Animals , Humans , Mice , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , DNA , RNA, Messenger/genetics , SARS-CoV-2 , Vaccination , Vaccines, Inactivated , Interferon-gamma/immunology , Interferon-gamma/metabolism
8.
Front Immunol ; 13: 864718, 2022.
Article in English | MEDLINE | ID: covidwho-20244339

ABSTRACT

mRNA based vaccines against COVID-19 have proven most successful at keeping SARS-CoV-2 pandemic at bay in many countries. Recently, there is an increased interest in heterologous prime-boost vaccination strategies for COVID-19 to maintain antibody responses for the control of continuously emerging SARS-CoV-2 variants of concern (VoCs) and to overcome other obstacles such as supply shortage, costs and reduced safety issues or inadequatly induced immune-responses. In this study, we investigated the antibody responses induced by heterologous prime-boost with vaccines based on mRNA and virus-like particles (VLPs). The VLP-based mCuMVTT-RBM vaccine candidate and the approved mRNA-1273 vaccine were used for this purpose. We find that homologous prime boost regimens with either mRNA or VLP induced high levels of high avidity antibodies. Optimal antibody responses were, however, induced by heterologous regimens both for priming with mRNA and boosting with VLP and vice versa, priming with VLP and boosting with mRNA. Thus, heterologous prime boost strategies may be able to optimize efficacy and economics of novel vaccine strategies.


Subject(s)
COVID-19 , SARS-CoV-2 , 2019-nCoV Vaccine mRNA-1273 , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunoglobulin G , RNA, Messenger/genetics , SARS-CoV-2/genetics
9.
BMC Genomics ; 24(1): 268, 2023 May 19.
Article in English | MEDLINE | ID: covidwho-2327005

ABSTRACT

BACKGROUND: The molecular mechanisms underlying the onset and progression of irreversible pulpitis have been studied for decades. Many studies have indicated a potential correlation between autophagy and this disease. Against the background of the competing endogenous RNA (ceRNA) theory, protein-coding RNA functions are linked with long noncoding RNAs (lncRNAs) and microRNAs (miRNAs). This mechanism has been widely studied in various fields but has rarely been reported in the context of irreversible pulpitis. The hub genes selected under this theory may represent the key to the interaction between autophagy and irreversible pulpitis. RESULTS: Filtering and differential expression analyses of the GSE92681 dataset, which contains data from 7 inflamed and 5 healthy pulp tissue samples, were conducted. The results were intersected with autophagy-related genes (ARGs), and 36 differentially expressed ARGs (DE-ARGs) were identified. Functional enrichment analysis and construction of the protein‒protein interaction (PPI) network of DE-ARGs were performed. Coexpression analysis was conducted between differentially expressed lncRNAs (DElncRNAs) and DE-ARGs, and 151 downregulated and 59 upregulated autophagy-related DElncRNAs (AR-DElncRNAs) were identified. StarBase and multiMiR were then used to predict related microRNAs of AR-DElncRNAs and DE-ARGs, respectively. We established ceRNA networks including 9 hub lncRNAs (HCP5 and AC112496.1 ↑; FENDRR, AC099850.1, ZSWIM8-AS1, DLX6-AS1, LAMTOR5-AS1, TMEM161B-AS1 and AC145207.5 ↓), which were validated by a qRT‒PCR analysis of pulp tissue from patients with irreversible pulpitis. CONCLUSION: We constructed two networks consisting of 9 hub lncRNAs based on the comprehensive identification of autophagy-related ceRNAs. This study may provide novel insights into the interactive relationship between autophagy and irreversible pulpitis and identifies several lncRNAs that may serve as potential biological markers.


Subject(s)
MicroRNAs , Pulpitis , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Gene Regulatory Networks , RNA, Messenger/genetics , RNA, Messenger/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism
10.
Pharmazie ; 78(5): 63-66, 2023 05 01.
Article in English | MEDLINE | ID: covidwho-2317853

ABSTRACT

There are case reports of mouth ulcers caused by the coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccine; however, the actual number and characteristics of cases are unknown. Therefore, we examined this issue using the Japanese Adverse Drug Event Report (JADER), a large Japanese database. We calculated the reported odds ratio (ROR) of drugs that may be specifically associated with mouth ulcers and assumed that a signal was present if the lower limit of the calculated ROR's 95% confidence interval (CI) was > 1. In addition, the time to symptom onset after administration of the COVID-19 mRNA and influenza HA vaccines was investigated. We found that the JADER database contained 4,661 mouth ulcer cases between April 2004 and March 2022. The COVID-19 mRNA vaccine was the eighth most common causative drug for mouth ulcers, with 204 reported cases. The ROR was 1.6 (95% CI, 1.4-1.9) and a signal was detected. There were 172 mouthulcer cases associated with the Pfizer-BioNTech's COVID-19 mRNA vaccine, 76.2% of which were female. The outcome was no unrecovered cases with the influenza HA vaccine, whereas the COVID-19 mRNA vaccine showed unrecovered cases (Pfizer-BioNTech: 12.2%, Moderna: 11.1%). The median time-to-onset of the mouth ulcers was two days for the COVID-19 mRNA vaccine and one day for the influenza HA vaccine, indicating that mouth ulcers caused by the COVID-19 mRNA vaccine were delayed adverse events. In this study, the COVID-19 mRNA vaccine was shown to cause mouth ulcers in a Japanese population.


Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , Influenza Vaccines , Influenza, Human , Oral Ulcer , Female , Humans , Male , Pharmaceutical Preparations , COVID-19 Vaccines/adverse effects , Oral Ulcer/chemically induced , Oral Ulcer/epidemiology , East Asian People , COVID-19/prevention & control , RNA, Messenger/genetics , mRNA Vaccines , Adverse Drug Reaction Reporting Systems
11.
Int Immunol ; 35(5): 213-220, 2023 05 08.
Article in English | MEDLINE | ID: covidwho-2317051

ABSTRACT

Vaccination for the prevention of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is considered the most promising approach to control the pandemic of coronavirus disease 2019 (COVID-19). Although various COVID-19 vaccines have been developed worldwide using several modalities, the vaccines that have shown the highest efficacy to date are mRNA vaccines. Despite their extensive usage, the mechanisms that stimulate the immune responses associated with their immunogenicity and reactogenicity remain largely unknown. In this review, we summarize and discuss current knowledge on immune responses to COVID-19 mRNA vaccines, including potential immune responses and correlating factors underlying the immunogenicity and reactogenicity of mRNA vaccines. We also describe recent trends in the optimization of lipid nanoparticles and vaccination routes. Further understanding of vaccine-elicited immune responses will guide the development of more effective and safe vaccines.


Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , SARS-CoV-2 , RNA, Messenger/genetics , mRNA Vaccines , Antibodies, Viral
12.
Front Immunol ; 14: 1172691, 2023.
Article in English | MEDLINE | ID: covidwho-2317032

ABSTRACT

The success of the first licensed mRNA-based vaccines against COVID-19 has created a widespread interest on mRNA technology for vaccinology. As expected, the number of mRNA vaccines in preclinical and clinical development increased exponentially since 2020, including numerous improvements in mRNA formulation design, delivery methods and manufacturing processes. However, the technology faces challenges such as the cost of raw materials, the lack of standardization, and delivery optimization. MRNA technology may provide a solution to some of the emerging infectious diseases as well as the deadliest hard-to-treat infectious diseases malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), for which an effective vaccine, easily deployable to endemic areas is urgently needed. In this review, we discuss the functional structure, design, manufacturing processes and delivery methods of mRNA vaccines. We provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV.


Subject(s)
Acquired Immunodeficiency Syndrome , COVID-19 , Communicable Diseases , Malaria , Tuberculosis , Humans , HIV/genetics , COVID-19 Vaccines , COVID-19/prevention & control , Tuberculosis/prevention & control , Malaria/prevention & control , RNA, Messenger/genetics
13.
J Am Chem Soc ; 145(20): 11375-11386, 2023 05 24.
Article in English | MEDLINE | ID: covidwho-2316797

ABSTRACT

Hypoxia is a common hallmark of human disease that is characterized by abnormally low oxygen levels in the body. While the effects of hypoxia on many small molecule-based drugs are known, its effects on several classes of next-generation medications including messenger RNA therapies warrant further study. Here, we provide an efficacy- and mechanism-driven study that details how hypoxia impacts the cellular response to mRNA therapies delivered using 4 different chemistries of lipid nanoparticles (LNPs, the frontrunner class of drug delivery vehicles for translational mRNA therapy utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines). Specifically, our work provides a comparative analysis as to how various states of oxygenation impact LNP-delivered mRNA expression, cellular association, endosomal escape, and intracellular ATP concentrations following treatment with 4 different LNPs across 3 different cell lines. In brief, we first identify that hypoxic cells express less LNP-delivered mRNA into protein than normoxic cells. Next, we identify generalizable cellular reoxygenation protocols that can reverse the negative effects that hypoxia imparts on LNP-delivered mRNA expression. Finally, mechanistic studies that utilize fluorescence-activated cell sorting, confocal microscopy, and enzyme inhibition reveal that decreases in mRNA expression correlate with decreases in intracellular ATP (rather than with differences in mRNA LNP uptake pathways). In presenting this data, we hope that our work provides a comprehensive efficacy and mechanism-driven study that explores the impact of differential oxygenation on LNP-delivered mRNA expression while simultaneously establishing fundamental criteria that may one day be useful for the development of mRNA drugs to treat hypoxia-associated disease.


Subject(s)
COVID-19 , Nanoparticles , Humans , Lipids , RNA, Messenger/genetics , COVID-19 Vaccines , Liposomes , Hypoxia , Adenosine Triphosphate , RNA, Small Interfering/genetics
14.
Curr Microbiol ; 80(6): 206, 2023 May 09.
Article in English | MEDLINE | ID: covidwho-2314797

ABSTRACT

Older age (>60 years) has been identified as the main risk factor for COVID-19. In this study, we aimed to evaluate the efficacy of Pfizer-BioNTech and CoronaVac vaccines against COVID-19 infection, serious illness, and mortality in the geriatric population. We found that 2 doses of CoronaVac vaccine were ineffective in protecting against COVID-19 infection in people over 65 years of age, while the vaccine efficacy (VE) of the mRNA vaccine against COVID-19 was 80% (95% CI 70-87). The VE of full vaccination with BioNTech was 89% (95% CI 53-97) against hospitalization, 79% (95% CI 0-97) against death, and 79% (95% CI 0-97) against intensive care unit (ICU) admission. However, the VE of full vaccination with CoronaVac was 50% (95% CI 33-63) against hospitalization, 53% (95% CI 26-70) against ICU admission, and 56% (95% CI 30-73) against death. In conclusion, we found that the mRNA vaccine has higher efficacy against severe COVID-19 infection and mortality in the geriatric population than the inactivated vaccine. Booster doses of vaccines should be considered in increasing the effectiveness of inactivated vaccines. Given the potential of SARS-CoV-2 mutations evading vaccination protection and the risk of reduced immunity over time, regular monitoring of vaccine effectiveness in the real world is critical.


Subject(s)
COVID-19 , Humans , Aged , COVID-19/prevention & control , COVID-19 Vaccines , SARS-CoV-2/genetics , mRNA Vaccines , RNA, Messenger/genetics
15.
J Biomed Mater Res A ; 110(5): 1101-1108, 2022 05.
Article in English | MEDLINE | ID: covidwho-2320830

ABSTRACT

Lipid nanoparticles (LNPs) play a crucial role in delivering messenger RNA (mRNA) therapeutics for clinical applications, including COVID-19 mRNA vaccines. While mRNA can be chemically modified to become immune-silent and increase protein expression, LNPs can still trigger innate immune responses and cause inflammation-related adverse effects. Inflammation can in turn suppress mRNA translation and reduce the therapeutic effect. Dexamethasone (Dex) is a widely used anti-inflammatory corticosteroid medication that is structurally similar to cholesterol, a key component of LNPs. Here, we developed LNP formulations with anti-inflammatory properties by partially substituting cholesterol with Dex as a means to reduce inflammation. We demonstrated that Dex-incorporated LNPs effectively abrogated the induction of tumor necrosis factor alpha (TNF-ɑ) in vitro and significantly reduced its expression in vivo. Reduction of inflammation using this strategy improved in vivo mRNA expression in mice by 1.5-fold. Thus, we envision that our Dex-incorporated LNPs could potentially be used to broadly to reduce the inflammatory responses of LNPs and enhance protein expression of a range of mRNA therapeutics.


Subject(s)
COVID-19 , Nanoparticles , Animals , Anti-Inflammatory Agents/pharmacology , Liposomes , Mice , Nanoparticles/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism
16.
Proc Natl Acad Sci U S A ; 119(32): e2204539119, 2022 08 09.
Article in English | MEDLINE | ID: covidwho-2311672

ABSTRACT

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-ß. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-ß production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.


Subject(s)
COVID-19 , Carrier Proteins , Interferon Type I , Viral Nonstructural Proteins , COVID-19/genetics , Carrier Proteins/metabolism , Cell Line , Eukaryotic Initiation Factor-4E/metabolism , Humans , Immunity, Innate , Interferon Type I/metabolism , Protein Biosynthesis , RNA, Messenger/genetics , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism , Virus Replication
18.
Cell Rep ; 42(5): 112443, 2023 05 30.
Article in English | MEDLINE | ID: covidwho-2306918

ABSTRACT

Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants.


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Antibody Formation , Mutation/genetics , RNA, Messenger/genetics , Vaccines, Combined , Antibodies, Viral
19.
Virol J ; 20(1): 64, 2023 04 07.
Article in English | MEDLINE | ID: covidwho-2295939

ABSTRACT

The mRNA vaccine technology was developed rapidly during the global pandemic of COVID-19. The crucial role of the COVID-19 mRNA vaccine in preventing viral infection also have been beneficial to the exploration and application of other viral mRNA vaccines, especially for non-replication structure mRNA vaccines of viral disease with outstanding research results. Therefore, this review pays attention to the existing mRNA vaccines, which are of great value for candidates for clinical applications in viral diseases. We provide an overview of the optimization of the mRNA vaccine development process as well as the good immune efficacy and safety shown in clinical studies. In addition, we also provide a brief description of the important role of mRNA immunomodulators in the treatment of viral diseases. After that, it will provide a good reference or strategy for research on mRNA vaccines used in clinical medicine with more stable structures, higher translation efficiency, better immune efficacy and safety, shorter production time, and lower production costs than conditional vaccines to be used as preventive or therapeutic strategy for the control of viral diseases in the future.


Subject(s)
COVID-19 , Viral Vaccines , Virus Diseases , Humans , COVID-19 Vaccines , COVID-19/prevention & control , Viral Vaccines/genetics , Vaccination , RNA, Messenger/genetics , mRNA Vaccines , Vaccines, Synthetic/genetics
20.
Adv Sci (Weinh) ; 10(11): e2300188, 2023 04.
Article in English | MEDLINE | ID: covidwho-2294455

ABSTRACT

Male infertility caused by genetic mutations is an important type of infertility. Currently, there is no reliable method in the clinic to address this medical need. The emergence of mRNA therapy provides a possible strategy for restoring mutant genes in the reproductive system. However, effective delivery of mRNA to spermatocytes remains a formidable challenge. Here a series of cholesterol-amino-phosphate (CAP) lipids are reported by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results demonstrate that CAP-derived lipid nanoparticles (CAP LNPs) can deliver RNA including traditional mRNA and self-amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and treat male infertility caused by the Dmc1 gene mutation. Notably, the delivery efficiency of CAP LNPs is significantly higher than that of the MC3 and ALC-0315 LNPs, which is consistent with the design of CAP molecules. More importantly, a single injection of CAP LNPs-saRNA can produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Overall, this study proves the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation.


Subject(s)
Infertility, Male , RNA , Humans , Mice , Male , Animals , Spermatogenesis/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Infertility, Male/genetics , Infertility, Male/therapy , Cholesterol
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