Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses

Science Translational Medicine, Год журнала: 2022, Номер 14(634)

Опубликована: Янв. 14, 2022

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape arisen over the course of current pandemic. Although vaccines largely been effective against past variants, number found on Omicron (B.1.1.529) spike protein appear to diminish protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing several SARS-CoV-2 we evaluated magnitude breadth neutralizing response time in individuals after infection mRNA-vaccinated individuals. We observed boosting increases wild-type (D614), Beta, Delta, variants; however, variant was most resistant neutralization. further vaccinated healthy adults had robust broad responses, whereas responses may reduced pregnant women, underscoring importance learning how maximize mRNA vaccine populations. Findings from this study show substantial heterogeneity vaccination support addition more conserved viral antigens existing vaccines.

Язык: Английский

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Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses

Nature Immunology, Год журнала: 2022, Номер 23(12), С. 1788 - 1798

Опубликована: Окт. 31, 2022

Язык: Английский

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Antiviral Drug Discovery for the Treatment of COVID-19 Infections

Viruses, Год журнала: 2022, Номер 14(5), С. 961 - 961

Опубликована: Май 4, 2022

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting vaccinated from infection, reducing severity of disease, and deterring transmission infection. However, vaccination faces many challenges, such as decline vaccine-induced immunity over time, decrease potency against some SARS-CoV-2 variants including Omicron variant, resulting breakthrough infections. challenges that facing highlight importance discovery antivirals serve another means tackle pandemic. To date, neutralizing antibodies block viral entry targeting spike protein make up largest class has received US FDA emergency use authorization (EUA) for treatment. In addition protein, other key targets direct-acting include enzymes are essential replication, RNA-dependent RNA polymerase proteases, judged approval remdesivir, EUA Paxlovid (nirmatrelvir + ritonavir) treating This review presents an overview current status future direction antiviral drug infections, covering important non-structural (nsp) 3 papain-like protease, nsp5 main nsp12/nsp7/nsp8 complex.

Язык: Английский

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COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis

Brain Behavior and Immunity, Год журнала: 2023, Номер 111, С. 211 - 229

Опубликована: Март 27, 2023

Язык: Английский

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Microbiota regulation of viral infections through interferon signaling

Trends in Microbiology, Год журнала: 2022, Номер 30(8), С. 778 - 792

Опубликована: Фев. 6, 2022

The gut microbiota modulates antiviral type I and III IFN responses, ultimately regulating viral infection outcomes.The is capable of modulating the response both in gastrointestinal tract at extraintestinal sites.The controls homeostatic tone infection-naïve state, preparing host for timely activation responses upon infection.Both commensal bacteria-derived ligands metabolites signal to different cell types regulate signaling pathways thereby indirectly control infection.The microbiota–IFN–virus axis holds therapeutic promise therapies vaccines humans, but extrapolation humans remains be demonstrated. interferon (IFN) major early innate immune against invading pathogens even mediating sterilizing immunity without support adaptive system. Cumulative evidence suggests that can modulate determining virological outcomes. This review outlines our current knowledge interactions between dissects mechanisms by which may alter expression diverse infections. offers a basis translating experimental from animal studies into human context identifies avenues leveraging improve infections performance vaccines. Coevolution intestinal (see Glossary) system has resulted delicate balance reciprocal maintain homeostasis gut. plays fundamental role induction, training, maintenance [1.Belkaid Y. Hand T.W. Role inflammation.Cell. 2014; 157: 121-141Abstract Full Text PDF PubMed Scopus (2472) Google Scholar]. At same time, evolved constrain symbiotic relationship with these microbes [2.Zheng D. et al.Interaction health disease.Cell Res. 2020; 30: 492-506Crossref (817) A critical shaping becomes readily apparent eukaryotic On one hand, directly interact virus particles influence their infectivity. Numerous have described able promote replication pathogenesis (reviewed [3.Li N. al.The infection: comprehensive review.Front. Immunol. 2019; 10: 1-16PubMed Scholar,4.Pfeiffer J.K. Virgin H.W. Transkingdom mammalian intestine.Science. 2016; 351aad5872Crossref (162) Scholar]). other prime activate [5.Yang M. al.Intestinal – promising target therapy?.Front. 2021; 12: 1-18Google Together, microbiota, immunity, complex triangular determine disease One recurring mechanism been found via modulation response. IFNs are class cytokines, secreted cells infection, potent activity [6.Borden E.C. al.Interferons age 50: past, future impact on biomedicine.Nat. Rev. Drug Discov. 2007; 6: 975-990Crossref (867) Scholar,7.McNab F. al.Type interferons infectious disease.Nat. 2015; 15: 87-103Crossref (1268) dual actions: first, they induce an immediate state infected neighboring cells, second, link mainly through priming dendritic (DCs) [7.McNab Scholar,8.Ye L. al.Interferon-λ orchestrates mucosal responses.Nat. 19: 614-625Crossref (119) Evidence date indicates either or suppress signaling, depending specific setting [9.Stefan K.L. al.Commensal natural resistance infection.Cell. 183: 1312-1324Abstract (75) Scholar, 10.Schaupp al.Microbiota-Induced instruct poised basal cells.Cell. 181: 1080-1096Abstract (83) 11.Bradley K.C. al.Microbiota-driven tonic signals lung stromal protect influenza infection.Cell Rep. 28: 245-256Abstract (140) 12.Baldridge M.T. interferon-λ persistence enteric murine norovirus infection.Science. 347: 266-269Crossref (290) 13.Grau K.R. regionalization acute regulated bile acid-mediated interferon.Nat. Microbiol. 5: 84-92Crossref (53) 14.Winkler E.S. microbiome restricts alphavirus dissemination acid-type axis.Cell. 182: 901-918Abstract (51) 15.Yang X.L. primes systemic interferon.mBio. 1-20Crossref 16.Chemudupati al.Butyrate reprograms interferon-stimulated genes.J. Virol. 94e00326-20Crossref (16) 17.Antunes K.H. al.Microbiota-derived acetate protects respiratory syncytial GPR43-type 1 response.Nat. Commun. 1-17Crossref 18.Ganal S.C. al.Priming killer nonmucosal mononuclear phagocytes requires instructive microbiota.Immunity. 2012; 37: 171-186Abstract (327) 19.Abt M.C. bacteria calibrate threshold immunity.Immunity. 158-170Abstract (649) Interestingly, appears conserved across wide range viruses and, parallel, numerous byproducts signaling. Understanding how will inform novel vaccination strategies. provides brief overview biology followed detailed delineation shown local remote sites, discussing underlying during We focus although microbiota-driven likely play anatomic such as skin. Finally, implications host–microbiota–viral pathogen strategies explored. cytokine family contains three distinct I, II, associated IFN, we here [20.Stanifer M.L. al.Differential regulation signaling.Int. J. Mol. Sci. 20: 1-22Crossref consists IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-δ, IFN-ω, IFN-ζ (mice), IFN-τ (ruminants), though IFN-α IFN-β best studied [21.Lazear H.M. al.Shared functions interferons.Immunity. 907-923Abstract (430) These cytokines broadly protection contribute restriction sites Type IFNs, consisting four subtypes IFN-λ, more prominent tracts [22.Broggi A. interferons: Balancing tissue tolerance invasion.J. Exp. Med. 217: 1-12Google Upon triggered sensing nucleic acid variety pattern-recognition receptors (PRRs). Both extracellular receptors, membrane-bound Toll-like (TLRs), cytosolic RIG-I-like (RLRs) DNA sensors [which include cyclic GAMP synthase (cGAS)], [8.Ye Subsequently, released bind respective autocrine manner (the itself) paracrine cells) [23.Lee A.J. Ashkar A.A. nature II interferons.Front. 2018; 9: 2061Crossref (300) heterodimer receptor composed IFNAR1 IFNAR2, while (or IFN-λ) comprised IFNLR1 IL-10RB. Despite complexes, share similar cascades involving phosphorylation JAK/STAT pathway translocation binding regulatory factors (IRFs) IFN-stimulated elements (ISREs), inducing genes (ISGs) [24.Ingle H. al.Distinct effects viruses.Viruses. 1-23Crossref (34) Expression ISGs drives uninfected resulting direct interference [25.Schneider W.M. al.Interferon-stimulated genes: web defenses.Annu. 32: 513-545Crossref (1711) Emerging paradigms suggest each unique roles controlling infection. IFN-λ whereas IFN-α/β involved localized function results limited subunit predominantly epithelial only subset cells. By contrast, subunits expressed nearly all nucleated [26.Kotenko S.V. Durbin J.E. Contribution immunity: location, location.J. Biol. Chem. 2017; 292: 7295-7303Abstract (68) Moreover, characterized rapid increase also decline high-magnitude ISG expression, induced lower magnitude, delayed, sustained [27.Id K.P. induction stimulated independent abundance.PLoS Pathog. 14e1007420Google differential localization kinetics confine excessive inflammatory systemically, unless fail curb Comprehensive comparisons available elsewhere Scholar,24.Ingle Scholar,28.Walker F.C. infections.Trends 42: 1009-1023Abstract (0) In addition important regulators arm Nearly express IFNAR2 therefore responsive IFN. Conventional DCs (cDC) particular rely cues functional maturation migration [29.Garcin G. Activity differentiation.PLoS One. 2013; 8e58465Crossref (17) Functional cDCs T B become activated proliferate [30.Crouse al.Regulation interferons.Nat. 231-242Crossref (274) formation germinal-center subclass distribution IgG depends [31.Dahlgren M.W. germinal centers intrinsic dependent Th1 Tfh lineages.bioRxiv. (Posted November 21, 2020)https://doi.org/10.1101/2020.11.20.390625Google beginning understood. extent IFNLR1, respond stimulation, controversial. Naïve require differentiate plasmablasts functionally active, permitting release antibody production [32.Syedbasha al.Interferon-lambda enhances differentiation naive mTORC1 pathway.Cell 33108211Abstract (10) CD8+ do not still activation, antigen uptake, [33.Hemann E.A. facilitate virus.Nat. 1035-1045Crossref addition, thymic lymphopoietin (TSLP) axis, produced M [34.Ye boosting lymphopoietin.Nat. 593-601Crossref (49) summary, powerful playing central orchestrating houses body's most densely populated [35.Shi Z. Gewirtz A.T. Together forever: bacterial–viral immunity.Viruses. 122Crossref However, it widely accepted tract. Correspondingly, occurs locally compartments (Box 1). means resident influences distal active area study. There least two possible mechanisms: (i) bacterial products enter circulation reach where residing cells; (ii) circulating sample components intestine then migrate parts body Further defining crosstalk essential harnessing potential immunity.Box 1Examples modulated microbiotaThe within [12.Baldridge Scholar,13.Grau Scholar,37.Van Winkle J.A. al.A interferon-lambda stimulates preemptive defense discrete pockets epithelium.bioRxiv. June 2, 2021)https://doi.org/10.1101/2021.06.02.446828Google IFN-λ-mediated signature (IECs). seen rotavirus depletion loss limiting host's capacity (MRV) [37.Van proximal gut, limit (MNV) inhibition microbiota-derived acids [13.Grau Disruption Ifnlr1 limits MNV's dependence bacteria, again implicating MNV as-yet unclear hypothesis histo-blood group antigens (HBGAs) required [79.Jones M.K. al.Enteric mouse cells.Science. 346: 755-759Crossref (573) patterns microbiota-induced location-dependent, model maintains supports infection.Gut demonstrated germ-free (GF) antibiotic-treated mice. enhanced absence . Reduced survival mice LCMV [19.Abt Scholar] VSV reduced spleen, representation compartment. During chikungunya (CHIKV) loads spleen serum GF higher due defective pDCs [14.Winkler Similarly, leads following Scholar,11.Bradley (RSV) [17.Antunes reaches far brain, peripheral blood increased EMCV titers brain [15.Yang Gut Prior uncovered delineating interactions. Here, outline key mechanistic themes underpinning microbiota–IFN relation infections: microbiota-mediated IFN; PRR activation; (Figure 1, Key figure). It note

Язык: Английский

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Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Фев. 17, 2023

Abstract Herein, we studied the impact of empty LNP (eLNP), component mRNA-based vaccine, on anti-viral pathways and immune function cells from young aged individuals. eLNP induced maturation monocyte derived dendritic (MDDCs). We further show that upregulated CD40 cytokine production in multiple DC subsets monocytes. This coincided with phosphorylation TANK binding kinase 1 (pTBK1) interferon response factor 7 (pIRF7). In to eLNP, healthy older adults (>65 yrs) have decreased expression, IFN-γ output compared (<65 yrs). Additionally, a dysregulated signaling stimulation, measured by defect type I IFN production, phagocytosis. Overall, our data eliciting innate is impaired resulting lower responses SARS-CoV-2 vaccines.

Язык: Английский

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Knife’s edge: Balancing immunogenicity and reactogenicity in mRNA vaccines

Experimental & Molecular Medicine, Год журнала: 2023, Номер 55(7), С. 1305 - 1313

Опубликована: Июль 10, 2023

Since the discovery of messenger RNA (mRNA), there have been tremendous efforts to wield them in development therapeutics and vaccines. During COVID-19 pandemic, two mRNA vaccines were developed approved record-breaking time, revolutionizing vaccine landscape. Although first-generation demonstrated over 90% efficacy, alongside strong immunogenicity humoral cell-mediated immune responses, their durability has lagged compared long-lived vaccines, such as yellow fever vaccine. worldwide vaccination campaigns saved lives estimated tens millions, side effects, ranging from mild reactogenicity rare severe diseases, reported. This review provides an overview mechanistic insights into responses adverse effects documented primarily for Furthermore, we discuss perspectives this promising platform challenges balancing effects.

Язык: Английский

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Durability of immune responses to mRNA booster vaccination against COVID-19

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(10)

Опубликована: Март 23, 2023

BackgroundMaintaining durable immunity following vaccination represents a major challenge, but whether mRNA booster improves durability is unknown.MethodsWe measured antibody responses in 55 healthy adults, who received dose of the Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated half-life titers. We also memory B T cell subset 28 participants. In 13 volunteers second vaccine, we serum titers responses.ResultsThe (third immunization) at 6 to 10 months increased serum-neutralizing (nAb) 76 days from 56 66 after primary 2-dose vaccination. A (fourth year further 88 days. However, despite this modestly improved nAb ancestral (WA.1) strain, there was loss neutralization capacity Omicron subvariants BA.2.75.2, BQ.1.1, XBB.1.5 (48-, 71-, 66-fold drop titers, respectively, relative WA.1 strain). Although only 45% 65% participants demonstrated detectable titer newer variants dose), response declined below detection limit almost all individuals by months. contrast, induced antigen-specific cells that persisted for least months.ConclusionThe marginally immunizations with vaccines.

Язык: Английский

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The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis

Aging Cell, Год журнала: 2023, Номер 22(6)

Опубликована: Март 8, 2023

Abstract Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers bidirectional information network between microbiota OA, which may provide a new way protect OA. However, role microbiota‐derived metabolites in ferroptosis‐relative remains unclear. The objective this study was analyze protective effect its metabolite capsiate (CAT) on vivo vitro experiments. From June 2021 February 2022, 78 patients were evaluated retrospectively divided into two groups: health group ( n = 39) 40). Iron oxidative stress indicators determined peripheral blood samples. And then experiments, surgically destabilized medial meniscus (DMM) mice model established treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) utilized inhibit SLC2A1 expression. Serum iron increased significantly but total binding capacity decreased than healthy people p < 0.0001). least absolute shrinkage selection operator clinical prediction suggested serum iron, capacity, transferrin, superoxide dismutase all independent predictors 0.001). Bioinformatics results SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript (MALAT1), HIF‐1α (Hypoxia Inducible Factor Alpha)‐related signaling pathways play important homeostasis In addition, 16s sequencing untargeted metabolomics used find negatively correlated Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration 0.0017). Moreover, reduced ferroptosis‐dependent vitro. against could be eliminated by silencing SLC2A1. upregulated levels DMM group. HIF‐1α, MALAT1, apoptosis after knockout chondrocyte cells Finally, downregulation expression Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves vivo. Our findings indicated inhibited HIF‐1a activating

Язык: Английский

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Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection

Immunity, Год журнала: 2023, Номер 56(4), С. 864 - 878.e4

Опубликована: Март 16, 2023

T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific cell responses for dominant CD4

Язык: Английский

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