Mucosal vaccine-induced cross-reactive CD8+ T cells protect against SARS-CoV-2 XBB.1.5 respiratory tract infection

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(3), P. 537 - 551

Published: Feb. 9, 2024

Abstract A nasally delivered chimpanzee adenoviral-vectored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (ChAd-SARS-CoV-2-S) is currently used in India (iNCOVACC). Here, we update this by creating ChAd-SARS-CoV-2-BA.5-S, which encodes a prefusion-stabilized BA.5 spike protein. Whereas serum neutralizing antibody responses induced monovalent or bivalent adenoviral vaccines were poor against the antigenically distant XBB.1.5 strain and insufficient to protect passive transfer experiments, mucosal cross-reactive memory T cell robust, protection was evident WA1/2020 D614G Omicron variants BQ.1.1 mice hamsters. However, depletion of CD8 + cells before challenge resulted loss upper lower tract infection. Thus, stimulate immunity emerging SARS-CoV-2 strains, mediate lung infection strains setting low levels antibodies.

Language: Английский

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B-cell and antibody responses to SARS-CoV-2: infection, vaccination, and hybrid immunity

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 21(2), P. 144 - 158

Published: Nov. 10, 2023

Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 prompted scientific, medical, and biotech communities to investigate infection- vaccine-induced immune responses the context this pathogen. B-cell antibody are at center these investigations, as neutralizing antibodies (nAbs) an important correlate protection (COP) from infection primary target SARS-CoV-2 vaccine modalities. In addition absolute levels, nAb longevity, neutralization breadth, immunoglobulin isotype subtype composition, presence mucosal sites have become topics for scientists health policy makers. recent pandemic was still is a unique setting which study de novo memory (MBC) dynamic interplay immunity. It also provided opportunity explore new platforms, such mRNA or adenoviral vector vaccines, unprecedented cohort sizes. Combined with technological advances years, situation has detailed mechanistic insights into development but revealed some unexpected findings. review, we summarize key findings last 2.5 years regarding immunity, believe significant value not only future vaccination approaches endemic settings.

Language: Английский

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Progressive loss of conserved spike protein neutralizing antibody sites in Omicron sublineages is balanced by preserved T cell immunity

Cell Reports, Journal Year: 2023, Volume and Issue: 42(8), P. 112888 - 112888

Published: July 31, 2023

Evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to emergence sublineages with different patterns neutralizing antibody evasion. We report that BA.4/BA.5 breakthrough infection individuals immunized SARS-CoV-2 wild-type-strain-based mRNA vaccines results in a boost BA.4.6, BF.7, BQ.1.1, and BA.2.75 neutralization but does not efficiently BA.2.75.2, XBB, or XBB.1.5 neutralization. In silico analyses showed spike glycoprotein lost most B cell epitopes, especially XBB.1.5. contrast, T epitopes are conserved across variants including responses mRNA-vaccinated, SARS-CoV-2-naive against wild-type strain, BA.1, were comparable, suggesting immunity recent may remain largely unaffected. While some effectively evade immunity, spike-protein-specific due nature polymorphic cell-mediated immune responses, continue contribute prevention/limitation COVID-19 manifestation.

Language: Английский

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Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(6), P. e1011569 - e1011569

Published: June 20, 2024

Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice cynomolgus macaques from severe disease. The mechanisms of NTD antibody-mediated protection are unknown. Here we show Fc mediate (non-nAb) MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not suppress infectious titers lung as potently (nAb) infusion, disease markers including gross discoloration were similar nAb groups. functional knockout substitutions abolished increased group. enhancement relative WT, supporting a positive association between functionality degree infection. For therapeutic administration antibodies, contributed virus suppression lessening discoloration, but presence neutralization required for optimal This study demonstrates non-nAbs can utilize Fc-mediated lower load prevent damage due coronavirus

Language: Английский

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High-resolution map of the Fc functions mediated by COVID-19-neutralizing antibodies

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(3)

Published: Jan. 10, 2024

A growing body of evidence shows that fragment crystallizable (Fc)-dependent antibody effector functions play an important role in protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To unravel the mechanisms drive these responses, we analyzed phagocytosis and complement deposition mediated by a panel 482 human monoclonal antibodies (nAbs) neutralizing original Wuhan virus, expressed as recombinant IgG1. Our study confirmed nAbs no longer SARS-CoV-2 Omicron variants can retain their Fc functions. Surprisingly, found with most potent function recognize N-terminal domain, followed those targeting class 3 epitopes receptor binding domain. Interestingly, direct against 1/2 motif, which are were weakest The divergent properties function-mediating use different B cell germlines observation polyclonal sera differ profile observed nAbs, suggesting non-neutralizing also contribute to These data provide high-resolution picture Fc-antibody response suggest contribution should be considered for design improved vaccines, selection therapeutic antibodies, evaluation correlates protection.

Language: Английский

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Placental transfer dynamics and durability of maternal COVID-19 vaccine-induced antibodies in infants

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109273 - 109273

Published: Feb. 20, 2024

Completion of a COVID-19 vaccination series during pregnancy effectively reduces hospitalization among infants less than 6 months age. The dynamics transplacental transfer maternal vaccine-induced antibodies, and their persistence in at 2, 6, 9, 12 months, have implications for new vaccine development optimal timing administration pregnancy. We evaluated anti-COVID antibody IgG subclass, Fc-receptor binding profile, activity against wild-type Spike RBD plus five variants concern (VOCs) 153 serum samples from 100 infants. Maternal IgG1 IgG3 responses persisted 2- 6-month to greater extent the other subclasses, with high antibodies placental neonatal FcγR3A. Lowest was observed Omicron RBD-specific region. timing, capabilities, fetal sex, VOC all impact through

Language: Английский

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Protective non-neutralizing SARS-CoV-2 monoclonal antibodies

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(8), P. 609 - 624

Published: July 20, 2024

Recent studies show an important role for non-neutralizing anti-spike antibodies, including monoclonal antibodies (mAbs), in robustly protecting against SARS-CoV-2 infection. These mAbs use Fc-mediated functions such as complement activation, phagocytosis, and cellular cytotoxicity. There is untapped potential using durable antibody treatments; because of their available conserved epitopes, they may not be sensitive to virus mutations neutralizing mAbs. Here, we discuss evidence mAb-mediated protection We explore how mAb can enhanced via novel antibody-engineering techniques. Important questions remain answered regarding the characteristics protective mAbs, models assays used study, risks ensuing detrimental inflammation, well durability mechanisms protection.

Language: Английский

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Alveolar Macrophages in Viral Respiratory Infections: Sentinels and Saboteurs of Lung Defense

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 407 - 407

Published: Jan. 5, 2025

Respiratory viral infections continue to cause pandemic and epidemic outbreaks in humans animals. Under steady-state conditions, alveolar macrophages (AlvMϕ) fulfill a multitude of tasks order maintain tissue homeostasis. Due their anatomic localization within the deep lung, AlvMϕ are prone detect react inhaled viruses thus play role early pathogenesis several respiratory infections. Here, detection pathogens causes diverse antiviral proinflammatory reactions. This fact not only makes them promising research targets, but also suggests as potential targets for therapeutic prophylactic approaches. review aims give comprehensive overview current knowledge about

Language: Английский

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Dissecting the properties of circulating IgG against streptococcal pathogens through a combined systems antigenomics-serology workflow

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 24, 2025

Abstract This study showcases an integrative mass spectrometry-based strategy combining systems antigenomics and serology to characterize human antibodies in clinical samples. involves using circulating plasma affinity-enrich antigenic proteins biochemically fractionated pools of bacterial proteins, followed by their identification quantification spectrometry. A selected subset the identified antigens is then expressed recombinantly isolate antigen-specific IgG, characterization structural functional properties these antibodies. We focused on Group streptococcus (GAS), a major pathogen lacking approved vaccine. The data shows that both healthy GAS-infected individuals have IgG against conserved streptococcal including toxins virulence factors. breadth remains relatively constant across but changes considerably GAS bacteremia. Moreover, analysis reveals individual variation titers, subclass distributions, Fc-signaling capacity, despite similar epitope Fc-glycosylation patterns. Finally, we show may cross-react with Streptococcus dysgalactiae (SD), occupies niches causes comparable infections. Collectively, our results highlight complexity GAS-specific antibody responses versatility methodology immune pathogens.

Language: Английский

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Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(12), P. 1961 - 1973.e11

Published: Nov. 20, 2023

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with antigenicity their spike (S) glycoproteins remain uncharacterized. Here, we show that African bat sarbecovirus PRD-0038 S has a broad angiotensin-converting enzyme 2 (ACE2) usage and receptor-binding domain (RBD) mutations further expand promiscuity enable human ACE2 utilization. We determine cryo-EM structure RBD bound to alcyone ACE2, explaining highlighting differences SARS-CoV-1 SARS-CoV-2. Characterization using monoclonal antibody reactivity reveals its distinct relative SARS-CoV-2 identifies cross-neutralizing antibodies for pandemic preparedness. vaccination elicits greater titers cross-reacting vaccine-mismatched 1a sarbecoviruses compared due broader antigenic targeting, motivating inclusion antigens in next-generation vaccines enhanced resilience viral evolution.

Language: Английский

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