Antibody Affinity Shapes the Choice between Memory and Germinal Center B Cell Fates

Cell, Год журнала: 2020, Номер 183(5), С. 1298 - 1311.e11

Опубликована: Окт. 29, 2020

Язык: Английский

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Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria

New England Journal of Medicine, Год журнала: 2022, Номер 387(5), С. 397 - 407

Опубликована: Авг. 3, 2022

New approaches for the prevention and elimination of malaria, a leading cause illness death among infants young children globally, are needed.We conducted phase 1 clinical trial to assess safety pharmacokinetics L9LS, next-generation antimalarial monoclonal antibody, its protective efficacy against controlled human malaria infection in healthy adults who had never or received vaccine malaria. The participants L9LS either intravenously subcutaneously at dose mg, 5 20 mg per kilogram body weight. Within 2 6 weeks after administration both control underwent which they were exposed mosquitoes carrying Plasmodium falciparum (3D7 strain).No concerns identified. an estimated half-life 56 days, it linearity, with highest mean (±SD) maximum serum concentration (Cmax) 914.2±146.5 μg milliliter observed lowest Cmax 41.5±4.7 those intravenously; was 164.8±31.1 68.9±22.3 subcutaneously. A total 17 recipients infection. Of single 15 (88%) protected Parasitemia did not develop any intravenous L9LS. developed intravenously, subcutaneously, all through 21 days Protection conferred by seen concentrations as low 9.2 milliliter.In this small trial, administered infection, without evident concerns. (Funded National Institute Allergy Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).

Язык: Английский

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A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver

Immunity, Год журнала: 2020, Номер 53(4), С. 733 - 744.e8

Опубликована: Сен. 17, 2020

Язык: Английский

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Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

Nature Medicine, Год журнала: 2020, Номер 26(7), С. 1135 - 1145

Опубликована: Май 25, 2020

Язык: Английский

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In silico molecular docking and ADME/T analysis of Quercetin compound with its evaluation of broad-spectrum therapeutic potential against particular diseases

Informatics in Medicine Unlocked, Год журнала: 2022, Номер 29, С. 100894 - 100894

Опубликована: Янв. 1, 2022

Progression in computational research has made it possible for the silico methods to offer epochal benefits both regulatory needs and pharmaceutical industry assess safety profile. Myriad amounts of flavonoids are present human diet. They showed potential therapeutic effects against a wide range illnesses. One most ubiquitously distributed extensively studied is flavonol Quercetin (Quercetin). The current study aspires reveal as potent inhibitor Tuberculosis, Malaria, Inflammatory diseases, Breast cancer, Obesity, Alzheimer's disease analogy standard drugs each disease. A molecular docking with specific proteins associated diseases was done using Schrodinger Maestro (v11.1) software. QikProp module used ADME prediction, admetSAR online database evaluated toxicity ligand. Molecular results also higher scores than commercially available drugs. Moreover, properties delineated no carcinogenicity mutagenicity along lower rat acute & acceptable oral level. possessed (−9.00, −6.36, −8.53, −7.28, −7.89, −6.68 kcal/mol) Anti-tuberculosis, Anti-malarial, Anti-inflammatory, Antineoplastic (Breast –cancer), Anti-obesity Anti-Alzheimers drugs, respectively when compared Therefore, from score, we can conclude that be more inhibitory agent selected market. However, congenial clinical empirical studies required explicit an effectual candidate drug equitable treatment above-referred diseases.

Язык: Английский

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Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses

Immunity, Год журнала: 2022, Номер 55(9), С. 1680 - 1692.e8

Опубликована: Авг. 16, 2022

Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. Pfs48/45 is a leading clinical TBV candidate antigen and recognized by the most potent monoclonal antibody (mAb) yet described; still, antigens has been hindered, largely its poor biochemical characteristics. Here, we used structure-based computational approaches design stabilized conformation potently inhibitory mAb, achieving >25°C higher thermostability compared with wild-type protein. Antibodies elicited mice immunized these engineered displayed on liposome-based or protein nanoparticle-based vaccine platforms exhibited 1–2 orders magnitude superior transmission-reducing activity, immunogens bearing antigen, driven improved quality. Our data provide founding principles for using molecular stabilization solely from structure-function information drive immune responses against parasitic target.

Язык: Английский

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Discovery and engineering of the antibody response to a prominent skin commensal

Nature, Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

Язык: Английский

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The RH5-CyRPA-Ripr Complex as a Malaria Vaccine Target

Trends in Parasitology, Год журнала: 2020, Номер 36(6), С. 545 - 559

Опубликована: Апрель 28, 2020

The antigens PfRH5, PfCyRPA, and PfRipr can induce strain-transcendent neutralizing antibodies, all three targets are essential highly conserved.PfRH5, form a stable complex (RCR) that is involved in the induction of an erythrocytic calcium spike during merozoite invasion.Passive transfer anti-CyRPA anti-PfRH5 antibodies protect against blood-stage P. falciparum animal models.Structural studies have mapped out first known critical inhibitory epitopes on PfRH5 PfCyRPA which be used for next-generation vaccine design.Early results from clinical trials been reported with more anticipated soon, will help guide development RCR-based vaccines. Despite ongoing efforts, effective Plasmodium remains elusive. Vaccines targeting pre-erythrocytic stages life cycle most advanced to date, affording moderate levels efficacy field trials. However, discovery members PfRH5-PfCyRPA-PfRipr capable inducing has renewed enthusiasm possibility preventing disease by parasite blood stage infection. With Phase I/II now underway using first-generation vaccines horizon PfRipr, this review explores rationale future potential RCR as target. Global malaria mortality morbidity declined sharply recent decades. Still, 2018 there were 228 million infections resulting 405 000 deaths, disproportionately shouldered developing world [1.WHO World Malaria Report 2019. WHO, 2019Google Scholar]. progress, continues intractable global health threat. Improved access insecticide-impregnated bed nets, vector control, availability antimalarial medications cornerstones control efforts continue play indispensable roles. even optimal deployment current tools still leave elimination high-transmission settings unattainable [2.Griffin J.T. et al.Reducing transmission Africa: model-based evaluation intervention strategies.PLoS Med. 2010; 7e1000324Crossref PubMed Scopus (372) Google A would one way achieve further reductions burden. observation passive immunoglobulin (Ig) confers immunity suggests conceivable [3.Cohen S. al.Gamma-globulin acquired human malaria.Nature. 1961; 192: 733-737Crossref (1014) One candidate GlaxoSmithKline, RTS,S/AS01, circumsporozoite protein (CSP) progressed beyond III into pilot implementation This milestone provides important proof-of-principle approach; however, improvement required given RTS,S/AS01 affords only partial protection modest duration [4.Olotu A. al.Seven-year among young African children.N. Engl. J. 2016; 374: 2519-2529Crossref (241) Nonetheless, success gives strong impetus continued effort investment develop vaccine. Currently, awaits proof-of-concept substantially improved CSP-based vaccine, while whole-sporozoite strategies face challenges regard scalability, immunogenicity infants, breadth [5.Walk al.Modest heterologous after sporozoite immunization: double-blind randomized controlled trial.BMC 2017; 15168–168Crossref (58) Scholar,6.Steinhardt L.C. al.Safety, tolerability, administered direct venous inoculation infants children: findings age de-escalation, dose-escalation, double-blind, study Western Kenya.Clin. Infect. Dis. 2019; ciz925PubMed An alternative complementary approach include subsequent pathogenic infection; death, disease, transmission. focuses recently described complex, elongated trimer formed surface binds erythrocyte basigin, new promising (see Glossary) (Figure 1A ). It outlines structure function each component, available data vitro animal-model efficacy, well immunogenicity. Though six species cause humans, these six, RH5 unique falciparum, orthologues CyRPA Ripr present [7.Galaway F. al.Resurrection ancestral invasion ligand molecular explanation origin humans.PLoS Biol. 17e3000490Crossref (26) responsible largest portion deaths subject review. Going forward, any reference 'malaria' refer malaria, unless otherwise specified. mainstay target invasive [8.Draper S.J. al.Malaria vaccines: advances horizons.Cell Host Microbe. 2018; 24: 43-56Abstract Full Text PDF (158) Unlike not necessarily need provide sterile infection, although ultimate goal efforts. Rather, sustained high-level parasitaemia prevent death episodes – potentially making immense contribution Moreover, rodent non-human primate models vaccine-controlled infection also suggest residual parasites ultimately cleared (likely via naturally immune responses) [9.Douglas A.D. al.A PfRH5-based efficacious strain aotus monkeys.Cell 2015; 17: 130-139Abstract (137) Scholar,10.Langhorne al.Immunity malaria: questions than answers.Nat. Immunol. 2008; 9: 725-732Crossref (616) distinction, then, between successful unsuccessful categorical based presence/absence but necessitate monitoring Historically, two obstacles prevented anti-merozoite parasite's reliance redundant host–pathogen interactions, pathways if blocked, polymorphism ligands, strain-specific immunity. latter was seen once-leading apical membrane antigen 1 (AMA1), conferred due its polymorphic nature [11.Thera M.A. trial assess vaccine.N. 2011; 365: 1004-1013Crossref (265) appear overcome conserved complex. Further speed cycle. former necessitates high concentration antibody, must act short window opportunity Scholar,12.Saul Kinetic constraints vaccine.Parasite 1987; 1-9Crossref (60) Scholar], multi-stage, multi-host cell makes expression compelling ephemeral, restricted spatially temporally over course Indeed, likelihood, rely multiple components different (Box 1) Scholar,13.Ewer K.J. al.Progress viral vectored multi-stage involving 'unnatural immunity'.Vaccine. 33: 7444-7451Crossref (42) Scholar, 14.Boes al.Analysis multi-component tackling cocktail challenge.PLoS One. 10e0131456Crossref (33) 15.Theisen M. both asexual life-cycle stages.Vaccine. 2014; 32: 2623-2630Crossref (75) Scholar].Box 1Erythrocyte InvasionP. begins injection sporozoites bloodstream Anopheles mosquito meal. migrate liver where they invade hepatocytes. Within liver, replicate asexually before being released approximately 7 days later. symptoms malaria. During progress ring-stage trophozoites schizonts egress 48 h initial invasion, releasing merozoites blood.Erythrocyte reviewed depth [35.Cowman A.F. al.The basis parasites.Cell 22: 232-245Abstract (147) Scholar] summarized briefly. cellular event significant perspective because it few times directly exposed system, thereby providing brief illness may averted.Host occurs steps: attachment, tight-junction formation, invasion. Initial attachment likely mediated proteins (MSPs). Following low-affinity tight occurs, erythrocyte-binding-like (EBL) reticulocyte-binding-like homolog (RH) gene families Subsequently, reorients, enabling deformation host receptor associated within [24.Volz J.C. al.Essential role PfRh5/PfRipr/CyRPA erythrocytes.Cell 20: 60-71Abstract (110) Scholar,27.Crosnier C. al.Basigin falciparum.Nature. 480: 534-537Crossref (447) Next comes formation junction. Here, supplies own inserting rhoptry neck (RONs) red membrane, then bound AMA1 Scholar,74.Srinivasan al.Binding RON2 triggers commitment invasion.Proc. Natl. Acad. Sci. U. 108: 13275-13280Crossref (207) 75.Healer al.Independent translocation micronemal merozoites.Infect. Immun. 2002; 70: 5751-5758Crossref (140) 76.Alexander D.L. al.Identification moving junction Toxoplasma gondii: collaboration distinct secretory organelles.PLoS Pathog. 2005; 1e17Crossref (331) Scholar].Invasion concludes propulsion end rearward actin-myosin motor [77.Keeley Soldati D. glideosome: machine powering motility host-cell Apicomplexa.Trends Cell 2004; 14: 528-532Abstract (174) engulfment parasitophorous vacuole. entire process completed 30 s, meaning narrow averted [78.Gilson P.R. Crabb B.S. Morphology kinetics phases merozoites.Int. Parasitol. 2009; 39: 91-96Crossref Once inside erythrocyte, divides schizogony 16–32 per infected [79.Cowman Invasion cells parasites.Cell. 2006; 124: 755-766Abstract (663) release begin fresh round blood. Erythrocyte averted. currently antigen. identified member PfRH family through homology-based search [16.Rodriguez al.PfRH5: novel reticulocyte-binding investigation receptor.PLoS 3e3300Crossref (78) linkage analysis [17.Hayton K. al.Erythrocyte binding polymorphisms determine species-specific invasion.Cell 4: 40-51Abstract (186) 63 kDa expressed mature schizont stages, localized rhoptries [18.Chen L. al.An EGF-like forms PfRh5 erythrocytes falciparum.PLoS 7e1002199Crossref (106) Scholar,19.Baum al.Reticulocyte-binding homologue 5 adhesin falciparum.Int. 371-380Crossref (183) processed cleaved 45 form, subsequently shed culture supernatant reveals kite-like architecture coming together three-helical bundles [20.Wright K.E. al.Structure basigin blocking antibodies.Nature. 515: 427-430Crossref (142) Scholar,21.Chen al.Crystal PfRh5, erythrocytes.eLife. 3e04187Crossref (49) same fold vivax 2a (RBP2a) ligand, demonstrating versatile properties [22.Gruszczyk al.Structurally erythrocyte-binding domain scaffold alternate engagement.Proc. 113: E191-E200Crossref (38) lacks transmembrane or glycosylphosphatidylinositol (GPI) anchor. Initially, cysteine-rich protective (PfCyRPA) thought anchor surface; since shown GPI [23.Reddy K.S. al.Multiprotein GPI-anchored crucial 112: 1179-1184Crossref (111) 24.Volz 25.Galaway al.P113 N terminus RH5.Nat. Commun. 8: 14333Crossref (45) P113, protein, thereafter bind terminus, suggesting possible [25.Galaway complicated P113 associate PTEX translocon, alongside additional, seemingly unrelated, biological [26.Elsworth B. al.Proteomic exporter loss stability upon truncation core PTEX150.Cell. Microbiol. 18: 1551-1569Crossref (52) needed understand whether targeted antibodies. [27.Crosnier As such, refractory genetic deletion Intriguingly, found other belonging Lavarenia subgenus, includes infect chimpanzees gorillas, indicating Scholar,17.Hayton Scholar,28.Knuepfer E. al.Divergent roles components, RIPR human-infective parasites.PLoS 15e1007809Crossref (17) Genomic 8 kb stretch DNA encoding gorilla alderi ancestor emergence lethal [29.Sundararaman S.A. al.Genomes cryptic chimpanzee reveal key evolutionary events leading malaria.Nat. 711078–11078Crossref (92) Scholar,30.Otto T.D. subgenus paths virulent 3: 687-697Crossref (83) defining species-specificity binding, determining infectivity [31.Wanaguru al.RH5-Basigin interaction plays major tropism falciparum.Proc. 2013; 110: 20735-20740Crossref (80) 32.Hayton al.Various support owl monkeys rats.Mol. Biochem. 187: 103-110Crossref (27) 33.Arevalo-Pinzon G. single amino acid change (PfRH5) RBC sequence modifies determines activity.Vaccine. 2012; 30: 637-646Crossref (14) 34.Plenderleith L.J. al.Adaptive evolution ape Laverania subgenus.mBio. 9e02237-17Crossref (10) In acting downstream Scholar,35.Cowman Binding blocked when attempt presence anti-PfRH5, anti-PfRipr, anti-basigin soluble correlated echinocytosis, conflicting recombinant able elevated intracellular concentrations Scholar,36.Aniweh Y. al.P. RH5-Basigin induces changes cytoskeleton RBC.Cell. 19e12747Crossref model that, inserts unfolds, forming pore [37.Wong W. Rh5–CyRPA–Ripr complex.Nature. 565: 118-121Crossref (50)

Язык: Английский

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Recent advances in therapeutic applications of neutralizing antibodies for virus infections: an overview

Immunologic Research, Год журнала: 2020, Номер 68(6), С. 325 - 339

Опубликована: Ноя. 8, 2020

Язык: Английский

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Heterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Май 4, 2021

Abstract Immunization with Plasmodium falciparum (Pf) sporozoites under chemoprophylaxis (PfSPZ-CVac) is the most efficacious approach to malaria vaccination. Implementation hampered by a complex regimen and missing evidence for efficacy against heterologous infection. We report results of double-blinded, randomized, placebo-controlled trial simplified, condensed immunization in malaria-naive volunteers (EudraCT-Nr: 2018-004523-36). Participants are immunized direct venous inoculation 1.1 × 10 5 aseptic, purified, cryopreserved PfSPZ (PfSPZ Challenge) PfNF54 strain or normal saline (placebo) on days 1, 6 29, simultaneous oral administration mg/kg chloroquine base. Primary endpoints vaccine tested controlled human infection (CHMI) using highly divergent, Pf7G8 safety. Twelve weeks following immunization, 10/13 participants group sterilely protected CHMI, while (5/5) receiving placebo develop parasitemia (risk difference: 77%, p = 0.004, Boschloo’s test). well tolerated self-limiting grade 1–2 headaches, pyrexia fatigue that diminish each induces 18-fold higher anti-Pf circumsporozoite protein (PfCSP) antibody levels than unprotected vaccinees (p 0.028). In addition anti-PfMSP2 antibodies strongly protection-associated microarray assessment. This PfSPZ-CVac efficacious, simple, safe, immunogenic.

Язык: Английский

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