key: cord-0700247-uhz07bub authors: Gruell, Henning; Vanshylla, Kanika; Weber, Timm; Barnes, Christopher O.; Kreer, Christoph; Klein, Florian title: Antibody-Mediated Neutralization of SARS-CoV-2 date: 2022-05-13 journal: Immunity DOI: 10.1016/j.immuni.2022.05.005 sha: fea3c4e461959726114a0dfecb05babbacecaf95 doc_id: 700247 cord_uid: uhz07bub Neutralizing antibodies can block infection, clear pathogens, and are essential to provide long-term immunity. Since the onset of the pandemic, SARS-CoV-2 neutralizing antibodies have been comprehensively investigated and critical information on their development, function, and potential use to prevent and treat COVID-19 have been revealed. With the emergence of SARS-CoV-2 immune escape variants, humoral immunity is being challenged, and a detailed understanding of neutralizing antibodies is essential to guide vaccine design strategies as well as antibody-mediated therapies. In this review, we summarize some of the key findings on SARS-CoV-2 neutralizing antibodies with a focus on their clinical application. After emerging in December 2019, the severe acute respiratory syndrome coronavirus 2 27 (SARS-CoV-2) rapidly spread across the globe sampling time points differed between individual trials, the vaccine-and trial-specific 294 levels of reported protection strongly correlated with induced neutralizing activity 295 (Khoury et al., 2021) . Vaccine-induced neutralizing titers that were ~20% of those found 296 in convalescent individuals were associated with ~50% protection from symptomatic 297 infection, while ~90% and ~95% of protective efficacy was modeled for neutralizing 298 titers of around 2-and 4-fold of those seen in convalescent individuals, respectively 299 (Khoury et al., 2021 CoV-2-neutralizing monoclonal antibodies occurred at a remarkable pace with first 504 human dosing within <6 months of the start of pandemic (Lilly, 2020) . Since then, 505 monoclonal antibodies have been investigated in clinical trials focusing on different 506 target populations (Figures 3A and B) . These included infected patients at early and late 507 stages of disease, individuals with recent exposure to the virus, and uninfected 508 participants receiving antibodies as pre-exposure prophylaxis ( Figure 3A) . While the 509 trial outcomes were largely dependent on the clinical scenarios, the results for different 510 antibodies tested within comparable study settings were highly consistent. Across trials, 511 SARS-CoV-2 neutralizing monoclonal antibodies were overall safe and well tolerated, and 512 pharmacokinetic parameters of unmodified antibodies were within in the expected range Upon encountering the SARS-CoV-2 spike protein, the human immune system is able to 591 generate potent neutralizing antibodies that represent one of our strongest assets to 592 prevent and treat COVID-19. High incidences of SARS-CoV-2 infections and immune-593 mediated selection pressure will drive continuous viral evolution and the emergence of 594 SARS-CoV-2 immune escape variants. While this will challenge antibody-mediated 595 immunity, recent advances in knowledge and techniques allow to effectively prepare a 596 potent antibody response to a more diverse and changing viral threat. This includes 597 adapted vaccine strategies to induce a broad SARS-CoV-2 humoral immunity and the 598 rapid isolation and development of potent cross-neutralizing SARS-CoV-2 monoclonal 599 antibodies for passive immunization. Since immune escape variants may emerge very 600 rapidly, it will be critical to enable neutralizing antibodies to target a broad spectrum of 601 viral variants. This may be achieved, for example, by vaccination strategies exposing to a 602 wider spectrum of SARS-CoV-2 variants and by using combinations of highly broadly 603 neutralizing antibodies for passive immunization. Finally, administrative and regulatory 604 aspects should be prepared to allow for a rapid response to new variants providing 605 neutralizing antibodies by active or passive immunization to protect individuals at risk 606 and to overcome the COVID-19 pandemic. 607 608 L 1 8 F T 1 9 R /I * T 2 0 N L 2 4 S Δ 2 5 -2 7 P 2 6 S A 6 7 V Δ 6 9 -7 0 D 8 0 A T 9 5 I D 1 3 8 Y G 1 4 2 D Δ 1 4 3 -1 4 5 Δ 1 4 4 E 1 5 6 G Δ 1 5 7 /1 5 8 R 1 9 0 S N 2 1 1 I V 2 1 3 G in s 2 1 4 E P E D 2 1 5 G Δ 2 4 1 -2 4 3 G 3 3 9 D S 3 7 1 L /F * S 3 7 3 P S 3 7 5 F T 3 7 6 A D 4 0 5 N R 4 0 8 S K 4 1 7 N /T * N 4 4 0 K L 4 5 2 R S 4 7 7 N T 4 7 8 K E 4 8 4 A /K * Q 4 9 3 R G 4 9 6 S Q 4 9 8 R N 5 0 1 Y Y 5 0 5 H T 5 4 7 K A 5 7 0 D D 6 1 4 G H 6 5 5 Y N 6 7 9 K P 6 8 1 H /R * A 7 0 1 V T 7 1 6 I N 7 6 4 K D 7 9 6 Y N 8 5 6 K D 9 5 0 N Q 9 5 4 H N 9 6 9 K L 9 8 1 F S 9 8 2 A T 1 0 2 7 I D 1 1 1 8 H V 1 1 7 6 F G 4 4 6 S Effect of mRNA Vaccine 688 Boosters against SARS-CoV-2 Omicron Infection in Qatar Waning mRNA-1273 Vaccine Effectiveness against SARS-CoV-2 Infection in 691 Qatar ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and 694 BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised 695 controlled trial. The Lancet Infectious Diseases A Neutralizing Monoclonal Antibody for 697 Hospitalized Patients with Covid-19 Responses to a Neutralizing 699 Monoclonal Antibody for Hospitalized Patients With COVID-19 According to Baseline 700 Antibody and Antigen Levels : A Randomized Controlled Trial B cell memory: building two walls of 703 protection against pathogens SARS-CoV-2 mRNA vaccination induces 706 functionally diverse antibodies to NTD, RBD, and S2 Duration of humoral immunity to 708 common viral and vaccine antigens Seasonal human coronavirus 711 antibodies are boosted upon SARS-CoV-2 infection but not associated with protection Extremely potent human monoclonal 715 antibodies from COVID-19 convalescent patients Protect Against Lower Respiratory Tract Disease in a Hamster Model Protection against SARS-CoV-2 after Covid-19 990 Vaccination and Previous Infection Delayed-interval BNT162b2 mRNA 993 COVID-19 vaccination enhances humoral immunity and induces robust T cell responses Intranasal Administration of a Monoclonal 997 Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection Nirsevimab for Prevention of RSV in Healthy 1000 Late-Preterm and Term Infants Studies in humanized mice and convalescent humans yield 1003 a SARS-CoV-2 antibody cocktail SARS-CoV-2 variants, 1006 spike mutations and immune escape Defining variant-resistant epitopes targeted by 1009 SARS-CoV-2 antibodies: A global consortium study Follicular dendritic cells: dynamic 1011 antigen libraries Safety, reactogenicity, and 1014 immunogenicity of homologous and heterologous prime-boost immunisation with 1015 ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study A Multibasic Cleavage Site in 1018 the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells SARS-CoV-2 Cell Entry 1022 Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor SARS-CoV-2 D614G variant exhibits efficient 1026 replication ex vivo and transmission in vivo Neutralization of SARS-CoV-2 by Destruction of 1029 the Prefusion Spike Antibody evasion properties of SARS-CoV-2 Omicron sublineages Assessing human B cell repertoire diversity and 1033 convergence Persistence and decay of human 1036 antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in 1037 COVID-19 patients An mRNA 1040 Vaccine against SARS-CoV-2 -Preliminary Report Isolation and characterization of cross-1043 neutralizing coronavirus antibodies from COVID-19+ subjects Emergence of the E484K 1046 mutation in SARS-COV-2-infected immunocompromised patients treated with 1047 bamlanivimab in Germany Broad cross-1050 reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived 1051 neutralizing antibodies The neutralizing 1054 antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates Control of human viral infections by natural killer cells Convalescent Plasma Antibody 1060 Levels and the Risk of Death from Covid-19 Early safety indicators of 1063 COVID-19 convalescent plasma in 5000 patients Human neutralizing antibodies elicited by SARS-CoV-2 infection FcgammaR-mediated SARS-CoV-2 1068 infection of monocytes activates inflammation Loss of Bcl-6-Expressing 1071 T Follicular Helper Cells and Germinal Centers in COVID-19 Early cross-coronavirus reactive signatures of 1074 humoral immunity against COVID-19 Structures and distributions of SARS-CoV-2 spike proteins on 1077 intact virions Prior infection with 1080 SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant-dependent 1081 manner Antibody Responses 1084 to SARS-CoV-2 mRNA Vaccines Are Detectable in Saliva GISAID's Role in Pandemic Response Neutralizing antibody levels are highly 1089 predictive of immune protection from symptomatic SARS-CoV-2 infection Measuring immunity to SARS-CoV-1093 2 infection: comparing assays and animal models A therapeutic neutralizing antibody targeting receptor binding domain of 1096 SARS-CoV-2 spike protein Safety, Virologic Efficacy, and 1099 Pharmacokinetics of CT-P59, a Neutralizing Monoclonal Antibody Against SARS-CoV Placebo-Controlled, Phase I Studies in 1101 Healthy Individuals and Patients With Mild SARS-CoV-2 Infection Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein 1105 receptor binding domain in patients with COVID-19 and healthy individuals Germinal centre-driven maturation of B cell 1109 response to mRNA vaccination Antibodies in HIV-1 vaccine development and therapy Enhanced neonatal Fc receptor function improves protection 1114 against primate SHIV infection Tracking Changes in SARS-CoV-2 1117 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus Early Convalescent Plasma 1121 for High-Risk Outpatients with Covid-19 Longitudinal Isolation of Potent 1124 Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients A Therapeutic Non-self-reactive SARS-CoV-2 1128 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model WHO International Standard for anti-SARS-CoV-2 immunoglobulin. 1132 The Lancet Breakthrough infections with 1135 SARS-CoV-2 omicron despite mRNA vaccine booster dose Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 1138 receptor A single intramuscular injection of monoclonal 1141 antibody MAD0004J08 induces in healthy adults SARS-CoV-2 neutralising antibody titres 1142 exceeding those induced by infection and vaccination Germinal center 1145 responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised 1146 individuals Antibody-dependent 1148 enhancement and SARS-CoV-2 vaccines and therapies Lectins enhance SARS-CoV-2 infection and 1151 influence neutralizing antibodies Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months Intramuscular AZD7442 Cilgavimab) for Prevention of Covid-19 In vitro and in vivo functions of SARS-CoV-2 1160 infection-enhancing and neutralizing antibodies The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity Pharmacokinetics, and Immunogenicity of a Monoclonal Antibody 1166 (SCTA01) Targeting SARS-CoV-2 in Healthy Adults: a Randomized, Double-Blind, 1167 Placebo-Controlled, Phase I Study Early High-Titer Plasma Therapy to 1170 Prevent Severe Covid-19 in Older Adults Press Release: Lilly Begins World's First Study of a Potential Antibody Treatment in Humans 1.617 by vaccine and convalescent serum Striking antibody evasion manifested by the Omicron variant of SARS-CoV-1180 2 Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 1183 spike Identification of SARS-CoV-2 spike 1186 mutations that attenuate monoclonal and serum antibody neutralization Antibody responses to SARS-CoV-2 in patients with COVID-19 The SARS-CoV-2 monoclonal antibody 1193 combination, AZD7442, is protective in nonhuman primates and has an extended half-life 1194 in humans Effectiveness of Covid-19 Vaccines against 1197 the B.1.617.2 (Delta) Variant Delayed production of neutralizing antibodies correlates with fatal 1200 COVID-19 Serological Assays Estimate 1203 Highly Variable SARS-CoV-2 Neutralizing Antibody Activity in Recovered COVID-19 Efficacy of the Covid-19 Vaccine against the B.1.351 Variant A broadly cross-reactive antibody neutralizes and protects 1210 against sarbecovirus challenge in mice Prevention and therapy of SARS-CoV-2 and the B.1.351 1213 variant in mice N-terminal domain antigenic mapping reveals 1216 a site of vulnerability for SARS-CoV-2 Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive 1219 antibody escape Correlates of protection against SARS-CoV-2 in 1222 rhesus macaques Safety, tolerability, pharmacokinetic characteristics, and immunogenicity of 1225 MW33: a Phase 1 clinical study of the SARS-CoV-2 RBD-targeting monoclonal antibody Single-shot Ad26 vaccine protects against 1229 SARS-CoV-2 in rhesus macaques SARS-CoV-2 B.1.617.2 Delta variant replication and 1232 immune evasion Temporal maturation of 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Subcutaneous Casirivimab and 1270 Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-1271 19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial SARS-CoV-2 Omicron Variant Neutralization after 1275 mRNA-1273 Booster Vaccination CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 1279 booster vaccination Mapping Neutralizing and 1282 Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-1283 Guided High-Resolution Serology Cross-neutralization of SARS-CoV-2 by a human 1286 monoclonal SARS-CoV antibody Broad betacoronavirus neutralization 1289 by a stem helix-specific human antibody Considerable escape of 1292 SARS-CoV-2 Omicron to antibody neutralization CoV-2 variant Delta to antibody neutralization Correlates of protection induced by vaccination Hyperimmune immunoglobulin 1300 for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, 1301 phase 3, randomised trial Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing 1304 Activity in Prepandemic Sera From Individuals With Recent Seasonal Coronavirus 1305 Infection The receptor binding domain of 1308 the viral spike protein is an immunodominant and highly specific target of antibodies in 1309 SARS-CoV-2 patients Broad and potent activity 1312 against SARS-like viruses by an engineered human monoclonal antibody Casirivimab-Imdevimab treatment is 1316 associated with reduced rates of hospitalization among high-risk patients with mild to 1317 moderate coronavirus disease-19 Convalescent plasma in patients admitted to 1319 hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform 1320 trial Casirivimab and imdevimab in patients 1322 admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, 1323 platform trial Prior SARS-CoV-2 infection 1326 rescues B and T cell responses to variants after first vaccine dose CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and 1330 Reveal Durable Humoral Immunity Convergent antibody responses to 1333 SARS-CoV-2 in convalescent individuals Resistance Mutations in SARS-CoV-2 Delta 1336 Variant after Sotrovimab Use Isolation of potent SARS-CoV-2 neutralizing antibodies and 1339 protection from disease in a small animal model Immune imprinting, breadth of variant recognition, 1342 and germinal center response in human SARS-CoV-2 infection and vaccination Defining the features and duration of antibody 1345 responses to SARS-CoV-2 infection associated with disease severity and outcome Antigen-Specific Adaptive 1349 Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease 1350 Severity Antibody potency, effector 1353 function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo B cell genomics behind cross-1357 neutralization of SARS-CoV-2 variants and SARS-CoV Plasma Neutralization of the 1360 SARS-CoV-2 Omicron Variant High genetic barrier to SARS-CoV-1363 2 polyclonal neutralizing antibody escape A vaccine-induced public antibody protects 1366 against SARS-CoV-2 and emerging variants Longitudinal observation and decline of 1369 neutralizing antibody responses in the three months following SARS-CoV-2 infection in 1370 humans Analysis of a SARS-CoV-2-Infected 1373 Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic 1374 Mutation Structural basis of receptor recognition by SARS-CoV-2 A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2 CoV-2 Neutralization Assays GISAID: Global initiative on sharing all influenza data -1384 from vision to reality A Randomized Trial of 1387 Convalescent Plasma in Covid-19 Severe Pneumonia How an outbreak became a pandemic: a 1390 chronological analysis of crucial junctures and international obligations in the early 1391 months of the COVID-19 pandemic Distinct systemic and mucosal immune responses 1394 during acute SARS-CoV-2 infection The N-terminal domain of spike glycoprotein mediates SARS-CoV-1397 2 infection by associating with L-SIGN and DC-SIGN Maturation and persistence of 1400 the anti-SARS-CoV-2 memory B cell response Cross-reactive serum and memory B-cell responses 1403 to spike protein in SARS-CoV-2 and endemic coronavirus infection mRNA vaccination boosts cross-1407 variant neutralizing antibodies elicited by SARS-CoV-2 infection SARS-CoV-2 RBD antibodies that maximize 1410 breadth and resistance to escape Prospective mapping of viral mutations that escape antibodies 1413 used to treat COVID-19 Complete map of SARS-1415 CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail 1416 with LY-CoV016 S Vaccine for COVID-19 IgA dominates the early neutralizing antibody 1422 response to SARS-CoV-2 Immunogenicity, safety, and 1425 reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, 1426 viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, 1427 randomised, phase 2, non-inferiority trial Neutralizing Monoclonal Antibodies 1430 That Target the Spike Receptor Binding Domain Confer Fc Receptor-Independent 1431 Protection against SARS-CoV-2 Infection in Syrian Hamsters Neutralizing and protective human 1434 monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike 1435 protein Rapid Generation of 1438 Neutralizing Antibody Responses in COVID-19 Patients Nanometer-resolution in situ structure of the SARS-CoV-2 postfusion spike 1441 protein Efficacy of Antiviral 1444 Agents against the SARS-CoV-2 Omicron Subvariant BA.2 Sequence signatures of two public antibody 1447 clonotypes that bind SARS-CoV-2 receptor binding domain Strong humoral immune responses 1450 against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a 16-week interval 1451 between doses Detection of a SARS-CoV-2 variant of concern 1454 in South Africa Cross-Variant Neutralizing Serum Activity 1457 after SARS-CoV-2 Breakthrough Infections Long-term immunogenicity of BNT162b2 1460 vaccination in older people and younger health-care workers Memory B cell repertoire for 1464 recognition of evolving SARS-CoV-2 spike Ultrapotent human antibodies protect 1467 against SARS-CoV-2 challenge via multiple mechanisms Effectiveness of mRNA-1273 against SARS-CoV-2 1470 Omicron and Delta variants SARS-CoV-2 infection induces long-lived bone 1473 marrow plasma cells in humans SARS-CoV-2 mRNA vaccines induce persistent 1476 human germinal centre responses Live imaging of SARS-CoV-2 infection in 1479 mice reveals that neutralizing antibodies require Fc function for optimal efficacy Neutralization of the SARS-CoV-1483 Mu Variant by Convalescent and Vaccine Serum 1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies Kinetics and correlates of 1490 the neutralizing antibody response to SARS-CoV-2 infection in humans Discovery of ultrapotent broadly 1494 neutralizing antibodies from SARS-CoV-2 elite neutralizers Durability of omicron-neutralising serum activity 1498 after mRNA booster immunisation in older adults Monoclonal antibodies protect aged rhesus 1502 macaques from SARS-CoV-2-induced immune activation and neuroinflammation CoV-2 Omicron variant in southern Africa Germinal Centers Prevalent, protective, and convergent IgG 1510 recognition of SARS-CoV-2 non-RBD spike epitopes Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein SARS-CoV-2 breakthrough 1516 infections elicit potent, broad, and durable neutralizing antibody responses Safety and Immunogenicity of Two RNA-1520 Based Covid-19 Vaccine Candidates A human monoclonal 1523 antibody blocking SARS-CoV-2 infection Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. 1526 Characterization of neutralizing antibody with prophylactic and therapeutic 1529 efficacy against SARS-CoV-2 in rhesus monkeys Analysis of memory B cells identifies conserved 1532 neutralizing epitopes on the N-terminal domain of variant SARS-Cov-2 spike proteins Naturally enhanced neutralizing 1536 breadth against SARS-CoV-2 one year after infection mRNA vaccine-elicited 1539 antibodies to SARS-CoV-2 and circulating variants Broad neutralization of SARS-related 1542 viruses by human monoclonal antibodies REGN-COV2, a Neutralizing Antibody Cocktail, in 1545 Outpatients with Covid-19 REGEN-COV Antibody Combination and 1548 Outcomes in Outpatients with Covid-19 Escape from neutralizing 1551 antibodies by SARS-CoV-2 spike protein variants LY-CoV1404 (bebtelovimab) potently 1554 neutralizes SARS-CoV-2 variants Human neutralizing antibodies against SARS-CoV-2 require 1557 intact Fc effector functions for optimal therapeutic protection Extrafollicular B cell responses correlate 1561 with neutralizing antibodies and morbidity in COVID-19 Cryo-EM structure of the 2019-nCoV spike in the prefusion 1564 conformation Three exposures to the spike protein of 1567 SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all 1568 variants of concern Antibody-mediated disruption of the SARS-CoV-2 1571 spike glycoprotein An Alternative Binding Mode of IGHV3-53 Antibodies 1574 to the SARS-CoV-2 Receptor Binding Domain A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to 1577 its receptor ACE2 Fc-engineered antibody therapeutics with 1580 improved anti-SARS-CoV-2 efficacy Structural basis for the 1582 recognition of SARS-CoV-2 by full-length human ACE2 Longitudinal analysis of antibody dynamics in COVID-19 convalescents reveals 1585 neutralizing responses up to 16 months after infection Molecular Architecture of the SARS-CoV-2 Virus DNA vaccine protection against SARS-1590 CoV-2 in rhesus macaques Structural basis of a shared antibody response to SARS-CoV-2 Recognition of the SARS-CoV-2 receptor 1595 binding domain by neutralizing antibodies A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and 1598 SARS-CoV Structural and Functional Analysis of 1601 the D614G SARS-CoV-2 Spike Protein Variant Enhanced antibody half-life improves in vivo 1604 activity Phase 1 Safety and Pharmacokinetics Studies of BRII-196 and BRII-198 CoV-2 Spike-Targeting Monoclonal Antibodies. medRxiv 1609 (2021b). Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine 1610 in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, 1611 phase 1/2 clinical trial Evidence of escape of SARS-CoV-2 1614 variant B.1.351 from natural and vaccine-induced sera A human antibody reveals a conserved site on beta-coronavirus 1617 spike proteins and confers protection against SARS-CoV-2 infection Enhancement versus neutralization by SARS-CoV-2 antibodies from a 1621 convalescent donor associates with distinct epitopes on the RBD Double lock of a potent human therapeutic monoclonal 1624 antibody against SARS-CoV-2 Compromised Humoral Functional Evolution Tracks with 1627 SARS-CoV-2 Mortality Potently neutralizing and protective human 1630 antibodies against SARS-CoV-2 Rapid isolation and profiling of a diverse panel 1633 of human monoclonal antibodies targeting the SARS-CoV-2 spike protein Neutralizing antibodies play a critical role to protect from SARS-CoV-2 infection and can be effectively used to prevent and treat COVID-19. In this review, Klein and colleagues summarize key findings on the development and mechanisms of SARS-CoV-2 neutralizing antibodies and discuss advances in the clinical application of antibody-mediated antiviral strategies.