Epitope Analysis of Anti-SARS-CoV-2 Neutralizing Antibodies

Abstract

Coronavirus disease 2019 is threatening thousands of millions of people around the world. In the absence of specific and highly effective medicines, the treatment of infected persons is still very challenging. As therapeutics, neutralizing antibodies (NAbs) have great potential. Many NAbs have been reported, and most target various regions on the receptor-binding domain of the spike (S) protein, or the N-terminal domain. Several NAbs and NAb cocktails have been authorized for emergency use, and more are in clinical trials or are under development. In this review, considering the angle of binding epitopes on the S protein, we summarize the functions and the underlying mechanisms of a set of well-recognized NAbs and provide guidance for vaccine design and the combinatorial use of these antibodies. In addition, we review the NAbs and NAb cocktails that have been approved for emergency use and discuss the effectiveness of these NAbs for combating severe acute respiratory syndrome coronavirus 2 mutants.

Keywords

coronavirus disease 2019 / severe acute respiratory syndrome coronavirus 2 / neutralizing antibody / epitope / therapeutics / vaccine

References

[1] BeigelJH, TomashekKM, DoddLE. Remdesivir for the Treatment of Covid-19-Preliminary Report. Reply. New Engl J Med, 2020, 383(10): 994

[2] GroupRC. Dexamethasone in hospitalized patients with Covid-19. New Engl J Med, 2021, 384(8): 693-704

[3] ShenC, WangZ, ZhaoF, et al.. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA, 2020, 323(16): 1582-1589

[4] SimonovichVA, Burgos PratxLD, ScibonaP, et al.. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med, 2021, 384(7): 619-629

[5] StanworthS. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomized controlled trial. Transfus Med, 2020, 371: m3939

[6] FinkelsteinMT, MermelsteinAG, Parker MillerE, et al.. Structural Analysis of Neutralizing Epitopes of the SARS-CoV-2 Spike to Guide Therapy and Vaccine Design Strategies. Viruses, 2021, 13(1): 134

[7] HuangY, SunH, YuH, et al.. Neutralizing antibodies against SARS-CoV-2: current understanding, challenge and perspective. Antib Ther, 2020, 3(4): 285-299

[8] CortiD, PurcellLA, SnellG, et al.. Tackling COVID-19 with neutralizing monoclonal antibodies. Cell, 2021, 184(17): 4593-4595

[9] ZhouH, ChenY, ZhangS, et al.. Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein. Nat Commun, 2019, 10(1): 3068

[10] WrappD, WangN, CorbettKS, et al.. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 2020, 367(6483): 1260-1263

[11] CaiY, ZhangJ, XiaoT, et al.. Distinct conformational states of SARS-CoV-2 spike protein. Science, 2020, 369(6511): 1586-1592

[12] WallsAC, TortoriciMA, SnijderJ, et al.. Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion. Proc Natl Acad Sci USA, 2017, 114(42): 11 157-11 162

[13] ZangR, Gomez CastroMF, McCuneBT, et al.. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol, 2020, 5(47): eabc3582

[14] WallsAC, ParkYJ, TortoriciMA, et al.. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, 2020, 181(2): 281-292 e6

[15] HoffmannM, Kleine-WeberH, SchroederS, et al.. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 2020, 181(2): 271-280 e8

[16] GlowackaI, BertramS, MullerMA, et al.. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol, 2011, 85(9): 4122-4134

[17] ShullaA, Heald-SargentT, SubramanyaG, et al.. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol, 2011, 85(2): 873-882

[18] HsiehCL, GoldsmithJA, SchaubJM, et al.. Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. Science, 2020, 369(6510): 1501-1505

[19] WhiteJM, DelosSE, BrecherM, et al.. Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit Rev Biochem Mol Biol, 2008, 43(3): 189-219

[20] BarnesCO, WestAP, Huey-TubmanKE, et al.. Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies. Cell, 2020, 182(4): 828-842 e16

[21] KreyeJ, ReinckeSM, KornauHC, et al.. A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model. Cell, 2020, 183(4): 1058-1069 e19

[22] ShiR, ShanC, DuanX, et al.. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature, 2020, 584(7819): 120-124

[23] WuY, WangF, ShenC, et al.. A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science, 2020, 368(6496): 1274-1278

[24] MeulenJT, van den BrinkEN, PoonLLM, et al.. Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants. PLoS Med, 2006, 3(7): e237

[25] HuoJ, ZhaoY, RenJ, et al.. Neutralization of SARS-CoV-2 by destruction of the prefusion Spike. Cell Host Microbe, 2020, 28(3): 445-454 e6

[26] ZhouD, DuyvesteynHME, ChenCP, et al.. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat Struct Mol Biol, 2020, 27(10): 950-958

[27] WrappD, DeVliegerD, CorbettKS, et al.. Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies. Cell, 2020, 181(5): 1004-1015 e15

[28] LvZ, DengYQ, YeQ, et al.. Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody. Science, 2020, 369(6510): 1505-1509

[29] CaoY, SuB, GuoX, et al.. Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells. Cell, 2020, 182(1): 73-84

[30] TortoriciMA, BeltramelloM, LemppFA, et al.. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Science, 2020, 370(6519): 950-957

[31] LiuL, WangP, NairMS, et al.. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature, 2020, 584(7821): 450-456

[32] JuB, ZhangQ, GeJ, et al.. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature, 2020, 584(7819): 115-119

[33] CustodioTF, DasH, ShewardDJ, et al.. Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2. Nat Commun, 2020, 11(1): 5588

[34] Pinto D, Park YJ, Beltramello M, et al. Structural and functional analysis of a potent sarbecovirus neutralizing antibody. bioRxiv, 2020,04.07.023903

[35] ChiX, YanR, ZhangJ, et al.. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science, 2020, 369(6504): 650-655

[36] WangS, QiuZY, HouYN, et al.. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Research, 2021, 31(2): 126-140

[37] Zhang L, Cao L, Gao X, et al. A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2. bioRxiv, 2020.

[38] PlanteJA, LiuY, LiuJ, et al.. Spike mutation D614G alters SARS-CoV-2 fitness. Nature, 2021, 592(7852): 116-121

[39] KorberB, FischerWM, GnanakaranS, et al.. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell, 2020, 182(4): 812-827 e19

[40] KiddM, RichterA, BestA, et al.. S-variant SARS-CoV-2 lineage B1. 1.7 is associated with significantly higher viral loads in samples tested by ThermoFisher TaqPath RT-qPCR. J Infect Dis, 2021, 223(10): 1666-1670

[41] MwendaM, SaasaN, SinyangeN, et al.. Detection of B.1.351 SARS-CoV-2 Variant Strain — Zambia, December 2020. Morb Mortal Weekly Rep, 2021, 70(8): 280-282

[42] da Silva FranciscoRJr, BenitesLF, LamarcaAP, et al.. Pervasive transmission of E484K and emergence of VUI-NP13L with evidence of SARS-CoV-2 co-infection events by two different lineages in Rio Grande do Sul, Brazil. Virus Res, 2021, 296: 198-345

[43] HoffmannM, AroraP, GrossR, et al.. SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell, 2021, 184(9): 2384-2393 e12

[44] CherianS, PotdarV, JadhavS, et al.. Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India. bioRxiv, 2021, 9(7): 1542

[45] Yadav PD, Sapkal GN, Abraham P, et al. Neutralization of variant under investigation B.1.617 with sera of BBV152 vaccinees. Clin Infect Dis, 2021:ciab411

[46] SinghJ, RahmanSA, EhteshamNZ, et al.. SARS-CoV-2 variants of concern are emerging in India. Nat Med, 2021, 27(7): 1131-1133

[47] PronkerES, WeenenTC, CommandeurH, et al.. Risk in vaccine research and development quantified. PLoS One, 2013, 8(3): e57755

[48] LeTT, CramerJP, ChenR, et al.. Evolution of the COVID-19 vaccine development landscape. Nat Rev Drug Discov, 2020, 19(10): 667-668

[49] Qi H, Ma M, Hu C, et al. Antibody binding epitope Mapping (AbMap) of hundred antibodies in a single run. Mol Cell Proteomics, 2021:100 059

[50] LiY, LaiDY, ZhangNH, et al.. Linear epitopes of SARS-CoV-2 spike protein elicit neutralizing antibodies in COVID-19 patients. Cell Mol Immunol, 2020, 17(10): 1095-1097

[51] ShiR, ShanC, DuanX, et al.. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature, 2020, 584(7819): 120-124

[52] HurlburtNK, SeydouxE, WanYH, et al.. Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation. Nat Commun, 2020, 11(1): 5413

[53] RogersTF, ZhaoR, HuangD, et al.. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science, 2020, 369(6506): 956-963

[54] DuS, CaoY, ZhuQ, et al.. Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy. Cell, 2020, 183(4): 1013-1023 e13

[55] Wu NC, Yuan M, Liu H, et al. An alternative binding mode of IGHV3-53 antibodies to the SARS-CoV-2 receptor binding domain. bioRxiv, 2020:2020.07.26.222232

[56] HansenJ, BaumA, PascalKE, et al.. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science, 2020, 369(6506): 1010-1014

[57] PiccoliL, ParkYJ, TortoriciMA, et al.. Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology. Cell, 2020, 183(4): 1024-1042 e21

[58] HuoJ, ZhaoY, RenJ, et al.. Neutralization of SARS-CoV-2 by destruction of the prefusion spike. Cell Host Microbe, 2020, 28(3): 445-454 e6

[59] PintoD, ParkYJ, BeltramelloM, et al.. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature, 2020, 583(7815): 290-295

[60] HuoJ, Le BasA, RuzaRR, et al.. Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2. Nat Struct Mol Biol, 2020, 27(9): 846-854

[61] HankeL, Vidakovics PerezL, ShewardDJ, et al.. An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction. Nat Commun, 2020, 11(1): 4420

[62] BarnesCO, JetteCA, AbernathyMF, et al.. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature, 2020, 588(7839): 682-687