scholarly journals Structural Basis for Accommodation of Emerging B.1.351 and B.1.1.7 Variants by Two Potent SARS-CoV-2 Neutralizing Antibodies

2021 ◽  
Author(s):  
Gabriele Cerutti ◽  
Micah Rapp ◽  
Yicheng Guo ◽  
Fabiana Bahna ◽  
Jude Bimela ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Structural Basis ◽  
Wild Type Virus ◽  
Receptor Binding Domain ◽  
Type Virus ◽  
Wild Type ◽  
Distinct Mechanism ◽  
The Uk

SummaryEmerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented a response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for both ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies like 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.

scholarly journals Vaccination with SARS-CoV-2 variants of concern protects mice from challenge with wild-type virus

PLoS Biology ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. e3001384
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Philip Meade ◽  
Nicholas Dambrauskas ◽  
Barbara Mühlemann ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Fold Reduction ◽  
Reactive Antibody

Vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have been highly efficient in protecting against Coronavirus Disease 2019 (COVID-19). However, the emergence of viral variants that are more transmissible and, in some cases, escape from neutralizing antibody responses has raised concerns. Here, we evaluated recombinant protein spike antigens derived from wild-type SARS-CoV-2 and from variants B.1.1.7, B.1.351, and P.1 for their immunogenicity and protective effect in vivo against challenge with wild-type SARS-CoV-2 in the mouse model. All proteins induced high neutralizing antibodies against the respective viruses but also induced high cross-neutralizing antibody responses. The decline in neutralizing titers between variants was moderate, with B.1.1.7-vaccinated animals having a maximum fold reduction of 4.8 against B.1.351 virus. P.1 induced the most cross-reactive antibody responses but was also the least immunogenic in terms of homologous neutralization titers. However, all antigens protected from challenge with wild-type SARS-CoV-2 in a mouse model.

scholarly journals Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

2021 ◽  
Vol 22 (11) ◽  
pp. 5464
Author(s):  
Stefano Borocci ◽  
Carmen Cerchia ◽  
Alessandro Grottesi ◽  
Nico Sanna ◽  
Ingrid Guarnetti Prandi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Structural Information ◽  
Conformational Transitions ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Dynamics Simulations ◽  
The Uk ◽  
The Impact

The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies.

scholarly journals Kinetics of Neutralizing Antibodies of COVID-19 Patients Tested Using Clinical D614G, B.1.1.7 and B 1.351 Isolates in Microneutralization Assays

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 996
Author(s):  
Jenni Virtanen ◽  
Ruut Uusitalo ◽  
Essi M. Korhonen ◽  
Kirsi Aaltonen ◽  
Teemu Smura ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Acute Infection ◽  
Clinical Isolates ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Kinetics Of

Increasing evidence suggests that some newly emerged SARS-CoV-2 variants of concern (VoCs) resist neutralization by antibodies elicited by the early-pandemic wild-type virus. We applied neutralization tests to paired recoveree sera (n = 38) using clinical isolates representing the first wave (D614G), VoC1, and VoC2 lineages (B.1.1.7 and B 1.351). Neutralizing antibodies inhibited contemporary and VoC1 lineages, whereas inhibition of VoC2 was reduced 8-fold, with 50% of sera failing to show neutralization. These results provide evidence for the increased potential of VoC2 to reinfect previously SARS-CoV-infected individuals. The kinetics of NAbs in different patients showed similar decline against all variants, with generally low initial anti-B.1.351 responses becoming undetectable, but with anti-B.1.1.7 NAbs remaining detectable (>20) for months after acute infection.

scholarly journals Structural Studies of Chikungunya Virus-Like Particles Complexed with Human Antibodies: Neutralization and Cell-to-Cell Transmission

2015 ◽  
Vol 90 (3) ◽  
pp. 1169-1177 ◽  
Author(s):  
Jason Porta ◽  
Vidya Mangala Prasad ◽  
Cheng-I Wang ◽  
Wataru Akahata ◽  
Lisa F. P. Ng ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Neutralizing Antibody ◽  
Mutant Virus ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Virus Like Particles ◽  
Fab Fragments ◽  
Cell Transmission ◽  
Viral Surface

ABSTRACTChikungunya virus is a positive-stranded RNA alphavirus. Structures of chikungunya virus-like particles in complex with strongly neutralizing antibody Fab fragments (8B10 and 5F10) were determined using cryo-electron microscopy and X-ray crystallography. By fitting the crystallographically determined structures of these Fab fragments into the cryo-electron density maps, we show that Fab fragments of antibody 8B10 extend radially from the viral surface and block receptor binding on the E2 glycoprotein. In contrast, Fab fragments of antibody 5F10 bind the tip of the E2 B domain and lie tangentially on the viral surface. Fab 5F10 fixes the B domain rigidly to the surface of the virus, blocking exposure of the fusion loop on glycoprotein E1 and therefore preventing the virus from becoming fusogenic. Although Fab 5F10 can neutralize the wild-type virus, it can also bind to a mutant virus without inhibiting fusion or attachment. Although the mutant virus is no longer able to propagate by extracellular budding, it can, however, enter the next cell by traveling through junctional complexes without being intercepted by a neutralizing antibody to the wild-type virus, thus clarifying how cell-to-cell transmission can occur.IMPORTANCEAlphaviral infections are transmitted mainly by mosquitoes. Chikungunya virus (CHIKV), which belongs to theAlphavirusgenus, has a wide distribution in the Old World that has expanded in recent years into the Americas. There are currently no vaccines or drugs against alphaviral infections. Therefore, a better understanding of CHIKV and its associated neutralizing antibodies will aid in the development of effective treatments.

scholarly journals Antibody Escape Kinetics of Equine Infectious Anemia Virus Infection of Horses

2015 ◽  
Vol 89 (13) ◽  
pp. 6945-6951 ◽  
Author(s):  
Elissa J. Schwartz ◽  
Seema Nanda ◽  
Robert H. Mealey
Keyword(s):  
Neutralizing Antibodies ◽  
Equine Infectious Anemia Virus ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Fitness Costs ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Kinetics Of ◽  
Virus Fitness

Lentivirus escape from neutralizing antibodies (NAbs) is not well understood. In this work, we quantified antibody escape of a lentivirus, using antibody escape data from horses infected with equine infectious anemia virus. We calculated antibody blocking rates of wild-type virus, fitness costs of mutant virus, and growth rates of both viruses. These quantitative kinetic estimates of antibody escape are important for understanding lentiviral control by antibody neutralization and in developing NAb-eliciting vaccine strategies.

scholarly journals Neutralizing antibody-independent immunity to SARS-CoV-2 in hamsters and hACE-2 transgenic mice immunized with a RBD/Nucleocapsid fusion protein

2021 ◽  
Author(s):  
Julia Castro ◽  
Marcilio Fumagalli ◽  
Natalia Hojo-Souza ◽  
Patrick Azevedo ◽  
Natalia Salazar ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Lung Inflammation ◽  
Neutralizing Antibodies ◽  
Chimeric Protein ◽  
Neutralizing Antibody ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
N Protein ◽  
Cell Responses

The nucleocapsid (N) and the receptor binding domain (RBD) of the Spike (S) proteins elicit robust antibody and T cell responses either in vaccinated or COVID-19 convalescent individuals. We generated a chimeric protein that comprises the sequences of RBD from S and N antigens (SpiN). SpiN was highly immunogenic and elicited a strong IFNγ response from T cells and high levels of antibodies to the inactivated virus, but no neutralizing antibodies. Importantly, hamsters and the human Angiotensin Convertase Enzyme-2-transgenic mice immunized with SpiN were highly resistant to challenge with the wild type SARS-CoV-2, as indicated by viral load, clinical outcome, lung inflammation and lethality. Thus, the N protein should be considered to induce T-cell-based immunity to improve SARS-CoV-2 vaccines, and eventually to circumvent the immune scape by variants.

scholarly journals Computational analyses of the G476S variant of SARS-CoV-2: A focus on the interaction with human ACE-2 and neutralizing antibodies

2020 ◽  
Author(s):  
Alexander Kwarteng ◽  
Ebenezer Asiedu ◽  
Augustina Angelina Sylverken
Keyword(s):  
Structural Dynamics ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Computational Approach ◽  
Receptor Binding Domain ◽  
Interaction Energies ◽  
Wild Type ◽  
S Protein ◽  
Conformation Changes ◽  
Computational Analyses

Abstract Recently, several mutations in the SARS-CoV-2 genome have been identified and reported. However, little is currently known about the influence of these mutations on the infectivity, transmissibility and antigenicity of the virus. Here, using an integrative computational approach, we characterized the G476S variant of SARS-CoV-2 focusing on interactions with ACE-2 and neutralizing antibodies. The substitution of Gly-476 to Ser-476 in the SARS-CoV-2 Receptor-binding domain (RBD) largely affected the structural dynamics of the S-protein leading to significant influence on the interactions with ACE-2 and neutralizing antibodies. Structural properties of the S-protein such as conformation changes, residual fluctuations and residue surface area largely varied between the wild-type and G476S variant, especially in the RBD. Analyses of the interaction energies between S-protein and ACE-2 suggest that the G476S variant may have enhanced interactions with ACE-2 compared to the wild-type. The G476S variant was found to have weaker interactions with the neutralizing antibody H014 compared to the wild-type. Collectively, our findings have implications for the infectivity and antigenicity of the G476S variant of SARS-CoV-2.

scholarly journals Changes of Humoral Immunity Response in SARS-CoV-2 Convalescent Patients over 8 months

2020 ◽  
Author(s):  
Pai Peng ◽  
Jie Hu ◽  
Hai-jun Deng ◽  
Bei-zhong Liu ◽  
Kai Wang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Sharp Rise ◽  
Specific Igg ◽  
The Mean ◽  
Second Wave ◽  
Igg Level ◽  
A Current

AbstractMany countries around the world have all seen a sharp rise in COVID-19 cases as the second wave since the beginning of October 2020. Decline of antibodies response to severe acute respiratory syndrome coronavirus (SARS-CoV-2) that was reported exclusively in the early month increases the risk of reinfection for convalescent individuals. There is a current need to follow the maintenance of special antibodies against SARS-CoV-2. Here, we reported changes of antibodies against SARS-CoV-2 in convalescent patients over 8 months. Antibodies of all 20 participants targeting SARS-CoV-2 spike receptor binding-domain (RBD) had decreased from a mean OD450 value 1.78 to 0.38 over 8 months. The neutralizing antibody (NAb) titers decreased from the mean ID50 value 836 to 170. The NAb titers were significantly correlated with IgG level during 8 months (P<0.001). Furthermore, while RBD-specific IgG existence of 25% (5/20) convalescent plasma was undetectable, the NAb titers of 15% (3/20) convalescent plasma decreased below the threshold. In addition, compared to wild-type SARS-CoV-2 (S-D614), lower titers of neutralizing antibodies against its G614 variant were shown at 8 months after symptom onset. This study has important implications when considering antibody protection against SARS-CoV-2 reinfection.

scholarly journals A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuping Xie ◽  
Antonio E. Muruato ◽  
Xianwen Zhang ◽  
Kumari G. Lokugamage ◽  
Camila R. Fontes-Garfias ◽  
...  
Keyword(s):  
High Throughput ◽  
Neutralization Test ◽  
A549 Cells ◽  
Neutralizing Antibody ◽  
Wild Type Virus ◽  
Antibody Activity ◽  
Type Virus ◽  
Serological Testing ◽  
Wild Type ◽  
Tenofovir Alafenamide

Abstract A high-throughput platform would greatly facilitate coronavirus disease 2019 (COVID-19) serological testing and antiviral screening. Here we present a high-throughput nanoluciferase severe respiratory syndrome coronavirus 2 (SARS-CoV-2-Nluc) that is genetically stable and replicates similarly to the wild-type virus in cell culture. SARS-CoV-2-Nluc can be used to measure neutralizing antibody activity in patient sera within 5 hours, and it produces results in concordance with a plaque reduction neutralization test (PRNT). Additionally, using SARS-CoV-2-Nluc infection of A549 cells expressing human ACE2 receptor (A549-hACE2), we show that the assay can be used for antiviral screening. Using the optimized SARS-CoV-2-Nluc assay, we evaluate a panel of antivirals and other anti-infective drugs, and we identify nelfinavir, rupintrivir, and cobicistat as the most selective inhibitors of SARS-CoV-2-Nluc (EC50 0.77 to 2.74 µM). In contrast, most of the clinically approved antivirals, including tenofovir alafenamide, emtricitabine, sofosbuvir, ledipasvir, and velpatasvir were inactive at concentrations up to 10 µM. Collectively, this high-throughput platform represents a reliable tool for rapid neutralization testing and antiviral screening for SARS-CoV-2.

scholarly journals Neutralizing Antibody Response of Vaccinees to SARS-CoV-2 Variants

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 517
Author(s):  
Gabriele Anichini ◽  
Chiara Terrosi ◽  
Gianni Gori Savellini ◽  
Claudia Gandolfo ◽  
Federico Franchi ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Standard Test ◽  
Wild Type Virus ◽  
Wild Type ◽  
Correlates Of Protection ◽  
The United Kingdom ◽  
Gold Standard Test ◽  
High Concern

Due to their increased transmissibility, three variants of high concern have emerged in the United Kingdom (also known as B.1.1.7 lineage or VOC-202012/01), South Africa (B.1.351 lineage), and Brazil (P1 lineage) with multiple substitutions in the spike protein. Since neutralizing antibodies elicited by vaccination are likely considered as correlates of protection for SARS-CoV-2 infection, it is important to analyze whether vaccinees with mRNA BNT162b2 are equally protected against these emerging SARS-CoV-2 variants. To this aim, we enrolled healthy subjects one month after complete vaccination with Comirnaty and evaluated the neutralizing response against the native Wuhan strain and the emerging B.1.1.7, B.1.351 and P1 lineages, by using the microneutralization assay, currently considered the gold standard test for the evaluation and detection of functional neutralizing antibodies. The most remarkable finding of this study was the significantly lower neutralizing antibody titer against B.1.351 lineage, compared to the wild-type virus. No significant differences were observed with the other two lineages. These findings provide evidence that vaccinated subjects may not be equally protected against all SARS-CoV-2 lineages.

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