scholarly journals Differential neutralization and inhibition of SARS-CoV-2 variants by antibodies elicited by COVID-19 mRNA vaccines

2021 ◽  
Author(s):  
Li Wang ◽  
Markus H Kainulainen ◽  
Nannan Jiang ◽  
Han Di ◽  
Gaston Bonenfant ◽  
...  

The divergence of SARS-CoV-2 into variants of concern/interest (VOC/VOI) necessitated analysis of their impact on vaccines. Escape from vaccine-induced antibodies by SARS-CoV-2 VOC/VOIs was analyzed to ascertain and rank their risk. The variants showed differential reductions in neutralization and replication titers by the post-vaccination sera with Beta variant showing the most neutralization escape that was mechanistically driven by mutations in both the N-terminal domain and receptor-binding domain of the spike.

2021 ◽  
Author(s):  
Gary Baisa ◽  
David Rancour ◽  
Keith Mansfield ◽  
Monika Burns ◽  
Lori Martin ◽  
...  

Abstract BackgroundVaccines that generate robust and long-lived protective immunity against SARS-CoV-2 infection are urgently required. MethodsWe assessed the potential of vaccine candidates based on the SARS-CoV-2 spike in cynomolgus macaques (M. fascicularis) by examining their ability to generate spike binding antibodies with neutralizing activity. Antigens were derived from two distinct regions of the spike S1 subunit, either the N-terminal domain or an extended C-terminal domain containing the receptor-binding domain and were fused to the human IgG1 Fc domain. Three groups of 2 animals each were immunized with either antigen, alone or in combination. The development of antibody responses was evaluated through 20 weeks post-immunization. ResultsA robust IgG response to the spike protein was detected as early as 2 weeks after immunization with either protein and maintained for over 20 weeks. Sera from animals immunized with antigens derived from the RBD were able to prevent binding of soluble spike proteins to the ACE2 receptor, shown by in vitro binding assays, while sera from animals immunized with the N-terminal domain alone lacked this activity. Crucially, sera from animals immunized with the extended receptor binding domain but not the N-terminal domain had potent neutralizing activity against SARS-CoV-2 pseudotyped virus, with titers in excess of 10,000, greatly exceeding that typically found in convalescent humans. Neutralizing activity persisted for more than 20 weeks. ConclusionsThese data support the utility of spike subunit-based antigens as a vaccine for use in humans.


Author(s):  
Gabriele Cerutti ◽  
Yicheng Guo ◽  
Tongqing Zhou ◽  
Jason Gorman ◽  
Myungjin Lee ◽  
...  

SummaryNumerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycans N17, N74, N122, and N149. This site – formed primarily by a mobile β-hairpin and several flexible loops – was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.


2021 ◽  
Author(s):  
Delphine Planas ◽  
Nell Saunders ◽  
Piet Maes ◽  
Florence Guivel Benhassine ◽  
Cyril Planchais ◽  
...  

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa. It has in the meantime spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of about 32 mutations in the Spike, located mostly in the N-terminal domain (NTD) and the receptor binding domain (RBD), which may enhance viral fitness and allow antibody evasion. Here, we isolated an infectious Omicron virus in Belgium, from a traveller returning from Egypt. We examined its sensitivity to 9 monoclonal antibodies (mAbs) clinically approved or in development, and to antibodies present in 90 sera from COVID-19 vaccine recipients or convalescent individuals. Omicron was totally or partially resistant to neutralization by all mAbs tested. Sera from Pfizer or AstraZeneca vaccine recipients, sampled 5 months after complete vaccination, barely inhibited Omicron. Sera from COVID-19 convalescent patients collected 6 or 12 months post symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titers 5 to 31 fold lower against Omicron than against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and to a large extent vaccine-elicited antibodies.


mBio ◽  
2021 ◽  
Author(s):  
Denise Haslwanter ◽  
M. Eugenia Dieterle ◽  
Anna Z. Wec ◽  
Cecilia M. O’Brien ◽  
Mrunal Sakharkar ◽  
...  

The U.S. FDA has issued emergency use authorizations (EUAs) for multiple investigational monoclonal antibody (MAb) therapies for the treatment of mild to moderate COVID-19.


2021 ◽  
Author(s):  
Delphine Planas ◽  
David Veyer ◽  
Artem Baidaliuk ◽  
Isabelle Staropoli ◽  
Florence Guivel-Benhassine ◽  
...  

The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1.617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1.617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1.617.2, relative to B.1.1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1.617.2. Thus, B.1.617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.


2021 ◽  
Author(s):  
Tzu-Jing Yang ◽  
Pei-Yu Yu ◽  
Yuan-Chih Chang ◽  
Ning-En Chang ◽  
Yu-Xi Tsai ◽  
...  

The surge of COVID-19 infection cases is spurred by emerging SARS-CoV-2 variants such as B.1.617. Here we report 38 cryo-EM structures, corresponding to the spike protein of the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Kappa (B.1.617.1) variants in different functional states with and without its receptor, ACE2. Mutations on the N-terminal domain not only alter the conformation of the highly antigenic supersite of the Delta variant, but also remodel the glycan shield by deleting or adding N-glycans of the Delta and Gamma variants, respectively. Substantially enhanced ACE2 binding was observed for all variants, whose mutations on the receptor binding domain modulate the electrostatics of the binding interfaces. Despite their abilities to escape host immunity, all variants can be potently neutralized by three unique antibodies.


Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. 650-655 ◽  
Author(s):  
Xiangyang Chi ◽  
Renhong Yan ◽  
Jun Zhang ◽  
Guanying Zhang ◽  
Yuanyuan Zhang ◽  
...  

Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo–eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.


Author(s):  
Yafei Liu ◽  
Noriko Arase ◽  
Jun-ichi Kishikawa ◽  
Mika Hirose ◽  
Songling Li ◽  
...  

AbstractmRNA-based vaccines provide effective protection against most common SARS-CoV-2 variants. However, identifying likely breakthrough variants is critical for future vaccine development. Here, we found that the Delta variant completely escaped from anti-N-terminal domain (NTD) neutralizing antibodies, while increasing responsiveness to anti-NTD infectivity-enhancing antibodies. Although Pfizer-BioNTech BNT162b2-immune sera neutralized the Delta variant, when four common mutations were introduced into the receptor binding domain (RBD) of the Delta variant (Delta 4+), some BNT162b2-immune sera lost neutralizing activity and enhanced the infectivity. Unique mutations in the Delta NTD were involved in the enhanced infectivity by the BNT162b2-immune sera. Sera of mice immunized by Delta spike, but not wild-type spike, consistently neutralized the Delta 4+ variant without enhancing infectivity. Given the fact that a Delta variant with three similar RBD mutations has already emerged according to the GISAID database, it is necessary to develop vaccines that protect against such complete breakthrough variants.


2021 ◽  
Author(s):  
Paola Cristina Resende ◽  
Felipe Gomes Naveca ◽  
Roberto Dias Lins ◽  
Filipe Zimmer Dezordi ◽  
Matheus V. F. Ferraz ◽  
...  

Mutations at both the receptor-binding domain (RBD) and the amino (N)-terminal domain (NTD) of the SARS-CoV-2 Spike (S) glycoprotein can alter its antigenicity and promote immune escape. We identified that SARS-CoV-2 lineages circulating in Brazil with mutations of concern in the RBD independently acquired convergent deletions and insertions in the NTD of the S protein, which altered the NTD antigenic-supersite and other predicted epitopes at this region. These findings support that the ongoing widespread transmission of SARS-CoV-2 in Brazil is generating new viral lineages that might be more resistant to neutralization than parental variants of concern.


2021 ◽  
Author(s):  
Hatem ◽  
Rashika El Rii

Severe acute respiratory syndrome corona virus (SARS-CoV)-2 obtained from patients infected despite being fully vaccinated with either BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) showed increased mutations rates in the N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike glycoprotein when compared with virus from unvaccinated controls (1). These changes are associated with immune evasion and diagnostic failures, prominent characteristics of variants of concern (2). Variants of concern (VOC) appeared to be overrepresented in numerous breakthrough infections of fully vaccinated people in the United States and (1, 3-6), and Israel (7). These findings confirm concerns about the relation of SARS-CoV-2 variants with vaccine breakthrough, and urged us to attempt clarifying the likely link between vaccination with the currently used vaccines and VOC emergence.


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