scholarly journals Computational Prediction of the Epitopes of HA1 Protein of Influenza Viruses to its Neutralizing Antibodies

Antibodies ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 2
Author(s):  
Xiaoyan Zeng ◽  
Fiona Legge ◽  
Chao Huang ◽  
Xiao Zhang ◽  
Yongjun Jiao ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Crystal Structures ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Computational Prediction ◽  
Binding Domain ◽  
Influenza Viruses ◽  
New Method ◽  
Receptor Binding Domain ◽  
Antibody Recognition

In this work, we have used a new method to predict the epitopes of HA1 protein of influenza virus to several antibodies HC19, CR9114, BH151 and 4F5. While our results reproduced the binding epitopes of H3N2 or H5N1 for the neutralizing antibodies HC19, CR9114, and BH151 as revealed from the available crystal structures, additional epitopes for these antibodies were also suggested. Moreover, the predicted epitopes of H5N1 HA1 for the newly developed antibody 4F5 are located at the receptor binding domain, while previous study identified a region 76-WLLGNP-81 as the epitope. The possibility of antibody recognition of influenza virus via different mechanism by binding to different epitopes of an antigen is also discussed.

scholarly journals Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite

2021 ◽  
Author(s):  
Gabriele Cerutti ◽  
Yicheng Guo ◽  
Tongqing Zhou ◽  
Jason Gorman ◽  
Myungjin Lee ◽  
...  
Keyword(s):  
Free Surface ◽  
Crystal Structures ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Viral Membrane ◽  
Terminal Domain ◽  
Flexible Loops

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.

scholarly journals Structural and energetic profiling of SARS-CoV-2 receptor binding domain antibody recognition and the impact of circulating variants

2021 ◽  
Vol 17 (9) ◽  
pp. e1009380
Author(s):  
Rui Yin ◽  
Johnathan D. Guest ◽  
Ghazaleh Taherzadeh ◽  
Ragul Gowthaman ◽  
Ipsa Mittra ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Design Strategies ◽  
Detailed Structure ◽  
Antibody Recognition ◽  
Domain Antibody ◽  
The Impact ◽  
Binding Determinants

The SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including Alpha (B.1.1.7) and Delta (B.1.617.2), some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. This detailed structure-based reference of antibody RBD recognition signatures can inform therapeutic and vaccine design strategies.

scholarly journals Attenuated Influenza Virions Expressing the SARS-CoV-2 Receptor-Binding Domain Induce Neutralizing Antibodies in Mice

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 987 ◽  
Author(s):  
Andrea N. Loes ◽  
Lauren E. Gentles ◽  
Allison J. Greaney ◽  
Katharine H. D. Crawford ◽  
Jesse D. Bloom
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Reverse Genetics ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Effective Vaccine ◽  
Receptor Binding Domain ◽  
Antibody Titers

An effective vaccine is essential for controlling the spread of the SARS-CoV-2 virus. Here, we describe an influenza virus-based vaccine for SARS-CoV-2. We incorporated a membrane-anchored form of the SARS-CoV-2 spike receptor binding domain (RBD) in place of the neuraminidase (NA) coding sequence in an influenza virus also possessing a mutation that reduces the affinity of hemagglutinin for its sialic acid receptor. The resulting ΔNA(RBD)-Flu virus can be generated by reverse genetics and grown to high titers in cell culture. A single-dose intranasal inoculation of mice with ΔNA(RBD)-Flu elicits serum neutralizing antibody titers against SAR-CoV-2 comparable to those observed in humans following natural infection (~1:200). Furthermore, ΔNA(RBD)-Flu itself causes no apparent disease in mice. It might be possible to produce a vaccine similar to ΔNA(RBD)-Flu at scale by leveraging existing platforms for the production of influenza vaccines.

scholarly journals Attenuated influenza virions expressing the SARS-CoV-2 receptor-binding domain induce neutralizing antibodies in mice

2020 ◽  
Author(s):  
Andrea N. Loes ◽  
Lauren E. Gentles ◽  
Allison J. Greaney ◽  
Katharine H. D. Crawford ◽  
Jesse D. Bloom
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Reverse Genetics ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Effective Vaccine ◽  
Receptor Binding Domain ◽  
Antibody Titers

AbstractAn effective vaccine is essential to controlling the spread of SARS-CoV-2 virus. Here, we describe an influenza-virus-based vaccine for SARS-CoV-2. We incorporated a membrane-anchored form of the SARS-CoV-2 Spike receptor binding domain (RBD) in place of the neuraminidase (NA) coding sequence in an influenza virus also possessing a mutation that reduces the affinity of hemagglutinin for its sialic acid receptor. The resulting ΔNA(RBD)-Flu virus can be generated by reverse genetics and grown to high titers in cell culture. A single-dose intranasal inoculation of mice with ΔNA(RBD)-Flu elicits serum neutralizing antibody titers against SAR-CoV-2 comparable to those observed in humans following natural infection (∼1:200). Furthermore, ΔNA(RBD)-Flu itself causes no apparent disease in mice. It might be possible to produce a vaccine similar to ΔNA(RBD)-Flu at scale by leveraging existing platforms for production of influenza vaccines.

A Single Vaccine Protects against SARS-CoV-2 and Influenza Virus in Mice

2021 ◽  
Author(s):  
Kangli Cao ◽  
Xiang Wang ◽  
Haoran Peng ◽  
Longfei Ding ◽  
Xiangwei Wang ◽  
...  
Keyword(s):  
Public Health ◽  
Virus Infection ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Respiratory Virus ◽  
Binding Domain ◽  
Influenza Viruses ◽  
Receptor Binding Domain ◽  
Respiratory Virus Infection ◽  
Do So

The ongoing SARS-CoV-2 pandemic posed a severe global threat on public health, as do so by influenza viruses (influenza) and other coronaviruses. Here we present chimpanzee adenovirus 68 (AdC68)-based vaccines designed to universally target coronaviruses and influenza. Our design is centered on an immunogen generated by fusing the SARS-CoV-2 receptor-binding domain (RBD) to the conserved stalk of H7N9 hemagglutinin (HA). Remarkably, the constructed vaccine effectively induced both SARS-CoV-2-targeting antibodies and anti-influenza antibodies in mice, consequently affording protection from lethal SARS-CoV-2 and H7N9 challenges and effective H3N2 control. We propose our AdC68 vectored coronavirus-influenza vaccine as a universal approach toward curbing respiratory virus-causing pandemics. IMPORTANCE The COVID-19 pandemic exemplifies the severe public health threat of respiratory virus infection, as do so by influenza A viruses. The currently envisioned strategy for prevention of respiratory virus-causing diseases requires comprehensive administration of vaccines tailored for individual virus. Here we present an alternative strategy by designing chimpanzee adenovirus 68-based vaccines targeting both SARS-CoV-2 receptor-binding-domain and conserved stalk of influenza hemagglutinin. When tested in mice, this strategy attained potent neutralizing antibodies against wild-type SARS-CoV-2 as well as its emerging variants, enabling an effective protection against lethal SARS-CoV-2 challenge. Notably, it also entitled a complete protection from lethal H7N9 challenge and efficient control of H3N2-induced morbidity. Our study opens a new avenue to universally curb respiratory virus infection by vaccination.

scholarly journals Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in COVID-19 patients and healthy individuals

2021 ◽  
pp. eabd6990
Author(s):  
Sang Il Kim ◽  
Jinsung Noh ◽  
Sujeong Kim ◽  
Younggeun Choi ◽  
Duck Kyun Yoo ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Healthy Individuals

Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 out of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were comprised of immunoglobulin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobulin heavy joining (IGHJ)6 genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different immunoglobulin heavy variable chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in six out of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

scholarly journals mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection

Science ◽  
2021 ◽  
pp. eabg9175 ◽  
Author(s):  
Leonidas Stamatatos ◽  
Julie Czartoski ◽  
Yu-Hsin Wan ◽  
Leah J. Homad ◽  
Vanessa Rubin ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Previous Infection

Emerging SARS-CoV-2 variants have raised concerns about resistance to neutralizing antibodies elicited by previous infection or vaccination. We examined whether sera from recovered and naïve donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants. Pre-vaccination sera from recovered donors neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351, but a single immunization boosted neutralizing titers against all variants and SARS-CoV-1 by up to 1000-fold. Neutralization was due to antibodies targeting the receptor binding domain and was not boosted by a second immunization. Immunization of naïve donors also elicited cross-neutralizing responses, but at lower titers. Our study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.

scholarly journals Comprehensive Deep Mutational Scanning Reveals the Immune-Escaping Hotspots of SARS-CoV-2 Receptor-Binding Domain Targeting Neutralizing Antibodies

2021 ◽  
Vol 12 ◽  
Author(s):  
Keng-Chang Tsai ◽  
Yu-Ching Lee ◽  
Tien-Sheng Tseng
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Human Immune System ◽  
Angiotensin Converting Enzyme 2 ◽  
Study Results ◽  
Rapid Spread ◽  
Care Systems ◽  
Computational Analyses

The rapid spread of SARS-CoV-2 has caused the COVID-19 pandemic, resulting in the collapse of medical care systems and economic depression worldwide. To combat COVID-19, neutralizing antibodies have been investigated and developed. However, the evolutions (mutations) of the receptor-binding domain (RBD) of SARS-CoV-2 enable escape from neutralization by these antibodies, further impairing recognition by the human immune system. Thus, it is critical to investigate and predict the putative mutations of RBD that escape neutralizing immune responses. Here, we employed computational analyses to comprehensively investigate the mutational effects of RBD on binding to neutralizing antibodies and angiotensin-converting enzyme 2 (ACE2) and demonstrated that the RBD residues K417, L452, L455, F456, E484, G485, F486, F490, Q493, and S494 were consistent with clinically emerging variants or experimental observations of attenuated neutralizations. We also revealed common hotspots, Y449, L455, and Y489, that exerted comparable destabilizing effects on binding to both ACE2 and neutralizing antibodies. Our results provide valuable information on the putative effects of RBD variants on interactions with neutralizing antibodies. These findings provide insights into possible evolutionary hotspots that can escape recognition by these antibodies. In addition, our study results will benefit the development and design of vaccines and antibodies to combat the newly emerging variants of SARS-CoV-2.

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