scholarly journals Breadth and function of antibody response to acute SARS-CoV-2 infection in humans

2021 ◽  
Vol 17 (2) ◽  
pp. e1009352 ◽  
Author(s):  
Kuan-Ying A. Huang ◽  
Tiong Kit Tan ◽  
Ting-Hua Chen ◽  
Chung-Guei Huang ◽  
Ruth Harvey ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Antibody Response ◽  
Somatic Mutations ◽  
Therapeutic Agents ◽  
Memory B Cells ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Neutralising Antibodies ◽  
And Function ◽  
Humoral Responses

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-receptor-binding domain (RBD), three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two recovered patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

Breadth and function of antibody response to acute SARS-CoV-2 infection in humans

2020 ◽  
Author(s):  
Kuan-Ying A. Huang ◽  
Tiong Kit Tan ◽  
Ting-Hua Chen ◽  
Chung-Guei Huang ◽  
Ruth Harvey ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cells ◽  
Antibody Response ◽  
Somatic Mutations ◽  
Therapeutic Agents ◽  
Memory B Cells ◽  
Wild Type ◽  
Neutralising Antibodies ◽  
And Function ◽  
Humoral Responses

AbstractSerological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-RBD, three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

scholarly journals mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

2021 ◽  
Author(s):  
Zijun Wang ◽  
Fabian Schmidt ◽  
Yiska Weisblum ◽  
Frauke Muecksch ◽  
Christopher O. Barnes ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Vesicular Stomatitis Virus ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Protein S ◽  
Memory B Cells ◽  
Receptor Binding Domain ◽  
Cell Responses ◽  
Specific Memory ◽  
Vesicular Stomatitis

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3–6. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers3,5,6. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

scholarly journals Murine Monoclonal Antibodies against the Receptor Binding Domain of SARS-CoV-2 Neutralize Authentic Wild-Type SARS-CoV-2 as Well as B.1.1.7 and B.1.351 Viruses and Protect In Vivo in a Mouse Model in a Neutralization-Dependent Manner

mBio ◽  
2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B. Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Mouse Model ◽  
Protective Effect ◽  
Receptor Binding ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Cross Neutralization ◽  
Murine Monoclonal Antibodies

Cross-neutralization of SARS-CoV-2 variants by RBD-targeting antibodies is still not well understood, and very little is known about the potential protective effect of nonneutralizing antibodies in vivo . Using a panel of mouse monoclonal antibodies, we investigate both of these points.

scholarly journals Decline of humoral responses against SARS-CoV-2 Spike in convalescent individuals

2020 ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Annemarie Laumaea ◽  
Sai Priya Anand ◽  
Jérémie Prévost ◽  
Romain Gasser ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Positive Role ◽  
Neutralization Activity ◽  
Specific Igg ◽  
Humoral Responses ◽  
Over Time

ABSTRACTIn the absence of effective vaccines and with limited therapeutic options, convalescent plasma is being collected across the globe for potential transfusion to COVID-19 patients. The therapy has been deemed safe and several clinical trials assessing its efficacy are ongoing. While it remains to be formally proven, the presence of neutralizing antibodies is thought to play a positive role in the efficacy of this treatment. Indeed, neutralizing titers of ≥1:160 have been recommended in some convalescent plasma trials for inclusion. Here we performed repeated analyses at one-month interval on 31 convalescent individuals to evaluate how the humoral responses against the SARS-CoV-2 Spike, including neutralization, evolve over time. We observed that receptor-binding domain (RBD)-specific IgG slightly decreased between six and ten weeks after symptoms onset but RBD-specific IgM decreased much more abruptly. Similarly, we observed a significant decrease in the capacity of convalescent plasma to neutralize pseudoparticles bearing SARS-CoV-2 S wild-type or its D614G variant. If neutralization activity proves to be an important factor in the clinical efficacy of convalescent plasma transfer, our results suggest that plasma from convalescent donors should be recovered rapidly after symptoms resolution.

scholarly journals Decline of Humoral Responses against SARS-CoV-2 Spike in Convalescent Individuals

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Guillaume Beaudoin-Bussières ◽  
Annemarie Laumaea ◽  
Sai Priya Anand ◽  
Jérémie Prévost ◽  
Romain Gasser ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Active Infection ◽  
Positive Role ◽  
Neutralization Activity ◽  
Neutralizing Activity ◽  
Specific Igg ◽  
Alternative Approaches ◽  
Humoral Responses

ABSTRACT In the absence of effective vaccines and with limited therapeutic options, convalescent plasma is being collected across the globe for potential transfusion to coronavirus disease 2019 (COVID-19) patients. The therapy has been deemed safe, and several clinical trials assessing its efficacy are ongoing. While it remains to be formally proven, the presence of neutralizing antibodies is thought to play a positive role in the efficacy of this treatment. Indeed, neutralizing titers of ≥1:160 have been recommended in some convalescent plasma trials for inclusion. Here, we performed repeated analyses at 1-month intervals on 31 convalescent individuals to evaluate how the humoral responses against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein, including neutralization, evolve over time. We observed that the levels of receptor-binding-domain (RBD)-specific IgG and IgA slightly decreased between 6 and 10 weeks after the onset of symptoms but that RBD-specific IgM levels decreased much more abruptly. Similarly, we observed a significant decrease in the capacity of convalescent plasma to neutralize pseudoparticles bearing wild-type SARS-CoV-2 S or its D614G variant. If neutralization activity proves to be an important factor in the clinical efficacy of convalescent plasma transfer, our results suggest that plasma from convalescent donors should be recovered rapidly after resolution of symptoms. IMPORTANCE While waiting for an efficient vaccine to protect against SARS-CoV-2 infection, alternative approaches to treat or prevent acute COVID-19 are urgently needed. Transfusion of convalescent plasma to treat COVID-19 patients is currently being explored; neutralizing activity in convalescent plasma is thought to play a central role in the efficacy of this treatment. Here, we observed that plasma neutralization activity decreased a few weeks after the onset of the symptoms. If neutralizing activity is required for the efficacy of convalescent plasma transfer, our results suggest that convalescent plasma should be recovered rapidly after the donor recovers from active infection.

scholarly journals mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Susanne Rauch ◽  
Nicole Roth ◽  
Kim Schwendt ◽  
Mariola Fotin-Mleczek ◽  
Stefan O. Mueller ◽  
...  
Keyword(s):  
Viral Replication ◽  
Vaccine Candidate ◽  
Wild Type ◽  
Neutralising Antibodies ◽  
Cell Responses ◽  
Naturally Occurring ◽  
Safe Vaccine ◽  
Suboptimal Dose ◽  
Humoral Responses ◽  
Clinical Candidate

AbstractmRNA technologies have recently proven clinical efficacy against coronavirus disease 2019 and are among the most promising technologies to address the current pandemic. Here, we show preclinical data for our clinical candidate CVnCoV, a lipid nanoparticle-encapsulated mRNA vaccine that encodes full-length, pre-fusion stabilised severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein. In contrast to previously published approaches, CVnCoV is exclusively composed of naturally occurring nucleotides. Immunisation with CVnCoV induced strong humoral responses with high titres of virus-neutralising antibodies and robust T-cell responses. CVnCoV vaccination protected hamsters from challenge with wild-type SARS-CoV-2, demonstrated by the absence of viral replication in the lungs. Hamsters vaccinated with a suboptimal dose of CVnCoV leading to breakthrough viral replication exhibited no evidence of vaccine-enhanced disease. Overall, data presented here provide evidence that CVnCoV represents a potent and safe vaccine candidate against SARS-CoV-2.

scholarly journals Human IgG neutralizing monoclonal antibodies block SARS-CoV-2 infection

2020 ◽  
Author(s):  
Jinkai Wan ◽  
Shenghui Xing ◽  
Longfei Ding ◽  
Yongheng Wang ◽  
Dandan Zhu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Therapeutic Potential ◽  
Memory B Cells ◽  
Antigen Binding ◽  
Receptor Binding Domain ◽  
Cell Cloning ◽  
Further Development ◽  
Cloning Technology

AbstractThe coronavirus induced disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a worldwide threat to human lives, and neutralizing antibodies present a great therapeutic potential in curing affected patients. We purified more than one thousand memory B cells specific to SARS-CoV-2 S1 or RBD (receptor binding domain) antigens from 11 convalescent COVID-19 patients, and a total of 729 naturally paired heavy and light chain fragments were obtained by single B cell cloning technology. Among these, 178 recombinant monoclonal antibodies were tested positive for antigen binding, and the top 13 binders with Kd below 0.5 nM are all RBD binders. Importantly, all these 13 antibodies could block pseudoviral entry into HEK293T cells overexpressing ACE2, with the best ones showing IC50s around 2-3 nM. We further identified 8 neutralizing antibodies against authentic virus with IC50s within 10 nM. Among these, 414-1 blocked authentic viral entry at IC50 of 1.75 nM and in combination with 105-38 could achieve IC50 as low as 0.45 nM. Meanwhile, we also found that 3 antibodies could cross-react with the SARS-CoV spike protein. Altogether, our study provided a panel of potent human neutralizing antibodies for COVID19 as therapeutics candidates for further development.

scholarly journals A SARS-CoV-2 neutralizing antibody with exceptional spike binding coverage and optimized therapeutic potentials

2020 ◽  
Author(s):  
Yu Guo ◽  
Lisu Huang ◽  
Guangshun Zhang ◽  
Yanfeng Yao ◽  
He Zhou ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Single Injection ◽  
Complex Structure ◽  
Neutralizing Antibody ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Global Public Health ◽  
Wild Type ◽  
Monkey Model

Abstract The Coronavirus Disease of 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health and economy. Therapeutic options such as monoclonal antibodies (mAbs) against SARS-CoV-2 are in urgent need. We have identified potent monoclonal antibodies binding to SARS-CoV-2 Spike protein from COVID-19 convalescent patients and one of these antibodies, P4A1, interacts directly and covers the majority of the Receptor Binding Motif (RBM) of Spike receptor-binding domain (RBD), shown by high-resolution complex structure analysis. We further demonstrated P4A1 binding and neutralizing activities against wild type and mutant spike proteins. P4A1 was subsequently engineered to reduce the potential risk for antibody-dependent enhancement (ADE) of infection and to extend its half-life. The engineered mAb exhibits optimized pharmacokinetic and safety profile, and results in complete viral clearance in a rhesus monkey model of COVID-19 following a single injection.

scholarly journals Receptor-binding domain-specific human neutralizing monoclonal antibodies against SARS-CoV and SARS-CoV-2

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Fei Yu ◽  
Rong Xiang ◽  
Xiaoqian Deng ◽  
Lili Wang ◽  
Zhengsen Yu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Global Public Health ◽  
Domain Specific ◽  
Treatment And Prevention ◽  
T Cell Immune Responses ◽  
And Function

Abstract The outbreaks of severe acute respiratory syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV and SARS-CoV-2, respectively, have posed severe threats to global public health and the economy. Treatment and prevention of these viral diseases call for the research and development of human neutralizing monoclonal antibodies (NMAbs). Scientists have screened neutralizing antibodies using the virus receptor-binding domain (RBD) as an antigen, indicating that RBD contains multiple conformational neutralizing epitopes, which are the main structural domains for inducing neutralizing antibodies and T-cell immune responses. This review summarizes the structure and function of RBD and RBD-specific NMAbs against SARS-CoV and SARS-CoV-2 currently under development.

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