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1.
Commun Biol ; 5(1): 262, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1799550

ABSTRACT

Understanding the underlying molecular mechanisms behind ADE of SARS-CoV-2 is critical for development of safe and effective therapies. Here, we report that two neutralizing mAbs, MW01 and MW05, could enhance the infection of SARS-CoV-2 pseudovirus on FcγRIIB-expressing B cells. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 could bind to RBDs in S trimer with both "up" and "down" states. While, the neutralizing mAb MW07, which has no ADE activity only binds to RBD in S trimer with "up" state. Monovalent MW01 and MW05 completely diminished the ADE activity compared with their bivalent counterparts. Moreover, both macropinocytosis and endocytosis are confirmed involving in ADE of SARS-CoV-2 pseudoviral infection. Blocking endosome transportation and lysosome acidification could inhibit the ADE activity mediated by MW05. Together, our results identified a novel ADE mechanism of SARS-CoV-2 pseudovirus in vitro, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction.


Subject(s)
Antibody-Dependent Enhancement , COVID-19 , Antibodies, Viral , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
2.
J Basic Clin Physiol Pharmacol ; 33(1): 13-16, 2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1613395

ABSTRACT

Antibody-dependent enhancement (ADE) can be seen in a variety of viruses. It has a deleterious impact on antibody treatment of viral infection. This effect was first discovered in the dengue virus, and it has since been discovered in the coronavirus. Over 213 million people have been affected by the rapid spread of the newly emerging coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The new coronavirus offers a significant threat and has sparked widespread concern. ADE in dengue virus and other viruses are discussed with possible effect on COVID-19 treatment and vaccine development will need to consider this phenomenon to ensure it is mitigated and avoided altogether. In these case scenarios, the role of ADE and its clinical consequences remains to be explored for this newly detected virus.


Subject(s)
Antibody-Dependent Enhancement , COVID-19 , COVID-19/drug therapy , COVID-19/immunology , Humans
3.
Viruses ; 13(12)2021 12 11.
Article in English | MEDLINE | ID: covidwho-1572660

ABSTRACT

Patients with COVID-19 generally raise antibodies against SARS-CoV-2 following infection, and the antibody level is positively correlated to the severity of disease. Whether the viral antibodies exacerbate COVID-19 through antibody-dependent enhancement (ADE) is still not fully understood. Here, we conducted in vitro assessment of whether convalescent serum enhanced SARS-CoV-2 infection or induced excessive immune responses in immune cells. Our data revealed that SARS-CoV-2 infection of primary B cells, macrophages and monocytes, which express variable levels of FcγR, could be enhanced by convalescent serum from COVID-19 patients. We also determined the factors associated with ADE, and found which showed a time-dependent but not viral-dose dependent manner. Furthermore, the ADE effect is not associated with the neutralizing titer or RBD antibody level when testing serum samples collected from different patients. However, it is higher in a medium level than low or high dilutions in a given sample that showed ADE effect, which is similar to dengue. Finally, we demonstrated more viral genes or dysregulated host immune gene expression under ADE conditions compared to the no-serum infection group. Collectively, our study provides insight into the understanding of an association of high viral antibody titer and severe lung pathology in severe patients with COVID-19.


Subject(s)
Antibody-Dependent Enhancement/immunology , Leukocytes/virology , SARS-CoV-2/pathogenicity , COVID-19/immunology , Cells, Cultured , Gene Expression Profiling , Humans , Immune Sera/immunology , Leukocytes/metabolism , Receptors, IgG/metabolism , Virus Replication/immunology
4.
Sci Rep ; 11(1): 23713, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1565736

ABSTRACT

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many vaccine trials have been initiated. An important goal of vaccination is the development of neutralizing antibody (Ab) against SARS-CoV-2. However, the possible induction of antibody-dependent enhancement (ADE) of infection, which is known for other coronaviruses and dengue virus infections, is a particular concern in vaccine development. Here, we demonstrated that human iPS cell-derived, immortalized, and ACE2- and TMPRSS2-expressing myeloid cell lines are useful as host cells for SARS-CoV-2 infection. The established cell lines were cloned and screened based on their function in terms of susceptibility to SARS-CoV-2-infection or IL-6 productivity. Using the resulting K-ML2 (AT) clone 35 for SARS-CoV-2-infection or its subclone 35-40 for IL-6 productivity, it was possible to evaluate the potential of sera from severe COVID-19 patients to cause ADE and to stimulate IL-6 production upon infection with SARS-CoV-2.


Subject(s)
Antibody-Dependent Enhancement , COVID-19/immunology , COVID-19/metabolism , Interleukin-6/metabolism , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cell Line , Humans , Myeloid Cells/immunology , Myeloid Cells/metabolism , Patients , Serine Endopeptidases/metabolism
6.
Emerg Microbes Infect ; 10(1): 2194-2198, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1504286

ABSTRACT

Inactivated coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), as potential vaccines have been reported to result in enhanced respiratory diseases (ERDs) in murine and nonhuman primate (NHP) pneumonia models after virus challenge, which poses great safety concerns of antibody-dependent enhancement (ADE) for the rapid wide application of inactivated SARS-CoV-2 vaccines in humans, especially when the neutralizing antibody levels induced by vaccination or initial infection quickly wane to nonneutralizing or subneutralizing levels over the time. With passive transfer of diluted postvaccination polyclonal antibodies to mimic the waning antibody responses after vaccination, we found that in the absence of cellular immunity, passive infusion of subneutralizing or nonneutralizing anti-SARS-CoV-2 antibodies could still provide some level of protection against infection upon challenge, and no low-level antibody-enhanced infection was observed. The anti-SARS-CoV-2 IgG-infused group and control group showed similar, mild to moderate pulmonary immunopathology during the acute phase of virus infection, and no evidence of vaccine-related pulmonary immunopathology enhancement was found. Typical immunopathology included elevated MCP-1, IL-8 and IL-33 in bronchoalveolar lavage fluid; alveolar epithelial hyperplasia; and exfoliated cells and mucus in bronchioles. Our results corresponded with the recent observations that no pulmonary immunology was detected in preclinical studies of inactivated SARS-CoV-2 vaccines in either murine or NHP pneumonia models or in large clinical trials and further supported the safety of inactivated SARS-CoV-2 vaccines.


Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement , COVID-19 Vaccines/immunology , COVID-19/immunology , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Alveolar Epithelial Cells/pathology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/toxicity , Bronchioles/chemistry , Bronchioles/pathology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , COVID-19/pathology , COVID-19/virology , Cytokines/analysis , Humans , Hyperplasia , Immunoglobulin G/immunology , Immunoglobulin G/toxicity , Lung/pathology , Macaca mulatta , Male , Mice , Mucus , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Vaccines, Inactivated/immunology
7.
mBio ; 12(5): e0198721, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1494967

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the detrimental effects of antibodies. Antibody-dependent enhancement (ADE) of infection is one of the biggest concerns in terms of not only the antibody reaction to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon reinfection with the virus but also the reaction to COVID-19 vaccines. In this study, we evaluated ADE of infection by using COVID-19 convalescent-phase plasma and BHK cells expressing human Fcγ receptors (FcγRs). We found that FcγRIIA and FcγRIIIA mediated modest ADE of infection against SARS-CoV-2. Although ADE of infection was observed in monocyte-derived macrophages infected with SARS-CoV-2, including its variants, proinflammatory cytokine/chemokine expression was not upregulated in macrophages. SARS-CoV-2 infection thus produces antibodies that elicit ADE of infection, but these antibodies do not contribute to excess cytokine production by macrophages. IMPORTANCE Viruses infect cells mainly via specific receptors at the cell surface. Antibody-dependent enhancement (ADE) of infection is an alternative mechanism of infection for viruses to infect immune cells that is mediated by antibodies and IgG receptors (FcγRs). Because ADE of infection contributes to the pathogenesis of some viruses, such as dengue virus and feline coronavirus, it is important to evaluate the precise mechanism of ADE and its contribution to the pathogenesis of SARS-CoV-2. Here, using convalescent-phase plasma from COVID-19 patients, we found that two types of FcγRs, FcγRIIA and FcγRIIIA, mediate ADE of SARS-CoV-2 infection. Although ADE of infection was observed for SARS-CoV-2 and its recent variants, proinflammatory cytokine production in monocyte-derived macrophages was not upregulated. These observations suggest that SARS-CoV-2 infection produces antibodies that elicit ADE of infection, but these antibodies may not be involved in aberrant cytokine release by macrophages during SARS-CoV-2 infection.


Subject(s)
Cytokines/metabolism , Macrophages/metabolism , Receptors, IgG/metabolism , SARS-CoV-2/pathogenicity , Animals , Antibody-Dependent Enhancement/physiology , Cell Line , Cricetinae , Humans , Real-Time Polymerase Chain Reaction , Receptors, IgG/genetics
8.
J Virol ; 95(19): e0068521, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1486511

ABSTRACT

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here, we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351, and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralizing antibody approaches. Furthermore, we report a preclinical characterization package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralization capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralized four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence, thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: while previous ACE2-based therapeutics have been described, ours has novel features, including (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Antibodies, Neutralizing/immunology , Antibody-Dependent Enhancement , COVID-19/immunology , HEK293 Cells , Humans , Kinetics , Mutation , Protein Binding , Protein Domains , Protein Interaction Domains and Motifs , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism
9.
Zhonghua Yu Fang Yi Xue Za Zhi ; 55(2): 171-176, 2021 Feb 06.
Article in Chinese | MEDLINE | ID: covidwho-1468517

ABSTRACT

Antibody-dependent enhancement (ADE) refers to the process in which some virus-specific antibodies (generally non-neutralizing antibodies) bind to the virus and bind to some cells expressing FcR on the surface through their Fc segment, thereby mediating the endocytosis and replication of the virus and enhancing the infection of the virus. This review summarized experience of ADE in respiratory syncytial virus, dengue virus, influenza virus infection and explored the possible mechanism of COVID-19 high incidence and severity of the disease, which implied challenges in the process of vaccine development and provided some insights for COVID-19 pathogenesis.


Subject(s)
COVID-19 , Dengue Virus , Dengue , Antibodies, Neutralizing , Antibodies, Viral , Antibody-Dependent Enhancement , Humans , SARS-CoV-2
10.
Cell Mol Immunol ; 19(2): 150-157, 2022 02.
Article in English | MEDLINE | ID: covidwho-1467097

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic that poses a great threat to human health worldwide. As the humoral immune response plays essential roles in disease occurrence and development, understanding the dynamics and characteristics of virus-specific humoral immunity in SARS-CoV-2-infected patients is of great importance for controlling this disease. In this review, we summarize the characteristics of the humoral immune response after SARS-CoV-2 infection and further emphasize the potential applications and therapeutic prospects of SARS-CoV-2-specific humoral immunity and the critical role of this immunity in vaccine development. Notably, serological antibody testing based on the humoral immune response can guide public health measures and control strategies; however, it is not recommended for population surveys in areas with very low prevalence. Existing evidence suggests that asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection, whereas SARS-CoV-2-infected children have a more effective humoral immune response than adults. The correlations between antibody (especially neutralizing antibody) titers and protection against SARS-CoV-2 reinfection should be further examined. In addition, the emergence of cross-reactions among different coronavirus antigens in the development of screening technology and the risk of antibody-dependent enhancement related to SARS-CoV-2 vaccination should be given further attention.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Immunity, Humoral , Pandemics/prevention & control , SARS-CoV-2/immunology , Vaccination/methods , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody-Dependent Enhancement/immunology , COVID-19/epidemiology , COVID-19/virology , Cross Reactions , Humans , Spike Glycoprotein, Coronavirus/immunology
11.
Int J Immunopathol Pharmacol ; 35: 20587384211050199, 2021.
Article in English | MEDLINE | ID: covidwho-1463209

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented global public health emergency with economic and social consequences. One of the main concerns in the development of vaccines is the antibody-dependent enhancement phenomenon, better known as ADE. In this review, we provide an overview of SARS-CoV-2 infection as well as the immune response generated by the host. On the bases of this principle, we also describe what is known about the ADE phenomenon in various viral infections and its possible role as a limiting factor in the development of new vaccines and therapeutic strategies.


Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement , COVID-19/immunology , SARS-CoV-2/immunology , Adaptive Immunity , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/therapeutic use , Host-Pathogen Interactions , Humans , Immunity, Innate , SARS-CoV-2/pathogenicity , Vaccination
12.
Antiviral Res ; 195: 105185, 2021 11.
Article in English | MEDLINE | ID: covidwho-1458855

ABSTRACT

Monoclonal antibodies (mAbs) are emerging as safe and effective therapeutics against SARS-CoV-2. However, variant strains of SARS-CoV-2 have evolved, with early studies showing that some mAbs may not sustain their efficacy in the face of escape mutants. Also, from the onset of the COVID-19 pandemic, concern has been raised about the potential for Fcγ receptor-mediated antibody-dependent enhancement (ADE) of infection. In this study, plaque reduction neutralization assays demonstrated that mAb 1741-LALA neutralizes SARS-CoV-2 strains B.1.351, D614 and D614G. MAbs S1D2-hIgG1 and S1D2-LALA mutant (STI-1499-LALA) did not neutralize B.1.351, but did neutralize SARS-CoV-2 strains D614 and D614G. LALA mutations did not result in substantial differences in neutralizing abilities between clones S1D2-hIgG1 vs STI-1499-LALA. S1D2-hIgG1, STI-1499-LALA, and convalescent plasma showed minimal ability to induce ADE in human blood monocyte-derived macrophages. Further, no differences in pharmacokinetic clearance of S1D2-hIgG1 vs STI-1499-LALA were observed in mice expressing human FcRn. These findings confirm that SARS-CoV-2 has already escaped some mAbs, and identify a mAb candidate that may neutralize multiple SARS-CoV-2 variants. They also suggest that risk of ADE in macrophages may be low with SARS-CoV-2 D614, and LALA Fc change impacts neither viral neutralization nor Ab clearance.


Subject(s)
Antibodies, Monoclonal/immunology , Antibody-Dependent Enhancement , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Chlorocebus aethiops , Humans , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutralization Tests , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
13.
Adv Immunol ; 151: 99-133, 2021.
Article in English | MEDLINE | ID: covidwho-1432696

ABSTRACT

In some cases, antibodies can enhance virus entry and replication in cells. This phenomenon is called antibody-dependent infection enhancement (ADE). ADE not only promotes the virus to be recognized by the target cell and enters the target cell, but also affects the signal transmission in the target cell. Early formalin-inactivated virus vaccines such as aluminum adjuvants (RSV and measles) have been shown to induce ADE. Although there is no direct evidence that there is ADE in COVID-19, this potential risk is a huge challenge for prevention and vaccine development. This article focuses on the virus-induced ADE phenomenon and its molecular mechanism. It also summarizes various attempts in vaccine research and development to eliminate the ADE phenomenon, and proposes to avoid ADE in vaccine development from the perspective of antigens and adjuvants.


Subject(s)
Antibody-Dependent Enhancement , COVID-19 , Antibodies, Viral , Humans , SARS-CoV-2
14.
Hum Vaccin Immunother ; 17(11): 4121-4125, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1429135

ABSTRACT

Current vaccines, which induce a B-cell-mediated antibody response against the spike protein of SARS-CoV-2, have markedly reduced infection rates. However, the emergence of new variants as a result of SARS-CoV-2 evolution requires the development of novel vaccines that are T-cell-based and that target mutant-specific spike proteins along with ORF1ab or nucleocapsid protein. This approach is more accommodative in inducing highly neutralizing antibodies, without the risk of antibody-dependent enhancement, as well as memory CD8+T-cell immunity.


Subject(s)
Antibody-Dependent Enhancement , COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Humans , RNA, Messenger , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination
15.
J Virol ; 95(19): e0068521, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1410201

ABSTRACT

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here, we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351, and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralizing antibody approaches. Furthermore, we report a preclinical characterization package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralization capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralized four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilizing soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence, thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: while previous ACE2-based therapeutics have been described, ours has novel features, including (i) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system, (ii) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection, and reduced risk of hyperinflammation, and (iii) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralization potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic MAb.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Antibodies, Neutralizing/immunology , Antibody-Dependent Enhancement , COVID-19/immunology , HEK293 Cells , Humans , Kinetics , Mutation , Protein Binding , Protein Domains , Protein Interaction Domains and Motifs , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism
18.
Front Immunol ; 12: 690976, 2021.
Article in English | MEDLINE | ID: covidwho-1337639

ABSTRACT

Different emerging viral infections may emerge in different regions of the world and pose a global pandemic threat with high fatality. Clarification of the immunopathogenesis of different emerging viral infections can provide a plan for the crisis management and prevention of emerging infections. This perspective article describes how an emerging viral infection evolves from microbial mutation, zoonotic and/or vector-borne transmission that progresses to a fatal infection due to overt viremia, tissue-specific cytotropic damage or/and immunopathology. We classified immunopathogenesis of common emerging viral infections into 4 categories: 1) deficient immunity with disseminated viremia (e.g., Ebola); 2) pneumocytotropism with/without later hyperinflammation (e.g., COVID-19); 3) augmented immunopathology (e.g., Hanta); and 4) antibody-dependent enhancement of infection with altered immunity (e.g., Dengue). A practical guide to early blocking of viral evasion, limiting viral load and identifying the fatal mechanism of an emerging viral infection is provided to prevent and reduce the transmission, and to do rapid diagnoses followed by the early treatment of virus neutralization for reduction of morbidity and mortality of an emerging viral infection such as COVID-19.


Subject(s)
COVID-19/immunology , Communicable Diseases, Emerging/immunology , Immune Evasion/immunology , SARS-CoV-2/physiology , Virus Diseases/immunology , Animals , Antibody-Dependent Enhancement , COVID-19/mortality , COVID-19/prevention & control , Humans , Pandemics , Survival Analysis , Virus Diseases/mortality , Virus Diseases/prevention & control
19.
MAbs ; 13(1): 1953683, 2021.
Article in English | MEDLINE | ID: covidwho-1327301

ABSTRACT

The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread social and economic disruption. Effective interventions are urgently needed for the prevention and treatment of COVID-19. Neutralizing monoclonal antibodies (mAbs) have demonstrated their prophylactic and therapeutic efficacy against SARS-CoV-2, and several have been granted authorization for emergency use. Here, we discover and characterize a fully human cross-reactive mAb, MW06, which binds to both SARS-CoV-2 and SARS-CoV spike receptor-binding domain (RBD) and disrupts their interaction with angiotensin-converting enzyme 2 (ACE2) receptors. Potential neutralization activity of MW06 was observed against both SARS-CoV-2 and SARS-CoV in different assays. The complex structure determination and epitope alignment of SARS-CoV-2 RBD/MW06 revealed that the epitope recognized by MW06 is highly conserved among SARS-related coronavirus strains, indicating the potential broad neutralization activity of MW06. In in vitro assays, no antibody-dependent enhancement (ADE) of SARS-CoV-2 infection was observed for MW06. In addition, MW06 recognizes a different epitope from MW05, which shows high neutralization activity and has been in a Phase 2 clinical trial, supporting the development of the cocktail of MW05 and MW06 to prevent against future escaping variants. MW06 alone and the cocktail show good effects in preventing escape mutations, including a series of variants of concern, B.1.1.7, P.1, B.1.351, and B.1.617.1. These findings suggest that MW06 recognizes a conserved epitope on SARS-CoV-2, which provides insights for the development of a universal antibody-based therapy against SARS-related coronavirus and emerging variant strains, and may be an effective anti-SARS-CoV-2 agent.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , SARS Virus/immunology , SARS-CoV-2/immunology , Amino Acid Sequence , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/therapeutic use , Antibody-Dependent Enhancement , COVID-19/drug therapy , COVID-19/therapy , Conserved Sequence , Cross Reactions , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Humans , Models, Molecular , Neutralization Tests , Pandemics , Protein Domains , Protein Interaction Domains and Motifs , SARS Virus/chemistry , SARS Virus/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
20.
Mol Cells ; 44(6): 392-400, 2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1249738

ABSTRACT

It has been more than a year since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged. Many studies have provided insights into the various aspects of the immune response in coronavirus disease 2019 (COVID-19). Especially for antibody treatment and vaccine development, humoral immunity to SARS-CoV-2 has been studied extensively, though there is still much that is unknown and controversial. Here, we introduce key discoveries on the humoral immune responses in COVID-19, including the immune dynamics of antibody responses and correlations with disease severity, neutralizing antibodies and their cross-reactivity, how long the antibody and memory B-cell responses last, aberrant autoreactive antibodies generated in COVID-19 patients, and the efficacy of currently available therapeutic antibodies and vaccines against circulating SARS-CoV-2 variants, and highlight gaps in the current knowledge.


Subject(s)
Antibodies, Neutralizing/biosynthesis , B-Lymphocytes/immunology , COVID-19/immunology , Immunoglobulin Class Switching , Immunoglobulin G/biosynthesis , SARS-CoV-2/pathogenicity , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/biosynthesis , Antibody-Dependent Enhancement , Autoantibodies/biosynthesis , B-Lymphocytes/virology , COVID-19/drug therapy , COVID-19/mortality , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , Immunity, Humoral/drug effects , Immunoglobulin A/biosynthesis , Immunoglobulin M/biosynthesis , Immunologic Memory , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis
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