scholarly journals Mutations in SARS-CoV-2 Variants Modulate the Microscopic Dynamics of Neutralizing Antibodies

2021 ◽  
Author(s):  
Dhiman Ray ◽  
Riley Nicolas Quijano ◽  
Ioan Andricioaei
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Graph Connectivity ◽  
World Population ◽  
The Novel ◽  
Long Distance ◽  
Correlated Motion ◽  
Novel Coronavirus ◽  
Microscopic Dynamics

Monoclonal antibodies have emerged as viable treatment for the COVID-19 disease caused by the SARS-CoV-2 virus. But the new viral variants can reduce the efficacy of the currently available antibodies, as well as diminish the vaccine induced immunity. Here, we demonstrate how the microscopic dynamics of the SARS-CoV-2 neutralizing monoclonal antibodies, can be modulated by the mutations present in the spike proteins of the variants currently circulating in the world population. We show that the dynamical perturbation in the antibody structure can be diverse, depending both on the nature of the antibody and on the location of the mutation. The correlated motion between the antibody and the receptor binding domain (RBD) can also be changed, altering the binding affinity. By constructing a protein graph connectivity network, we could delineate the mutant induced modifications in the allosteric information flow pathway through the antibody, and observed the presence of both localized and long distance effects. We identified a loop consisting of residues 470-490 in the RBD which works like an anchor preventing the detachment of the antibodies, and individual mutations in that region can significantly affect the antibody binding propensity. Our study provides fundamental and atomistically detailed insight on how virus neutralization by monoclonal antibody can be impacted by the mutations in the epitope, and can potentially facilitate the rational design of monoclonal antibodies, effective against the new variants of the novel coronavirus.

scholarly journals The emergence of SARS-CoV-2 variants threatens to decrease the efficacy of neutralizing antibodies and vaccines

2021 ◽  
Author(s):  
Kensaku Murano ◽  
Youjia Guo ◽  
Haruhiko Siomi
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
The Novel ◽  
Therapeutic Antibodies ◽  
Human Origin ◽  
New Challenges ◽  
Novel Coronavirus

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19) pandemic. As of August 2021, more than 200 million people have been infected with the virus and 4.3 million have lost their lives. Various monoclonal antibodies of human origin that neutralize the SARS-CoV-2 infection have been isolated from convalescent patients for therapeutic and prophylactic purposes. Several vaccines have been developed to restrict the spread of the virus and have been rapidly administered. However, the rollout of vaccines has coincided with the spread of variants of concern. Emerging variants of SARS-CoV-2 present new challenges for therapeutic antibodies and threaten the efficacy of current vaccines. Here, we review the problems faced by neutralizing antibodies and vaccines in the midst of the increasing spread of mutant viruses.

scholarly journals Comparison of Four SARS-CoV-2 Neutralization Assays

Vaccines ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 13
Author(s):  
Lydia Riepler ◽  
Annika Rössler ◽  
Albert Falch ◽  
André Volland ◽  
Wegene Borena ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Neutralizing Antibodies ◽  
The Other ◽  
In Vitro Assays ◽  
The Novel ◽  
Effective Protection ◽  
Vaccine Candidates ◽  
Vesicular Stomatitis ◽  
Novel Coronavirus

Neutralizing antibodies are a major correlate of protection for many viruses including the novel coronavirus SARS-CoV-2. Thus, vaccine candidates should potently induce neutralizing antibodies to render effective protection from infection. A variety of in vitro assays for the detection of SARS-CoV-2 neutralizing antibodies has been described. However, validation of the different assays against each other is important to allow comparison of different studies. Here, we compared four different SARS-CoV-2 neutralization assays using the same set of patient samples. Two assays used replication competent SARS-CoV-2, a focus forming assay and a TCID50-based assay, while the other two assays used replication defective lentiviral or vesicular stomatitis virus (VSV)-based particles pseudotyped with SARS-CoV-2 spike. All assays were robust and produced highly reproducible neutralization titers. Titers of neutralizing antibodies correlated well between the different assays and with the titers of SARS-CoV-2 S-protein binding antibodies detected in an ELISA. Our study showed that commonly used SARS-CoV-2 neutralization assays are robust and that results obtained with different assays are comparable.

Structurally Mapping Antigenic Epitopes of Adeno-Associated Virus 9: Development of Antibody Escape Variants

2021 ◽  
Author(s):  
Shanan N. Emmanuel ◽  
J. Kennon Smith ◽  
Jane Hsi ◽  
Yu-Shan Tseng ◽  
Matias Kaplan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Monoclonal Antibodies ◽  
Gene Delivery ◽  
General Population ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Transduction Efficiency ◽  
Viral Neutralization ◽  
Patient Cohort ◽  
Antigenic Epitopes

Adeno-associated viruses (AAV) serve as vectors for therapeutic gene delivery. AAV9 vectors have been FDA approved, as Zolgensma®, for the treatment of spinal muscular atrophy and is being evaluated in clinical trials for the treatment of neurotropic and musculotropic diseases. A major hurdle for AAV-mediated gene delivery is the presence of pre-existing neutralizing antibodies in 40 to 80% of the general population. These pre-existing antibodies can reduce therapeutic efficacy through viral neutralization, and the size of the patient cohort eligible for treatment. In this study, cryo-electron microscopy and image reconstruction was used to define the epitopes of five anti-AAV9 monoclonal antibodies (MAbs); ADK9, HL2368, HL2370, HL2372, and HL2374, on the capsid surface. Three of these, ADK9, HL2370, and HL2374, bound on or near the icosahedral 3-fold axes, HL2368 to the 2/5-fold wall, and HL2372 to the region surrounding the 5-fold axes. Pseudo-atomic modeling enabled the mapping and identification of antibody contact amino acids on the capsid, including S454 and P659. These epitopes overlap with previously defined parvovirus antigenic sites. Capsid amino acids critical for the interactions were confirmed by mutagenesis followed by biochemical assays testing recombinant AAV9 (rAAV9) variants capable of escaping recognition and neutralization by the parental MAbs. These variants retained parental tropism and had similar or improved transduction efficiency compared to AAV9. These engineered rAAV9 variants could expand the patient cohort eligible for AAV9-mediated gene delivery by avoiding pre-existing circulating neutralizing antibodies. IMPORTANCE The use of recombinant AAVs (rAAVs) as delivery vectors for therapeutic genes is becoming increasingly popular, especially following the FDA approval of Luxturna® and Zolgensma®, based on serotypes AAV2 and AAV9, respectively. However, high titer anti-AAV neutralizing antibodies in the general population, exempts patients from treatment. The goal of this study is to circumvent this issue by creating AAV variant vectors not recognized by pre-existing neutralizing antibodies. The mapping of the antigenic epitopes of five different monoclonal antibodies (MAbs) on AAV9, to recapitulate a polyclonal response, enabled the rational design of escape variants with minimal disruption to cell tropism and gene expression. This study, which included four newly developed and now commercially available MAbs, provides a platform for the engineering of rAAV9 vectors that can be used to deliver genes to patients with pre-exiting AAV antibodies.

Elucidation of the Binding Regions of PAI-1 Neutralizing Antibodies Using Chimeric Variants of Human and Rat PAI-1

2001 ◽  
Vol 85 (05) ◽  
pp. 866-874 ◽  
Author(s):  
A. P. Bijnens ◽  
T. H. Ngo ◽  
A. Gils ◽  
J. Dewaele ◽  
I. Knockaert ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Plasminogen Activator ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Biochemical Characterization ◽  
Tissue Type ◽  
Binding Region ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inhibitory Antibodies ◽  
Pai 1

SummaryIncreased levels of plasminogen activator inhibitor-1 (PAI-1), the main physiological inhibitor of tissue-type plasminogen activator (t-PA) in plasma, are a known risk factor for thromboembolic and cardiovascular diseases. The elucidation of the binding site of inhibitory monoclonal antibodies may contribute to the rational design of PAI-1 modulating therapeutics. In this study, homolog-scanning mutagenesis was used to identify the binding region of a variety of human PAI-1 inhibitory antibodies, lacking cross-reactivity with rat PAI-1. Therefore, eight chimeric human/rat PAI-1 variants, containing rat PAI-1 substitutions at the N-terminal or C-terminal end with splicing sites at positions 26, 81, 187, 277 or 327, were generated and purified. Biochemical characterization revealed that all chimeras were folded properly. Subsequently, surface plasmon resonance was used to determine the affinity of various monoclonal antibodies for these chimera. Comparative analysis of the affinity and ELISA data allowed the identification of the major binding region of the inhibitory antibodies MA-8H9D4, MA-33B8F7, MA-44E4, MA-42A2F6 and MA-56A7C10. Thus, three segments in human PAI-1 containing each at least one site involved in the neutralization of PAI-1 activity could be identified, i.e. (1) the segment from residue 81 to residue 187 (comprising -helices hD, hE and hF, -strands s4C, s3A, s2A and s1A and the loops connecting these elements), (2) the segment between residues 277 and 327 (hI, thIs5A, s5A and s6A) and (3) the region C-terminal from amino acid 327, including the reactive site loop. The current data, together with previous data, indicate that PAI-1 contains at least four different regions that could be considered as putative targets to modulate its activity.

scholarly journals A Structural Landscape of Neutralizing Antibodies Against SARS-CoV-2 Receptor Binding Domain

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling Niu ◽  
Kathryn N. Wittrock ◽  
Gage C. Clabaugh ◽  
Vikram Srivastava ◽  
Michael W. Cho
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Binding Domain ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Virus Life Cycle ◽  
Novel Coronavirus

SARS-CoV-2, the novel coronavirus responsible for the ongoing COVID-19 pandemic, has been spreading rampantly. The global scientific community has responded rapidly to understand immune correlates of protection to develop vaccines and immunotherapeutics against the virus. The major goal of this mini review is to summarize current understanding of the structural landscape of neutralizing antibodies (nAbs) that target the receptor binding domain (RBD) of viral spike (S) glycoprotein. The RBD plays a critical role in the very first step of the virus life cycle. Better understanding of where and how nAbs bind the RBD should enable identification of sites of vulnerability and facilitate better vaccine design and formulation of immunotherapeutics. Towards this goal, we compiled 38 RBD-binding nAbs with known structures. Review of these nAb structures showed that (1) nAbs can be divided into five general clusters, (2) there are distinct non-neutralizing faces on the RBD, and (3) maximum of potentially four nAbs could bind the RBD simultaneously. Since most of these nAbs were isolated from virus-infected patients, additional analyses of vaccine-induced nAbs could facilitate development of improved vaccines.

scholarly journals Formulating a Scalable Approach to Patron-Requested Digitization in Archives

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Kevin S. Hawkins ◽  
Julie Judkins
Keyword(s):  
Risk Assessment ◽  
Copyright Law ◽  
The Novel ◽  
Long Distance ◽  
Novel Coronavirus ◽  
Distance Travel ◽  
Long Distance Travel

The novel coronavirus of 2019 (COVID-19) crisis has forced archives to rethink their modes of providing access to physical collections. Whereas difficult copyright questions raised by reproducing items could previously be skirted by requiring researchers to work with materials in person, the long-term closure of reading rooms and decrease in long-distance travel mean that archives need a workflow for handling user digitization requests that is scalable and requires consulting only easily identifiable information and, assuming full reproduction is off the table, reproducing items in a collection under 17 U.S.C. § 108 or through a strategy of rapid risk assessment. There is a challenge in creating a policy that will work across different formats and genres of archival materials, so this article offers some suggestions for how to think about these parameters according to US copyright law and calls for a committee of experts to work out a model policy that could serve remote users of archival collections even after the COVID-19 crisis has passed.

scholarly journals The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

2021 ◽  
Vol 17 (12) ◽  
pp. e1010162
Author(s):  
Alexandra Melton ◽  
Lara A. Doyle-Meyers ◽  
Robert V. Blair ◽  
Cecily Midkiff ◽  
Hunter J. Melton ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Macaca Nemestrina ◽  
The Novel ◽  
Pigtail Macaque ◽  
Immunodeficiency Virus ◽  
Cytotoxic Molecules ◽  
Pathologic Lesions ◽  
Novel Coronavirus

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over five million people worldwide as of December 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

scholarly journals Food Containing Bioactive Flavonoids and Other Phenolic or Sulfur Phytochemicals With Antiviral Effect: Can We Design a Promising Diet Against COVID-19?

2021 ◽  
Vol 8 ◽  
Author(s):  
Martina Ghidoli ◽  
Federico Colombo ◽  
Stefano Sangiorgio ◽  
Michela Landoni ◽  
Luca Giupponi ◽  
...  
Keyword(s):  
Rational Design ◽  
Complementary Therapy ◽  
Antiviral Effect ◽  
The Novel ◽  
Therapeutic Approaches ◽  
Degree Of Protection ◽  
Global Pandemic ◽  
Cultivated Plant ◽  
Novel Coronavirus ◽  
Inflammatory Action

Since in late 2019, when the coronavirus 2 (SARS-CoV-2) pathogen of coronavirus disease 2019 (COVID-19) started to spread all over the world, causing the awful global pandemic we are still experiencing, an impressive number of biologists, infectious disease scientists, virologists, pharmacologists, molecular biologists, immunologists, and other researchers working in laboratories of all the advanced countries focused their research on the setting up of biotechnological tools, namely vaccines and monoclonal antibodies, as well as of rational design of drugs for therapeutic approaches. While vaccines have been quickly obtained, no satisfactory anti-Covid-19 preventive, or therapeutic approach has so far been discovered and approved. However, among the possible ways to achieve the goal of COVID-19 prevention or mitigation, there is one route, i.e., the diet, which until now has had little consideration. In fact, in the edible parts of plants supplying our food, there are a fair number of secondary metabolites mainly belonging to the large class of the flavonoids, endowed with antiviral or other health beneficial activities such as immunostimulating or anti-inflammatory action that could play a role in contributing to some extent to prevent or alleviate the viral infection and/or counteract the development of SARS induced by the novel coronavirus. In this review, a number of bioactive phytochemicals, in particular flavonoids, proven to be capable of providing some degree of protection against COVID-19, are browsed, illustrating their beneficial properties and mechanisms of action as well as their distribution in cultivated plant species which supply food for the human diet. Furthermore, room is also given to information regarding the amount in food, the resistance to cooking processes and, as a very important feature, the degree of bioavailability of these compounds. Concluding, remarks and perspectives for future studies aimed at increasing and improving knowledge and the possibility of using this natural complementary therapy to counteract COVID-19 and other viral pathologies are discussed.

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