scholarly journals Intranasal administration of a monoclonal neutralizing antibody protects mice against SARS-CoV-2 infection

2021 ◽  
Author(s):  
Sandro Halwe ◽  
Alexandra Kupke ◽  
Kanika Vanshylla ◽  
Falk Liberta ◽  
Henning Gruell ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Pharmacokinetic Profile ◽  
Lung Pathology ◽  
Therapeutic Drugs ◽  
Intranasal Application ◽  
Important Drug

Despite recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both, prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2 and retains activity against the variants of concern B.1.1.7 and B.1.351. Importantly, not only systemic but also intranasal application of DZIF-10c abolished presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.

scholarly journals Intranasal Administration of a Monoclonal Neutralizing Antibody Protects Mice Against SARS-CoV-2 Infection

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1498
Author(s):  
Sandro Halwe ◽  
Alexandra Kupke ◽  
Kanika Vanshylla ◽  
Falk Liberta ◽  
Henning Gruell ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Pharmacokinetic Profile ◽  
Lung Pathology ◽  
Therapeutic Drugs ◽  
Intranasal Application ◽  
Important Drug

Despite the recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of the SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2, retains full activity against the variant of concern (VOC) B.1.1.7 and still neutralizes the VOC B.1.351, although with reduced potency. Importantly, not only systemic but also intranasal application of DZIF-10c abolished the presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology when administered prophylactically. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies.

scholarly journals Functionalized Nanoparticles in Prevention and Targeted Therapy of Viral Diseases With Neurotropism Properties, Special Insight on COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Meishen Ren ◽  
Yin Wang ◽  
Yan Luo ◽  
Xueping Yao ◽  
Zexiao Yang ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Neutralizing Antibodies ◽  
Functionalized Nanoparticles ◽  
Neurotropic Viruses ◽  
The Central Nervous System ◽  
Recent Trends ◽  
Simplex Virus

Neurotropic viruses have neural-invasive and neurovirulent properties to damage the central nervous system (CNS), leading to humans’ fatal symptoms. Neurotropic viruses comprise a lot of viruses, such as Zika virus (ZIKV), herpes simplex virus (HSV), rabies virus (RABV), and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Effective therapy is needed to prevent infection by these viruses in vivo and in vitro. However, the blood-brain barrier (BBB) usually prevents macromolecules from entering the CNS, which challenges the usage of the traditional probes, antiviral drugs, or neutralizing antibodies in the CNS. Functionalized nanoparticles (NPs) have been increasingly reported in the targeted therapy of neurotropic viruses due to their sensitivity and targeting characteristics. Therefore, the present review outlines efficient functionalized NPs to further understand the recent trends, challenges, and prospects of these materials.

scholarly journals LACK OF IDENTITY IN NEUTRALIZING AND HEMAGGLUTINATION-INHIBITING ANTIBODIES AGAINST INFLUENZA VIRUSES

1950 ◽  
Vol 91 (1) ◽  
pp. 65-86 ◽  
Author(s):  
Duard L. Walker ◽  
Frank L. Horsfall
Keyword(s):  
Influenza Virus ◽  
Hemagglutination Inhibition ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Immune Serum ◽  
Influenza Viruses ◽  
In Ovo ◽  
Neutralization Line

There is an exponential linear relationship between the quantity of influenza virus neutralized and the quantity of immune serum employed in in ovo neutralization. The slope of the neutralization line is extremely steep. The concentration of neutralizing antibody can be measured with considerable precision in ovo if the constant virus-varying serum technique is utilized. The amounts of hemagglutination-inhibiting and neutralizing antibodies which are absorbed by a given quantity of influenza virus (PR8) were found to be predictable and the degree of reactivity of these two antibodies was shown to be directly related to the extent of immunization. It was demonstrated that there are marked discrepancies in correlation between antibody titers obtained by in vitro hemagglutination-inhibition and in vivo neutralization techniques and that neutralizing antibody is preferentially absorbed by a given quantity of virus. Inasmuch as the results were found not to be attributable to peculiarities of the techniques employed, it appears that the antibodies measured by hemagglutination-inhibition in vitro and by neutralization in vivo are not identical.

scholarly journals Effect of Preexisting Immunity on an Adenovirus Vaccine Vector: In Vitro Neutralization Assays Fail To Predict Inhibition by Antiviral Antibody In Vivo

2009 ◽  
Vol 83 (11) ◽  
pp. 5567-5573 ◽  
Author(s):  
Susan L. Pichla-Gollon ◽  
Shih-Wen Lin ◽  
Scott E. Hensley ◽  
Marcio O. Lasaro ◽  
Larissa Herkenhoff-Haut ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Adenovirus ◽  
T Cell Response ◽  
Fundamental Properties ◽  
High Prevalence ◽  
Antiviral Antibody ◽  
Adenovirus Vectors

ABSTRACT A major obstacle to the use of adenovirus vectors derived from common human serotypes, such as human adenovirus 5 (AdHu5), is the high prevalence of virus-neutralizing antibodies in the human population. We previously constructed a variant of chimpanzee adenovirus 68 (AdC68) that maintained the fundamental properties of the carrier but was serologically distinct from AdC68 and resisted neutralization by AdC68 antibodies. In the present study, we tested whether this modified vector, termed AdCDQ, could induce transgene product-specific CD8+ T cells in mice with preexisting neutralizing antibody to wild-type AdC68. Contrary to our expectation, the data show conclusively that antibodies that fail to neutralize the AdCDQ mutant vector in vitro nevertheless impair the vector's capacity to transduce cells and to stimulate a transgene product-specific CD8+ T-cell response in vivo. The results thus suggest that in vitro neutralization assays may not reliably predict the effects of virus-specific antibodies on adenovirus vectors in vivo.

scholarly journals Isolation of a panel of ultra-potent human antibodies neutralizing SARS-CoV-2 and viral variants of concern

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Andrey A. Gorchakov ◽  
Sergey V. Kulemzin ◽  
Sergey V. Guselnikov ◽  
Konstantin O. Baranov ◽  
Tatyana N. Belovezhets ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Lung Pathology ◽  
Human Monoclonal Antibodies ◽  
Systematic Analysis ◽  
Treatment And Prevention ◽  
Rational Development ◽  
Small Molecule Drugs

AbstractIn the absence of virus-targeting small-molecule drugs approved for the treatment and prevention of COVID-19, broadening the repertoire of potent SARS-CoV-2-neutralizing antibodies represents an important area of research in response to the ongoing pandemic. Systematic analysis of such antibodies and their combinations can be particularly instrumental for identification of candidates that may prove resistant to the emerging viral escape variants. Here, we isolated a panel of 23 RBD-specific human monoclonal antibodies from the B cells of convalescent patients. A surprisingly large proportion of such antibodies displayed potent virus-neutralizing activity both in vitro and in vivo. Four of the isolated nAbs can be categorized as ultrapotent with an apparent IC100 below 16 ng/mL. We show that individual nAbs as well as dual combinations thereof retain activity against currently circulating SARS-CoV-2 variants of concern (such as B.1.1.7, B.1.351, B.1.617, and C.37), as well as against other viral variants. When used as a prophylactics or therapeutics, these nAbs could potently suppress viral replication and prevent lung pathology in SARS-CoV-2-infected hamsters. Our data contribute to the rational development of oligoclonal therapeutic nAb cocktails mitigating the risk of SARS-CoV-2 escape.

scholarly journals Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice.

2021 ◽  
Author(s):  
Alexandra Schafer ◽  
David R Martinez ◽  
John J Won ◽  
Fernanado R Moreira ◽  
Ariane J Brown ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Therapeutic Efficacy ◽  
Treatment Options ◽  
Pharmacokinetic Profile ◽  
Nucleoside Analog ◽  
Lung Pathology ◽  
Orally Bioavailable ◽  
Therapeutic Monoclonal Antibodies

The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 should be explored as a potential treatment for COVID-19 in humans.

scholarly journals Influence of N-Linked Glycosylation of Porcine Reproductive and Respiratory Syndrome Virus GP5 on Virus Infectivity, Antigenicity, and Ability To Induce Neutralizing Antibodies

2006 ◽  
Vol 80 (8) ◽  
pp. 3994-4004 ◽  
Author(s):  
Israrul H. Ansari ◽  
Byungjoon Kwon ◽  
Fernando A. Osorio ◽  
Asit K. Pattnaik
Keyword(s):  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Respiratory Syndrome Virus ◽  
Virus Infectivity ◽  
Neutralization Epitope ◽  
Enhanced Sensitivity

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) glycoprotein 5 (GP5) is the most abundant envelope glycoprotein and a major inducer of neutralizing antibodies in vivo. Three putative N-linked glycosylation sites (N34, N44, and N51) are located on the GP5 ectodomain, where a major neutralization epitope also exists. To determine which of these putative sites are used for glycosylation and the role of the glycan moieties in the neutralizing antibody response, we generated a panel of GP5 mutants containing amino acid substitutions at these sites. Biochemical studies with expressed wild-type (wt) and mutant proteins revealed that the mature GP5 contains high-mannose-type sugar moieties at all three sites. These mutations were subsequently incorporated into a full-length cDNA clone. Our data demonstrate that mutations involving residue N44 did not result in infectious progeny production, indicating that N44 is the most critical amino acid residue for infectivity. Viruses carrying mutations at N34, N51, and N34/51 grew to lower titers than the wt PRRSV. In serum neutralization assays, the mutant viruses exhibited enhanced sensitivity to neutralization by wt PRRSV-specific antibodies. Furthermore, inoculation of pigs with the mutant viruses induced significantly higher levels of neutralizing antibodies against the mutant as well as the wt PRRSV, suggesting that the loss of glycan residues in the ectodomain of GP5 enhances both the sensitivity of these viruses to in vitro neutralization and the immunogenicity of the nearby neutralization epitope. These results should have great significance for development of PRRSV vaccines of enhanced protective efficacy.

scholarly journals A single dose of recombinant VSV-ΔG-spike vaccine provides protection against SARS-CoV-2 challenge

2020 ◽  
Author(s):  
Yfat Yahalom-Ronen ◽  
Hadas Tamir ◽  
Sharon Melamed ◽  
Boaz Politi ◽  
Ohad Shifman ◽  
...  
Keyword(s):  
Single Dose ◽  
Neutralizing Antibodies ◽  
Rapid Development ◽  
Body Weight Loss ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Lung Pathology ◽  
Golden Syrian Hamster

AbstractThe COVID-19 pandemic caused by SARS-CoV-2 that emerged in December 2019 in China resulted in over 7.8 million infections and over 430,000 deaths worldwide, imposing an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we generated a replication competent recombinant VSV-ΔG-spike vaccine, in which the glycoprotein of VSV was replaced by the spike protein of the SARS-CoV-2. In vitro characterization of the recombinant VSV-ΔG-spike indicated expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in vivo model for COVID-19 was implemented. We show that vaccination of hamsters with recombinant VSV-ΔG-spike results in rapid and potent induction of neutralizing antibodies against SARS-CoV-2. Importantly, single-dose vaccination was able to protect hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss of the immunized hamsters compared to unvaccinated hamsters. Furthermore, whereas lungs of infected hamsters displayed extensive tissue damage and high viral titers, immunized hamsters’ lungs showed only minor lung pathology, and no viral load. Taken together, we suggest recombinant VSV-ΔG-spike as a safe, efficacious and protective vaccine against SARS-CoV-2 infection.

scholarly journals The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates

2021 ◽  
Author(s):  
Dapeng Li ◽  
Robert J Edwards ◽  
Kartik Manne ◽  
David R. Martinez ◽  
Alexandra Schäfer ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Nonhuman Primates ◽  
Safety Concern ◽  
Lung Pathology ◽  
Receptor Binding Domain ◽  
Biologically Relevant ◽  
Cryo Electron Microscopy ◽  
History Of

SummarySARS-CoV-2 neutralizing antibodies (NAbs) protect against COVID-19, making them a focus of vaccine design. A safety concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated potent NAbs against the receptor-binding domain (RBD) and the N-terminal domain (NTD) of SARS-CoV-2 spike protein from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV-1 infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of antibody binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both in vitro neutralizing and infection-enhancing RBD or infection-enhancing NTD antibodies protected from SARS-CoV-2 challenge in non-human primates and mice. One of 30 monkeys infused with enhancing antibodies had lung pathology and bronchoalveolar lavage cytokine evidence suggestive of enhanced disease. Thus, these in vitro assessments of enhanced antibody-mediated infection do not necessarily indicate biologically relevant in vivo infection enhancement.

scholarly journals SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients

2020 ◽  
Author(s):  
William B. Klimstra ◽  
Natasha L. Tilston-Lunel ◽  
Sham Nambulli ◽  
James Boslett ◽  
Cynthia M. McMillen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Serum Samples ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
Similar Disease ◽  
Antibody Titers ◽  
Low Passage

AbstractSARS-CoV-2, the causative agent of COVID-19, emerged at the end of 2019 and by mid-June 2020, the virus has spread to at least 215 countries, caused more than 8,000,000 confirmed infections and over 450,000 deaths, and overwhelmed healthcare systems worldwide. Like SARS-CoV, which emerged in 2002 and caused a similar disease, SARS-CoV-2 is a betacoronavirus. Both viruses use human angiotensin-converting enzyme 2 (hACE2) as a receptor to enter cells. However, the SARS-CoV-2 spike (S) glycoprotein has a novel insertion that generates a putative furin cleavage signal and this has been postulated to expand the host range. Two low passage (P) strains of SARS-CoV-2 (Wash1: P4 and Munich: P1) were cultured twice in Vero-E6 cells and characterized virologically. Sanger and MinION sequencing demonstrated significant deletions in the furin cleavage signal of Wash1: P6 and minor variants in the Munich: P3 strain. Cleavage of the S glycoprotein in SARS-CoV-2-infected Vero-E6 cell lysates was inefficient even when an intact furin cleavage signal was present. Indirect immunofluorescence demonstrated the S glycoprotein reached the cell surface. Since the S protein is a major antigenic target for the development of neutralizing antibodies we investigated the development of neutralizing antibody titers in serial serum samples obtained from COVID-19 human patients. These were comparable regardless of the presence of an intact or deleted furin cleavage signal. These studies illustrate the need to characterize virus stocks meticulously prior to performing either in vitro or in vivo pathogenesis studies.

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