scholarly journals Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals

2021 ◽  
Author(s):  
Elaine C. Chen ◽  
Pavlo Gilchuk ◽  
Seth J. Zost ◽  
Naveenchandra Suryadevara ◽  
Emma S. Winkler ◽  
...  
Keyword(s):  
Antibody Responses ◽  
Viral Escape ◽  
Spike Protein ◽  
Heptad Repeat ◽  
Healthy Individuals ◽  
Large Numbers ◽  
Escape Mutants ◽  
Insight Into ◽  
Selection Of

Unrelated individuals can produce genetically similar clones of antibodies, known as public clonotypes, which have been seen in responses to different infectious diseases as well as healthy individuals. Here we identify 37 public clonotypes in memory B cells from convalescent survivors of SARS-CoV-2 infection or in plasmablasts from an individual after vaccination with mRNA-encoded spike protein. We identified 29 public clonotypes, including clones recognizing the receptor-binding domain (RBD) in the spike protein S1 subunit (including a neutralizing, ACE2-blocking clone that protects in vivo), and others recognizing non-RBD epitopes that bound the heptad repeat 1 region of the S2 domain. Germline-revertant forms of some public clonotypes bound efficiently to spike protein, suggesting these common germline-encoded antibodies are preconfigured for avid recognition. Identification of large numbers of public clonotypes provides insight into the molecular basis of efficacy of SARS-CoV-2 vaccines and sheds light on the immune pressures driving the selection of common viral escape mutants.

scholarly journals Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants

2011 ◽  
Vol 208 (13) ◽  
pp. 2599-2606 ◽  
Author(s):  
Whitney E. Purtha ◽  
Thomas F. Tedder ◽  
Syd Johnson ◽  
Deepta Bhattacharya ◽  
Michael S. Diamond
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Large Fraction ◽  
West Nile Virus Infection ◽  
Immune Serum ◽  
Memory B Cells ◽  
Viral Escape ◽  
Variant Virus ◽  
Escape Mutants

Memory B cells (MBCs) and long-lived plasma cells (LLPCs) persist after clearance of infection, yet the specific and nonredundant role MBCs play in subsequent protection is unclear. After resolution of West Nile virus infection in mice, we demonstrate that LLPCs were specific for a single dominant neutralizing epitope, such that immune serum poorly inhibited a variant virus that encoded a mutation at this critical epitope. In contrast, a large fraction of MBC produced antibody that recognized both wild-type (WT) and mutant viral epitopes. Accordingly, antibody produced by the polyclonal pool of MBC neutralized WT and variant viruses equivalently. Remarkably, we also identified MBC clones that recognized the mutant epitope better than the WT protein, despite never having been exposed to the variant virus. The ability of MBCs to respond to variant viruses in vivo was confirmed by experiments in which MBCs were adoptively transferred or depleted before secondary challenge. Our data demonstrate that class-switched MBC can respond to variants of the original pathogen that escape neutralization of antibody produced by LLPC without a requirement for accumulating additional somatic mutations.

scholarly journals Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8+-T-Cell Escape Variants of Influenza Virus

2005 ◽  
Vol 79 (13) ◽  
pp. 8545-8559 ◽  
Author(s):  
Graeme E. Price ◽  
Lei Huang ◽  
Rong Ou ◽  
Menghua Zhang ◽  
Demetrius Moskophidis
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Vaccine Development ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Viral Escape ◽  
Viral Control ◽  
Ctl Escape ◽  
Selection Of

ABSTRACT Antigenic variation is a viral strategy exploited to promote survival in the face of the host immune response and represents a major challenge for efficient vaccine development. Influenza viruses are pathogens with high transmissibility and mutation rates, enabling viral escape from immunity induced by prior infection or vaccination. Intense selection from neutralizing antibody drives antigenic changes in the surface glycoproteins, resulting in emergence of new strains able to reinfect hosts immune to previously circulating viruses. CD8+ cytotoxic T cells (CTLs) also provide protective immunity from influenza virus infection and may contribute to the antigenic evolution of influenza viruses. Utilizing mice transgenic for an influenza virus NP366-374 peptide-specific T-cell receptor, we demonstrated that the respiratory tract is a suitable site for generation of escape variants of influenza virus selected by CTL in vivo. In this report the contributions of the perforin and Fas pathways utilized by influenza virus-specific CTLs in viral clearance and selection of CTL escape variants have been evaluated. While transgenic CTLs deficient in either perforin- or Fas-mediated pathways are efficient in initial pulmonary viral control, variant virus emergence was observed in all the mice studied, although the spectrum of viral CTL escape variants selected varied profoundly. Thus, a less-restricted repertoire of escape variants was observed in mice with an intact perforin cytotoxic pathway compared with a limited variant diversity in perforin pathway-deficient mice, although maximal variant diversity was observed in mice having both Fas and perforin pathways intact. We conclude that selection of viral CTL escape variants reflects coordinate action between the tightly controlled perforin/granzyme pathway and the more promiscuous Fas/FasL pathway.

scholarly journals Feline Coronavirus Antivirals: A Review

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1150
Author(s):  
Manon Delaplace ◽  
Hélène Huet ◽  
Adèle Gambino ◽  
Sophie Le Poder
Keyword(s):  
Research Area ◽  
Viral Escape ◽  
Viral Pathogens ◽  
Feline Infectious Peritonitis ◽  
Escape Mutants ◽  
Asymptomatic Infections ◽  
Therapeutic Compounds ◽  
Feline Coronavirus

Feline coronaviruses (FCoV) are common viral pathogens of cats. They usually induce asymptomatic infections but some FCoV strains, named Feline Infectious Peritonitis Viruses (FIPV) lead to a systematic fatal disease, the feline infectious peritonitis (FIP). While no treatments are approved as of yet, numerous studies have been explored with the hope to develop therapeutic compounds. In recent years, two novel molecules (GS-441524 and GC376) have raised hopes given the encouraging results, but some concerns about the use of these molecules persist, such as the fear of the emergence of viral escape mutants or the difficult tissue distribution of these antivirals in certain affected organs. This review will summarize current findings and leads in the development of antiviral therapy against FCoV both in vitro and in vivo, with the description of their mechanisms of action when known. It highlights the molecules, which could have a broader effect on different coronaviruses. In the context of the SARS-CoV-2 pandemic, the development of antivirals is an urgent need and FIP could be a valuable model to help this research area.

scholarly journals Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

2021 ◽  
Author(s):  
Vincent Dussupt ◽  
Rajeshwer S. Sankhala ◽  
Letzibeth Mendez-Rivera ◽  
Samantha M. Townsley ◽  
Fabian Schmidt ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Low Dose ◽  
Viral Escape ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Viral Inactivation ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Monoclonal Antibodies ◽  
Potent Protection

AbstractPrevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

scholarly journals Erythrocyte-targeted immunomodulatory antigens enabled by in vivo selection of D-peptides

2020 ◽  
Author(s):  
Alexander R. Loftis ◽  
Genwei Zhang ◽  
Coralie Backlund ◽  
Anthony J. Quartararo ◽  
Novalia Pishesha ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
T Cell ◽  
Protective Antigen ◽  
Peptide Library ◽  
Antibody Responses ◽  
Peptide Antigen ◽  
Cell Responses ◽  
In Vivo Selection ◽  
Selection Of

AbstractTargeting of antigens to erythrocytes can be used to selectively mitigate their immunogenicity, but the methods to equip a variety of cargoes with erythrocyte-targeting properties are limited. Here we identified a D-peptide that targets murine erythrocytes and decreases anti-drug antibody responses when conjugated to the protective antigen from Bacillus anthracis, a protein of therapeutic interest. The D-peptide likewise decreases inflammatory anti-ovalbumin (OVA) CD8+ T cell responses when attached to a peptide antigen derived from OVA. To discover this targeting ligand, we leveraged mass spectrometry to decode a randomized D-peptide library selected in mice, extending the application of synthetic libraries to in vivo affinity selections.

In vivo screening of salinity tolerance in Giant Swamp Taro (Cyrtosperma merkusii)

2014 ◽  
Vol 32 (1) ◽  
pp. 33
Author(s):  
Shiwangni Rao ◽  
Mary Taylor ◽  
Anjeela Jokhan
Keyword(s):  
Salt Tolerance ◽  
Sea Water ◽  
Soil Conditions ◽  
The Pacific ◽  
Salinity Levels ◽  
Water Inundation ◽  
Poor Soil ◽  
Insight Into ◽  
Selection Of

Giant Swamp Taro (Cyrtosperma merkusii) is a staple food crop in the Pacific, especially in the low lying atoll islands such as Tuvalu and Kiribati. This is owing to its ability to survive under poor soil conditions and harsh environments. However, as a result of the effects of climate change such as sea water inundation and intrusion into the fresh ground water lens, this crop is now under threat. To address this issue an adaption approach was taken whereby, Cyrtosperma merkusii was screened in vivo for salt tolerance. The epistemology followed random selection of two cultivars Ikaraoi and Katutu. These two cultivars were subjected to 0% (0 parts per trillion), 0.5% (5 ppt), 1% (10 ppt), 1.5% (15 ppt) and 2% (20 ppt) of salt in Yates’s advance seedling common potting mix. Both cultivars were able to tolerate salinity levels up-to 5ppt which is significantly more than the salt tolerance in glycophytes of 2.83 ppt. This research provides an insight into the variation of salt tolerance that may exist in C.merkusii gene pool, which can be used to adapt to natural disasters and buffer its impacts.

scholarly journals In vitro and in vivo preclinical studies predict REGEN-COV protection against emergence of viral escape in humans

2021 ◽  
Author(s):  
Richard Copin ◽  
Alina Baum ◽  
Elzbieta Wloga ◽  
Kristen E. Pascal ◽  
Stephanie Giordano ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Therapeutic Option ◽  
Viral Escape ◽  
Spike Protein ◽  
In Vivo Studies ◽  
Preclinical Studies ◽  
Global Pandemic ◽  
Emerging Virus

SummaryMonoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in nature or identified from preclinical in vitro and in vivo studies and in the clinic. This study demonstrates that a combination of noncompeting antibodies not only provides full coverage against currently circulating variants but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

scholarly journals Allosteric pathway selection in templated assembly

2019 ◽  
Vol 5 (10) ◽  
pp. eaaw3353 ◽  
Author(s):  
Martijn van Galen ◽  
Ruben Higler ◽  
Joris Sprakel
Keyword(s):  
Building Blocks ◽  
Supramolecular Interactions ◽  
High Fidelity ◽  
Self Assembling ◽  
Molecular Building Blocks ◽  
Large Numbers ◽  
Solution Aggregation ◽  
Allosteric Pathway ◽  
Insight Into ◽  
Selection Of

Assembling large numbers of molecular building blocks into functional nanostructures is no trivial task. It relies on guiding building blocks through complex energy landscapes shaped by synergistic and antagonistic supramolecular interactions. In nature, the use of molecular templates is a potent strategy to navigate the process to the desired structure with high fidelity. Yet, nature’s templating strategy remains to be fully exploited in man-made nanomaterials. Designing effective template-guided self-assembling systems can only be realized through precise insight into how the chemical design of building blocks and the resulting balance of repulsive and attractive forces give rise to pathway selection and suppression of trapped states. We develop a minimal model to unravel the kinetic pathways and pathway selection of the templated assembly of molecular building blocks on a template. We show how allosteric activation of the associative interactions can suppress undesired solution-aggregation pathways and gives rise to a true template-assembly path.

Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo

Nature ◽  
1990 ◽  
Vol 346 (6285) ◽  
pp. 629-633 ◽  
Author(s):  
Hanspeter Pircher ◽  
Demetrius Moskophidis ◽  
Urs Rohrer ◽  
Kurt Bürki ◽  
Hans Hengartner ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Escape ◽  
Cytotoxic T Cell ◽  
Resistant Virus ◽  
Selection Of

scholarly journals Different In Vivo Effects of HIV-1 Immunodominant Epitope-Specific Cytotoxic T Lymphocytes on Selection of Escape Mutant Viruses

2010 ◽  
Vol 84 (11) ◽  
pp. 5508-5519 ◽  
Author(s):  
Hirokazu Koizumi ◽  
Masao Hashimoto ◽  
Mamoru Fujiwara ◽  
Hayato Murakoshi ◽  
Takayuki Chikata ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Neutralizing Antibodies ◽  
Escape Mutant ◽  
Escape Mutants ◽  
Hiv 1 ◽  
Selection Of ◽  
Strong Ability

ABSTRACT HIV-1 escape mutants are well known to be selected by immune pressure via HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies. The ability of the CTLs to suppress HIV-1 replication is assumed to be associated with the selection of escape mutants from the CTLs. Therefore, we first investigated the correlation between the ability of HLA-A*1101-restricted CTLs recognizing immunodominant epitopes in vitro and the selection of escape mutants. The result showed that there was no correlation between the ability of these CTLs to suppress HIV-1 replication in vitro and the appearance of escape mutants. The CTLs that had a strong ability to suppress HIV-1 replication in vitro but failed to select escape mutants expressed a higher level of PD-1 in vivo, whereas those that had a strong ability to suppress HIV-1 replication in vitro and selected escape mutants expressed a low level of PD-1. Ex vivo analysis of these CTLs revealed that the latter CTLs had a significantly stronger ability to recognize the epitope than the former ones. These results suggest that escape mutations are selected by HIV-1-specific CTLs that have a stronger ability to recognize HIV-1 in vivo but not in vitro.

Sign in / Sign up

Export Citation Format

Share Document