scholarly journals Preserved Omicron Spike specific antibody binding and Fc-recognition across COVID-19 vaccine platforms

2021 ◽  
Author(s):  
Yannic C Bartsch ◽  
Xin Tong ◽  
Jaewon Kang ◽  
María J Avendaño ◽  
Eileen F Serrano ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Significant Loss ◽  
Multiple Infections ◽  
Specific Antibodies ◽  
Igg Binding ◽  
Effector Activity ◽  
Selective Preservation

Despite the dramatic spread of Omicron globally, even among highly vaccinated populations, death rates have not increased concomitantly. These data argue that alternative immune mechanisms, beyond neutralization, may continue to confer protection against severe disease. Beyond their ability to bind and block infection, antibodies contribute to control and clearance of multiple infections via their ability to direct antiviral immunity via Fc-effector mechanisms. Thus, here we probed the ability of vaccine induced antibodies, across three COVID-19 vaccines, to drive Fc-effector activity against Omicron. Despite the significant loss of IgM, IgA and IgG binding to the Omicron Receptor Binding Domain (RBD) across BNT162b2, mRNA-1273, and CoronaVac vaccines, stable isotype binding was observed across all of these vaccines to the Omicron Spike. Compromised RBD binding IgG was accompanied by a significant loss of cross RBD-specific antibody Fcγ-receptor binding by the CoronaVac vaccine, but preservation of RBD-specific FcγR2a and Fcγ3a binding across the mRNA vaccines. Conversely, Spike-specific antibodies exhibited persistent binding to Fcγ-receptors, across all three vaccines, albeit higher binding was observed with the mRNA vaccines, marked by a selective preservation of FcγR2a and Fcγ3a binding antibodies. Thus, despite the significant to near complete loss of Omicron neutralization across several vaccine platforms against Omicron, vaccine induced Spike-specific antibodies continue to recognize the virus and recruit Fc-receptors pointing to a persistent capacity for extra-neutralizing antibodies to contribute Omicron disease attenuation.

scholarly journals The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients

2020 ◽  
Vol 5 (48) ◽  
pp. eabc8413 ◽  
Author(s):  
Lakshmanane Premkumar ◽  
Bruno Segovia-Chumbez ◽  
Ramesh Jadi ◽  
David R. Martinez ◽  
Rajendra Raut ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Clinical Symptoms ◽  
Severe Disease ◽  
Population Level ◽  
Respiratory Illness ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Specific Antibodies

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.

scholarly journals Sequential Infection in Ferrets with Antigenically Distinct Seasonal H1N1 Influenza Viruses Boosts Hemagglutinin Stalk-Specific Antibodies

2015 ◽  
Vol 90 (2) ◽  
pp. 1116-1128 ◽  
Author(s):  
Greg A. Kirchenbaum ◽  
Donald M. Carter ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Specific Antibody ◽  
H1n1 Virus ◽  
H1n1 Influenza ◽  
Influenza Viruses ◽  
Specific Antibodies ◽  
Antibody Titers ◽  
Sequential Infection ◽  
Virus Isolates

ABSTRACTBroadly reactive antibodies targeting the conserved hemagglutinin (HA) stalk region are elicited following sequential infection or vaccination with influenza viruses belonging to divergent subtypes and/or expressing antigenically distinct HA globular head domains. Here, we demonstrate, through the use of novel chimeric HA proteins and competitive binding assays, that sequential infection of ferrets with antigenically distinct seasonal H1N1 (sH1N1) influenza virus isolates induced an HA stalk-specific antibody response. Additionally, stalk-specific antibody titers were boosted following sequential infection with antigenically distinct sH1N1 isolates in spite of preexisting, cross-reactive, HA-specific antibody titers. Despite a decline in stalk-specific serum antibody titers, sequential sH1N1 influenza virus-infected ferrets were protected from challenge with a novel H1N1 influenza virus (A/California/07/2009), and these ferrets poorly transmitted the virus to naive contacts. Collectively, these findings indicate that HA stalk-specific antibodies are commonly elicited in ferrets following sequential infection with antigenically distinct sH1N1 influenza virus isolates lacking HA receptor-binding site cross-reactivity and can protect ferrets against a pathogenic novel H1N1 virus.IMPORTANCEThe influenza virus hemagglutinin (HA) is a major target of the humoral immune response following infection and/or seasonal vaccination. While antibodies targeting the receptor-binding pocket of HA possess strong neutralization capacities, these antibodies are largely strain specific and do not confer protection against antigenic drift variant or novel HA subtype-expressing viruses. In contrast, antibodies targeting the conserved stalk region of HA exhibit broader reactivity among viruses within and among influenza virus subtypes. Here, we show that sequential infection of ferrets with antigenically distinct seasonal H1N1 influenza viruses boosts the antibody responses directed at the HA stalk region. Moreover, ferrets possessing HA stalk-specific antibody were protected against novel H1N1 virus infection and did not transmit the virus to naive contacts.

scholarly journals Structures of Two Human Astrovirus Capsid/Neutralizing Antibody Complexes Reveal Distinct Epitopes and Inhibition of Virus Attachment to Cells

2021 ◽  
Author(s):  
Lena Ricemeyer ◽  
Nayeli Aguilar-Hernández ◽  
Tomás López ◽  
Rafaela Espinosa ◽  
Sarah Lanning ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Viral Gastroenteritis ◽  
Receptor Binding Site ◽  
Virus Attachment ◽  
Human Astroviruses ◽  
Human Astrovirus

Human astrovirus is an important cause of viral gastroenteritis worldwide. Young children, the elderly, and the immunocompromised are especially at risk for contracting severe disease. However, no vaccines exist to combat human astrovirus infection. Evidence points to the importance of antibodies in enabling protection of healthy adults from reinfection. To develop an effective subunit vaccine that broadly protects against diverse astrovirus serotypes, we must understand how neutralizing antibodies target the capsid surface at the molecular level. Here, we report the structures of the human astrovirus capsid spike domain bound to two neutralizing monoclonal antibodies. These antibodies bind two distinct conformational epitopes on the spike surface. We add to existing evidence that the human astrovirus capsid spike contains a receptor-binding domain and demonstrate that both antibodies neutralize human astrovirus by blocking virus attachment to host cells. We identify patches of conserved amino acids that overlap or border the antibody epitopes and may constitute a receptor-binding site. Our findings provide a basis to develop therapies that prevent and treat human astrovirus gastroenteritis. Importance Human astroviruses infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies block virus infection. Here, we determined crystal structures of the astrovirus capsid protein in complex with two virus-neutralizing antibodies. We show that the antibodies bind two distinct sites on the capsid spike domain; however, both antibodies block virus attachment to human cells. Importantly, our findings support the use of the human astrovirus capsid spike as an antigen in a subunit-based vaccine to prevent astrovirus disease.

scholarly journals Exponential increase in neutralizing and spike specific antibodies following vaccination of COVID-19 convalescent plasma donors

2021 ◽  
Author(s):  
Molly A. Vickers ◽  
Alan Sariol ◽  
Judith Leon ◽  
Alexandra Ehlers ◽  
Aaron V. Locher ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Case Series ◽  
Neutralizing Antibody ◽  
Fold Increase ◽  
Chemiluminescence Immunoassay ◽  
Specific Antibodies ◽  
Exponential Increase ◽  
Single Vaccination ◽  
Antibody Levels

AbstractBackgroundWith the recent approval of COVID-19 vaccines, recovered COVID-19 subjects who are vaccinated may be ideal candidates to donate COVID-19 convalescent plasma (CCP).Case SeriesThree recovered COVID-19 patients were screened to donate CCP. All had molecularly confirmed COVID-19, and all were antibody positive by chemiluminescence immunoassay (DiaSorin) prior to vaccination. All were tested again for antibodies 11 to 21 days after they received the first dose of the vaccine (Pfizer). All showed dramatic increases (∼50 fold) in spike-specific antibody levels and had at least a 20-fold increase in the IC50 neutralizing antibody titer based on plaque reduction neutralization testing (PRNT). The spike-specific antibody levels following vaccination were significantly higher than those seen in any non-vaccinated COVID-19 subjects tested to date at our facility.ConclusionSpike-specific and neutralizing antibodies demonstrated dramatic increases following a single vaccination post COVID-19 infection which significantly exceeded values seen with COVID-19 infection alone. Recovered COVID-19 subjects who are vaccinated may make ideal candidates for CCP donation.

scholarly journals Early Antibodies Specific for the Neutralizing Epitope on the Receptor Binding Subunit of the Lymphocytic Choriomeningitis Virus Glycoprotein Fail To Neutralize the Virus

2007 ◽  
Vol 81 (21) ◽  
pp. 11650-11657 ◽  
Author(s):  
Bruno Eschli ◽  
Raphaël M. Zellweger ◽  
Alexander Wepf ◽  
Karl S. Lang ◽  
Katharina Quirin ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Wild Type ◽  
Neutralizing Epitope ◽  
Specific Antibodies ◽  
Deficient Mice ◽  
Binding Subunit

ABSTRACT Lymphocytic choriomeningitis virus (LCMV) is a murine arenavirus whose glycoprotein consists of a transmembrane subunit (GP-2) and a receptor-binding subunit (GP-1). LCMV-neutralizing antibodies (nAbs) are directed against a single site on GP-1 and occur 1 month after the infection of cytotoxic-T-lymphocyte (CTL) deficient mice. In wild-type mice, however, CTLs control early infection, and weak nAb titers emerge very late (after 70 to 150 days) if at all. Production of recombinant GP-1 in native conformation enabled us to study the emergence of GP-1-binding antibodies directed against the neutralizing epitope. By combining binding and neutralization assays, we correlated the development of binding antibodies versus nAbs in wild-type and CTL-deficient mice after infection with different LCMV doses. We found that wild-type mice developed GP-1-specific antibodies already by day 8 after exposure to high but not low doses, demonstrating that naive GP-1-specific B cells were infrequent. Furthermore, the induced antibodies bound to the neutralizing GP-1 epitope but failed to neutralize the virus and therefore were of low affinity. In CTL-deficient mice, where massive viremia quickly levels initial differences in viral load, low and high doses induced low-affinity non-neutralizing GP-1-binding antibodies with kinetics similar to high-dose-infected wild-type mice. Only in CTL-deficient mice, however, the GP-1-specific antibodies developed into nAbs within 1 month. We conclude that LCMV uses a dual strategy to evade nAb responses in wild-type mice. First, LCMV exploits a “hole” in the murine B-cell repertoire, which provides only a small and narrow initial pool of low-affinity GP-1-specific B cells. Second, affinity maturation of the available low-affinity non-neutralizing antibodies is impaired.

scholarly journals Preserved recognition of Omicron Spike following COVID-19 mRNA vaccination in pregnancy

2022 ◽  
Author(s):  
Yannic C Bartsch ◽  
Caroline Atyeo ◽  
Jaewon Kang ◽  
Kathryn J Gray ◽  
Andrea G. Edlow ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Disease Severity ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Fc Receptor ◽  
Binding Domain ◽  
Vaccine Uptake ◽  
Receptor Binding Domain ◽  
In Pregnancy

Summary Background SARS-CoV-2 infection is associated with enhanced disease severity in pregnant women. Despite the potential of COVID-19 vaccines to reduce severe disease, vaccine uptake remained relatively low among pregnant women. Just as coordinated messaging from the CDC and leading obstetrics organizations began to increase vaccine confidence in this vulnerable group, the evolution of SARS-CoV-2 variants of concerns (VOC) including the Omicron VOC raised new concerns about vaccine efficacy, given their ability to escape vaccine-induced neutralizing antibodies. Early data point to a milder disease course following omicron VOC infection in vaccinated individuals. Thus, these data suggest that alternate vaccine induced immunity, beyond neutralization, may continue to attenuate omicron disease, such as antibody-Fc-mediated activity. However, whether vaccine induced antibodies raised in pregnancy continue to bind and leverage Fc-receptors remains unclear. Methods VOC including Omicron receptor binding domain (RBD) or full Spike specific antibody isotype binding titers and FcγR binding were analyzed in pregnant women after the full dose regimen of either Pfizer/BioNtech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay. Findings Comparable, albeit reduced, isotype recognition was observed to the Omicron Spike and receptor binding domain (RBD) following both vaccines. Yet, despite the near complete loss of Fc-receptor binding to the Omicron RBD, Fc-receptor binding was largely preserved to the Omicron Spike. Interpretation Reduced binding titer to the Omicron RBD aligns with observed loss of neutralizing activity. Despite the loss of neutralization, preserved Omicron Spike recognition and Fc-receptor binding potentially continues to attenuate disease severity in pregnant women. Funding NIH and the Bill and Melinda Gates Foundation

scholarly journals The RBD Of The Spike Protein Of SARS-Group Coronaviruses Is A Highly Specific Target Of SARS-CoV-2 Antibodies But Not Other Pathogenic Human and Animal Coronavirus Antibodies

2020 ◽  
Author(s):  
Lakshmanane Premkumar ◽  
Bruno Segovia-Chumbez ◽  
Ramesh Jadi ◽  
David R. Martinez ◽  
Rajendra Raut ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Symptoms ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Population Level ◽  
Respiratory Illness ◽  
Specific Antibodies ◽  
Antibody Assays ◽  
Human Sera ◽  
Human Coronaviruses

AbstractA new Severe Acute Respiratory Syndrome Coronavirus variant (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus present with clinically inapparent, mild or severe disease. Currently, the presence of the virus in individual patients and at the population level is being monitored by testing symptomatic cases by PCR for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the viral spike (S) protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV specific antibodies in people. Here we use a large panel of human sera (70 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate the performance of the RBD as an antigen for accurate detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) to antibodies induced by SARS-CoVs. We observed a robust correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, strongly support the use of RBD-based antibody assays for population-level surveillance and as a correlate of neutralizing antibody levels in people who have recovered from SARS-CoV-2 infections.

scholarly journals Cross neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike

2021 ◽  
Author(s):  
Patrick Wilson ◽  
Siriruk Changrob ◽  
Yanbin Fu ◽  
Jenna Guthmiller ◽  
Peter Halfmann ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Cross Neutralization

Abstract Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484 and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and the variants of concern, including B.1.1.7 (alpha), P.1 (gamma) and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to wildtype (WT) SARS-CoV-2 do possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern.

scholarly journals Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies

2021 ◽  
Author(s):  
Frauke Muecksch ◽  
Yiska Weisblum ◽  
Christopher O. Barnes ◽  
Fabian Schmidt ◽  
Dennis Schaefer-Babajew ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Germinal Centers ◽  
Viral Escape ◽  
Receptor Binding Domain ◽  
Antibody Diversity ◽  
Specific Antibodies ◽  
Cognate Antigen ◽  
Pandemic Threat

SummaryAntibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.

scholarly journals Protective efficacy of a SARS-CoV-2 DNA vaccine in wild-type and immunosuppressed Syrian hamsters

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Rebecca L. Brocato ◽  
Steven A. Kwilas ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Lucia M. Principe ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Severe Disease ◽  
Disease Model ◽  
Wild Type ◽  
Jet Injection ◽  
Syrian Hamsters ◽  
Dna Targeting

AbstractA worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.

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