scholarly journals A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity

2021 ◽  
Author(s):  
Simone I Richardson ◽  
Nelia P Manamela ◽  
Boitumelo M Motsoeneng ◽  
Haajira Kaldine ◽  
Frances Ayres ◽  
...  
Keyword(s):  
Disease Severity ◽  
Neutralizing Antibodies ◽  
Cross Reactivity ◽  
Vaccine Effectiveness ◽  
Effector Function ◽  
Vaccine Protection ◽  
Effector Activity ◽  
Spike Sequence

SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.

scholarly journals Estimates of reduced vaccine effectiveness against hospitalization, infection, transmission and symptomatic disease of a new SARS-CoV-2 variant, Omicron (B.1.1.529), using neutralizing antibody titers

2021 ◽  
Author(s):  
Billy J Gardner ◽  
A. Marm Kilpatrick
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Vaccine Effectiveness ◽  
Vaccine Protection ◽  
Infection Transmission ◽  
Symptomatic Disease ◽  
Antibody Titers ◽  
Protection Against Infection

The emergence of the Omicron variant (B.1.1.529) of SARS-CoV-2 has raised concerns about how mutations in the spike protein might influence immune escape and vaccine protection against infection and disease, COVID-19. Initial estimates of immune escape measure neutralizing antibody titers, which have been shown to be a correlate of protection for COVID-19, but vary among studies. However, no studies have examined variation in vaccine effectiveness (VE) using estimated reductions in neutralizing antibody titers across virus variants. We quantified consistency in relative neutralizing antibody titers across studies. We then examined relationships between variant-specific reductions in neutralizing antibodies and protection against documented infection, symptomatic disease, and hospitalizations across variants and vaccines. We found considerable variation in variant-specific neutralizing antibody titers between studies, but within-study comparisons across variants were far more robust. There was insufficient data to estimate VE for a single vaccine across variants, especially for higher levels of immune evasion (>7-fold reductions in neutralizing antibody titers) observed with the Omicron variant (40-fold). Instead, we leveraged variation among both vaccines and virus variants to estimate VE - neutralizing antibody titer relationships across a 30 to 100-fold range of neutralizing antibody titers reduction. Omicron increased the risk of hospitalization four to five-fold and increased the risk of symptomatic disease seven to ten-fold for mRNA vaccinees, with similar relative effects for recently vaccinated, or individuals with waned antibody titers. Third doses restored titers and protection to levels similar to waned immunity against Delta. Overall, these analyses indicate that vaccine effectiveness against severe disease is significantly diminished for waned individuals, and protection against infection, symptomatic disease and transmission is nearly eliminated. However, third doses significantly ameliorate these reductions but only restore protection to levels equivalent to waned protection against the Delta variant. The invasion of Omicron is likely to result in widespread infection, and substantial hospitalizations unless widespread boosting of immunity occurs.

scholarly journals Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 932
Author(s):  
Annekathrin Haberland ◽  
Oxana Krylova ◽  
Heike Nikolenko ◽  
Peter Göttel ◽  
Andre Dallmann ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Cross Reactivity ◽  
Enzyme Linked Immunosorbent Assay ◽  
Resonance Spectroscopy ◽  
Plastic Plate ◽  
Calorimetric Titration ◽  
Background Signal ◽  
High Background ◽  
Specific Virus ◽  
Binding Sequence

COVID-19 is a pandemic respiratory disease that is caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-SARS-CoV-2 antibodies are essential weapons that a patient with COVID-19 has to combat the disease. When now repurposing a drug, namely an aptamer that interacts with SARS-CoV-2 proteins for COVID-19 treatment (BC 007), which is, however, a neutralizer of pathogenic autoantibodies in its original indication, the possibility of also binding and neutralizing anti-SARS-CoV-2 antibodies must be considered. Here, the highly specific virus-neutralizing antibodies have to be distinguished from the ones that also show cross-reactivity to tissues. The last-mentioned could be the origin of the widely reported SARS-CoV-2-induced autoimmunity, which should also become a target of therapy. We, therefore, used enzyme-linked immunosorbent assay (ELISA) technology to assess the binding of well-characterized publicly accessible anti-SARS-CoV-2 antibodies (CV07-209 and CV07-270) with BC 007. Nuclear magnetic resonance spectroscopy, isothermal calorimetric titration, and circular dichroism spectroscopy were additionally used to test the binding of BC 007 to DNA-binding sequence segments of these antibodies. BC 007 did not bind to the highly specific neutralizing anti-SARS-CoV-2 antibody but did bind to the less specific one. This, however, was a lot less compared to an autoantibody of its original indication (14.2%, range 11.0–21.5%). It was also interesting to see that the less-specific anti-SARS-CoV-2 antibody also showed a high background signal in the ELISA (binding on NeutrAvidin-coated or activated but noncoated plastic plate). These initial experiments suggest that the risk of binding and neutralizing highly specific anti-SARS CoV-2 antibodies by BC 007 should be low.

Immune Evasion of SARS-CoV-2 Variants of Concern is Driven by Low Affinity to Neutralizing Antibodies

2021 ◽  
Author(s):  
Matheus Ferraz ◽  
Emerson Moreira ◽  
Danilo F. Coêlho ◽  
Gabriel Wallau ◽  
Roberto Lins
Keyword(s):  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Cross Reactivity ◽  
Class I ◽  
Minor Role ◽  
A Minor

SARS-CoV-2 VOCs immune evasion is mainly due to lower cross-reactivity from previously elicited class I/II neutralizaing antibodies, while increased affinity to hACE2 plays a minor role. Affinity between antibodies and...

Predicting the Effectiveness of the Pfizer-BioNTech BNT162b2 Vaccine from SARS-CoV-2 Variants Neutralisation Data

2021 ◽  
Author(s):  
Oleg Volkov ◽  
Svetlana Borozdenkova ◽  
Alexander Gray
Keyword(s):  
Real Life ◽  
Vaccine Effectiveness ◽  
Vaccine Protection ◽  
Life Effectiveness ◽  
Correlates Of Protection ◽  
Antibody Titres ◽  
Effectiveness Studies

Modelling frameworks for vaccine protection are sorely needed to fight the Covid-19 pandemic with vaccines. We propose such a framework for the BNT162b2 and potentially other vaccines. It identifies correlates of protection based on live SARS-CoV-2 variants neutralising antibody titres from vaccinated individuals. We applied it to predict vaccine effectiveness in overall populations and age subgroups. It was validated by predicting effectiveness against the B.1.167.2 (Delta) variant. The predictions, of 51.7% (34%, 69%) after one and of 88.6% (76%, 97%) after two vaccine doses, were close to the corresponding means, 49% and 85.4%, of observations in real-life effectiveness studies. We illustrate its applications to inform decisions, such as about the doses and timing of vaccine boosters.

scholarly journals Reliably Assessing Duration of Protection for COVID-19 Vaccines

2021 ◽  
Author(s):  
Danyu Lin ◽  
Donglin Zeng ◽  
Yu Gu ◽  
Thomas Fleming ◽  
Phillip Krause
Keyword(s):  
Piecewise Linear ◽  
Piecewise Linear Function ◽  
Vaccine Effectiveness ◽  
Vaccine Protection ◽  
Time Period ◽  
Duration Of Protection ◽  
Reliable Methods ◽  
Protective Effectiveness ◽  
Vaccine Effect ◽  
Observation Period

Decision-making about booster dosing for COVID-19 vaccine recipients hinges on reliable methods for evaluating the longevity of vaccine protection. We show that modeling of protection as a piecewise linear function of time since vaccination for the log hazard ratio of the vaccine effect provides more reliable estimates of vaccine effectiveness at the end of an observation period and also more reliably detects plateaus in protective effectiveness as compared with the traditional method of estimating a constant vaccine effect over each time period. This approach will be useful for analyzing data pertaining to COVID-19 vaccines and other vaccines where rapid and reliable understanding of vaccine effectiveness over time is desired.

scholarly journals Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

2021 ◽  
Author(s):  
Claudia A. Jette ◽  
Alexander A. Cohen ◽  
Priyanthi N.P. Gnanapragasam ◽  
Frauke Muecksch ◽  
Yu E. Lee ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Cross Reactivity ◽  
Antibody Therapeutics ◽  
Binding Domains ◽  
Cryptic Epitope ◽  
Binding Antibody ◽  
Β Sheet ◽  
Potent Neutralization

SummaryMany anti-SARS-CoV-2 neutralizing antibodies target the ACE2-binding site on viral spike receptor-binding domains (RBDs). The most potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly-emergent zoonotic sarbecoviruses and variants, but usually show only weak neutralization potencies. We characterized two class 4 anti-RBD antibodies derived from COVID-19 donors that exhibited broad recognition and potent neutralization of zoonotic coronavirus and SARS-CoV-2 variants. C118-RBD and C022-RBD structures revealed CDRH3 mainchain H-bond interactions that extended an RBD β-sheet, thus reducing sensitivity to RBD sidechain changes, and epitopes that extended from the cryptic epitope to occlude ACE2 binding. A C118-spike trimer structure revealed rotated RBDs to allow cryptic epitope access and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.

scholarly journals Previous Infection Combined with Vaccination Produces Neutralizing Antibodies With Potency Against SARS-CoV-2 Variants

2021 ◽  
Author(s):  
F Javier Ibarrondo ◽  
Christian Hofmann ◽  
Ayub Ali ◽  
Paul Ayoub ◽  
Donald B Kohn ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Neutralizing Antibodies ◽  
Spike Protein ◽  
Original Sequence ◽  
Neutralizing Activity ◽  
Previous Infection ◽  
Protein Mutations ◽  
Antigenic Exposure ◽  
Prior Infection ◽  
Spike Sequence

SARS-CoV-2 continues to evolve in humans. Spike protein mutations increase transmission and potentially evade antibodies raised against the original sequence used in current vaccines. Our evaluation of serum neutralizing activity in both persons soon after SARS-CoV-2 infection (in April 2020 or earlier) or vaccination without prior infection confirmed that common spike mutations can reduce antibody antiviral activity. However, when the persons with prior infection were subsequently vaccinated, their antibodies attained an apparent biologic ceiling of neutralizing potency against all tested variants, equivalent to the original spike sequence. These findings indicate that additional antigenic exposure further improves antibody efficacy against variants.

scholarly journals Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada

2021 ◽  
Author(s):  
Danuta M Skowronski ◽  
Solmaz Setayeshgar ◽  
Macy Zou ◽  
Natalie Prystajecky ◽  
John R Tyson ◽  
...  
Keyword(s):  
British Columbia ◽  
Single Dose ◽  
Vaccine Effectiveness ◽  
Community Dwelling ◽  
Rt Pcr ◽  
Vaccine Protection ◽  
Post Vaccination ◽  
Randomized Controlled ◽  
Specimen Collection ◽  
Negative Controls

Introduction: Randomized-controlled trials of mRNA vaccine protection against SARS-CoV-2 included relatively few elderly participants. We assess singe-dose mRNA vaccine effectiveness (VE) in adults ≥70-years-old in British Columbia (BC), Canada where the second dose was deferred by up to 16 weeks and where a spring 2021 wave uniquely included co-dominant circulation of B.1.1.7 and P.1 variants of concern (VOC). Methods: Analyses included community-dwelling adults ≥70-years-old with specimen collection between April 4 (epidemiological week 14) and May 1 (week 17). Adjusted VE was estimated by test-negative design through provincial laboratory and immunization data linkage. Cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Vaccine status was defined by receipt of a single-dose ≥21 days before specimen collection, but a range of intervals was assessed. In variant-specific analyses, test-positive cases were restricted to those genetically-characterized as B.1.1.7, P.1 or non-VOC. Results: VE analyses included 16,993 specimens: 1,226 (7.2%) test-positive cases and 15,767 test-negative controls. Of 1,131 (92%) viruses genetically categorized, 509 (45%), 314 (28%) and 276 (24%) were B.1.1.7, P.1 and non-VOC lineages, respectively. VE was negligible at 14% (95% CI 0-26) during the period 0-13 days post-vaccination but increased from 43% (95% CI 30-53) at 14-20 days to 75% (95% CI 63-83) at 35-41 days post-vaccination. VE at ≥21 days was 65% (95% CI 58-71) overall: 72% (95% CI 58-81), 67% (95% CI 57-75) and 61% (95% CI 45-72) for non-VOC, B.1.1.7 and P.1, respectively. Conclusions: A single dose of mRNA vaccine reduced the risk of SARS-CoV-2 in adults ≥70-years-old by about two-thirds, with protection only minimally reduced against B.1.1.7 and P.1 variants. Substantial single-dose protection in older adults reinforces the option to defer the second dose when vaccine supply is scarce and broader first-dose coverage is needed.

scholarly journals Evaluation of Live Attenuated Influenza A Virus H6 Vaccines in Mice and Ferrets

2008 ◽  
Vol 83 (1) ◽  
pp. 65-72 ◽  
Author(s):  
Zhongying Chen ◽  
Celia Santos ◽  
Amy Aspelund ◽  
Laura Gillim-Ross ◽  
Hong Jin ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Serum Antibody ◽  
Cross Reactivity ◽  
Phenotypic Properties ◽  
Vaccine Candidates ◽  
Virus Challenge ◽  
Avian Influenza A Virus ◽  
Internal Gene

ABSTRACT Avian influenza A virus A/teal/HK/W312/97 (H6N1) possesses seven gene segments that are highly homologous to those of highly pathogenic human influenza H5N1 viruses, suggesting that a W312-like H6N1 virus might have been involved in the generation of the A/HK/97 H5N1 viruses. The continuous circulation and reassortment of influenza H6 subtype viruses in birds highlight the need to develop an H6 vaccine to prevent potential influenza pandemics caused by the H6 viruses. Based on the serum antibody cross-reactivity data obtained from 14 different H6 viruses from Eurasian and North American lineages, A/duck/HK/182/77, A/teal/HK/W312/97, and A/mallard/Alberta/89/85 were selected to produce live attenuated H6 candidate vaccines. Each of the H6 vaccine strains is a 6:2 reassortant ca virus containing HA and NA gene segments from an H6 virus and the six internal gene segments from cold-adapted A/Ann Arbor/6/60 (AA ca), the master donor virus that is used to make live attenuated influenza virus FluMist (intranasal) vaccine. All three H6 vaccine candidates exhibited phenotypic properties of temperature sensitivity (ts), ca, and attenuation (att) conferred by the internal gene segments from AA ca. Intranasal administration of a single dose of the three H6 ca vaccine viruses induced neutralizing antibodies in mice and ferrets and fully protected mice and ferrets from homologous wild-type (wt) virus challenge. Among the three H6 vaccine candidates, the A/teal/HK/W312/97 ca virus provided the broadest cross-protection against challenge with three antigenically distinct H6 wt viruses. These data support the rationale for further evaluating the A/teal/HK/W312/97 ca vaccine in humans.

Abstract 496: Genetic Neutrophil Deficiency Ameliorates Cerebral Ischemia-Reperfusion Injury

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ryan A Frieler ◽  
Yutein Chung ◽  
Jianrui Song ◽  
Thomas M Vigil ◽  
Richard M Mortensen
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Knockout Mice ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Types ◽  
Artery Occlusion ◽  
Cross Reactivity

Background: Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Neutralizing antibodies and inhibition of neutrophil chemotactic molecules can be protective during models of stroke, but many of these techniques have the potential to result in cross-reactivity and non-specificity with other immune cell types. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Methods: Myeloid Mcl1 knockout mice were subjected to transient 90-min middle cerebral artery occlusion and infarct size was assessed by MRI after 24 hours reperfusion. Immune cell mobilization and infiltration was assessed by flow cytometry after 24 hours reperfusion. Results: We found that myeloid Mcl1 knockout mice had significantly reduced infarct size when compared to heterozygous and wild type control mice (MyMcl1 +/+ : 78.0 mm 3 ; MyMcl1 +/- : 83.4 mm 3 ; MyMcl1 -/- : 55.1 mm 3 ). This was accompanied by a nearly complete absence of neutrophils in the ischemic hemisphere of myeloid Mcl1 knockout mice. Although myeloid Mcl1 knockout mice were protected from cerebral infarction, no significant differences in the expression of inflammatory genes were detected. Inhibition of neutrophil chemotaxis using CXCR2 pepducin treatment partially reduced neutrophil mobilization and recruitment to the brain after stroke, but did not reduce infarct size 24 hours after transient MCA occlusion. Conclusions: These data confirm that neutrophils have an important role in infarct development during stroke pathophysiology and suggest that complete deficiency, but not partial inhibition, is necessary to prevent neutrophil-mediated injury during stroke.

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