scholarly journals Discovering neutralizing antibodies targeting the stem epitope of H1N1 influenza hemagglutinin with synthetic phage-displayed antibody libraries

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Chao-Ping Tung ◽  
Ing-Chien Chen ◽  
Chung-Ming Yu ◽  
Hung-Pin Peng ◽  
Jhih-Wei Jian ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
H1n1 Influenza ◽  
Influenza Hemagglutinin ◽  
Antibody Libraries

Broadly-neutralizing antibodies that bind to the influenza hemagglutinin stalk domain enhance the effectiveness of neuraminidase inhibitors via Fc-mediated effector functions

2021 ◽  
Author(s):  
Ali Zhang ◽  
Hanu Chaudhari ◽  
Yonathan Agung ◽  
Michael D'Agostino ◽  
Jann Ang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Influenza Virus Infection ◽  
Dependent Manner ◽  
Neuraminidase Inhibitors ◽  
Immune Effector ◽  
Effector Cells ◽  
Individual Level ◽  
Influenza Hemagglutinin ◽  
Stalk Domain

The conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next generation universal influenza vaccines. Protection provided by hemagglutinin stalk binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level, and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual's titers of stalk-binding antibodies, and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.

scholarly journals Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2

2011 ◽  
Vol 7 (6) ◽  
pp. e1002081 ◽  
Author(s):  
Wei Wang ◽  
Christine M. Anderson ◽  
Christopher J. De Feo ◽  
Min Zhuang ◽  
Hong Yang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
H1n1 Influenza ◽  
2009 H1n1

scholarly journals The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Bargavi Thyagarajan ◽  
Jesse D Bloom
Keyword(s):  
Amino Acid ◽  
H1n1 Influenza ◽  
Influenza Hemagglutinin ◽  
Functional Variants ◽  
Viral Hemagglutinin ◽  
Before And After ◽  
Amino Acid Mutations ◽  
And Function ◽  
Phylogenetic Models ◽  
Better Than

Influenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the ≈104 amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenza's antigenic evolution.

scholarly journals Prospects of HA-Based Universal Influenza Vaccine

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Anwar M. Hashem
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Globular Domain ◽  
Universal Vaccine ◽  
Viral Hemagglutinin ◽  
Heterosubtypic Immunity ◽  
Antibody Libraries ◽  
Universal Influenza Vaccine ◽  
Immunodominant Epitopes

Current influenza vaccines afford substantial protection in humans by inducing strain-specific neutralizing antibodies (Abs). Most of these Abs target highly variable immunodominant epitopes in the globular domain of the viral hemagglutinin (HA). Therefore, current vaccines may not be able to induce heterosubtypic immunity against the divergent influenza subtypes. The identification of broadly neutralizing Abs (BnAbs) against influenza HA using recent technological advancements in antibody libraries, hybridoma, and isolation of single Ab-secreting plasma cells has increased the interest in developing a universal influenza vaccine as it could provide life-long protection. While these BnAbs can serve as a source for passive immunotherapy, their identification represents an important step towards the design of such a universal vaccine. This review describes the recent advances and approaches used in the development of universal influenza vaccine based on highly conserved HA regions identified by BnAbs.

scholarly journals Computationally optimized broadly reactive vaccine based upon swine H1N1 influenza hemagglutinin sequences protects against both swine and human isolated viruses

2019 ◽  
Vol 15 (9) ◽  
pp. 2013-2029 ◽  
Author(s):  
Amanda L. Skarlupka ◽  
Simon O. Owino ◽  
Lui P. Suzuki-Williams ◽  
Corey J. Crevar ◽  
Donald M. Carter ◽  
...  
Keyword(s):  
H1n1 Influenza ◽  
Influenza Hemagglutinin

scholarly journals CD4+ T cells recognize unique and conserved 2009 H1N1 influenza hemagglutinin epitopes after natural infection and vaccination

2013 ◽  
Vol 25 (8) ◽  
pp. 447-457 ◽  
Author(s):  
Junbao Yang ◽  
Eddie James ◽  
Theresa J. Gates ◽  
Jonathan H. DeLong ◽  
Rebecca E. LaFond ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Natural Infection ◽  
H1n1 Influenza ◽  
Influenza Hemagglutinin ◽  
2009 H1n1

Cross-neutralization antibodies against SARS-CoV-2 and RBD mutations from convalescent patient antibody libraries

2020 ◽  
Author(s):  
Yan Lou ◽  
Wenxiang Zhao ◽  
Haitao Wei ◽  
Min Chu ◽  
Ruihua Chao ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Therapeutic Agents ◽  
Therapeutic Interventions ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Antibodies ◽  
Global Pandemic ◽  
Antibody Libraries ◽  
Cross Neutralization

AbstractThe emergence of coronavirus disease 2019 (COVID-19) pandemic led to an urgent need to develop therapeutic interventions. Among them, neutralizing antibodies play crucial roles for preventing viral infections and contribute to resolution of infection. Here, we describe the generation of antibody libraries from 17 different COVID-19 recovered patients and screening of neutralizing antibodies to SARS-CoV-2. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Then the positive clones were sequenced and reconstituted into whole human IgG for epitope binning assays. After that, all 19 IgG were classified into 6 different epitope groups or Bins. Although all these antibodies were shown to have ability to bind RBD, the antibodies in Bin2 have more superiority to inhibit the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 can also strongly bind with mutant RBDs (W463R, R408I, N354D, V367F and N354D/D364Y) derived from SARS-CoV-2 strain with increased infectivity, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, these neutralizing antibodies strongly restrict the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, these antibodies can even block the entry of live SARS-CoV-2 into cells at only 12.5 nM. These results suggest that these neutralizing human antibodies from the patient-derived antibody libraries have the potential to become therapeutic agents against SARS-CoV-2 and its mutants in this global pandemic.

scholarly journals Epigallocatechin-3-Gallate as a Novel Vaccine Adjuvant

2021 ◽  
Vol 12 ◽  
Author(s):  
Yucheol Cheong ◽  
Minjin Kim ◽  
Jina Ahn ◽  
Hana Oh ◽  
Jongkwan Lim ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Fold Increase ◽  
Globular Domain ◽  
Vaccine Adjuvants ◽  
Vaccine Platform ◽  
Lethal Challenge ◽  
Influenza Hemagglutinin ◽  
Viral Vaccine ◽  
Inactivated Vaccines ◽  
Sparing Effect

Vaccine adjuvants from natural resources have been utilized for enhancing vaccine efficacy against infectious diseases. This study examined the potential use of catechins, polyphenolic materials derived from green tea, as adjuvants for subunit and inactivated vaccines. Previously, catechins have been documented to have irreversible virucidal function, with the possible applicability in the inactivated viral vaccine platform. In a mouse model, the coadministration of epigallocatechin-3-gallate (EGCG) with influenza hemagglutinin (HA) antigens induced high levels of neutralizing antibodies, comparable to that induced by alum, providing complete protection against the lethal challenge. Adjuvant effects were observed for all types of HA antigens, including recombinant full-length HA and HA1 globular domain, and egg-derived inactivated split influenza vaccines. The combination of alum and EGCG further increased neutralizing (NT) antibody titers with the corresponding hemagglutination inhibition (HI) titers, demonstrating a dose-sparing effect. Remarkably, EGCG induced immunoglobulin isotype switching from IgG1 to IgG2a (approximately >64–700 fold increase), exerting a more balanced TH1/TH2 response compared to alum. The upregulation of IgG2a correlated with significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) function (approximately 14 fold increase), providing a potent effector-mediated protection in addition to NT and HI. As the first report on a novel class of vaccine adjuvants with built-in virucidal activities, the results of this study will help improve the efficacy and safety of vaccines for pandemic preparedness.

scholarly journals Establishment of pan-Influenza A (H1-H18) and pan-Influenza B (pre-split, Vic/Yam) Pseudotype Libraries for efficient vaccine antigen selection

2021 ◽  
Author(s):  
Joanne M Del Rosario ◽  
Kelly da Costa ◽  
Benedikt Asbach ◽  
Francesca Ferrara ◽  
Matteo Ferrari ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Influenza Viruses ◽  
Vaccine Antigen ◽  
Influenza Surveillance ◽  
Influenza B ◽  
Strategic Objectives ◽  
Influenza Hemagglutinin ◽  
Dosing Regimens

We have developed an influenza hemagglutinin (HA) pseudotype library encompassing Influenza A subtypes HA1-18, and Influenza B subtypes (both lineages) to be employed in influenza pseudotype microneutralization (pMN) assays. The pMN is highly sensitive and specific for de-tecting virus-specific neutralizing antibodies against influenza viruses and can be used to assess antibody functionality in vitro. Here we show the production of these viral HA pseudotypes and their employment as substitutes for wildtype viruses in influenza serological and neutralization assays. We demonstrate its utility in detecting serum response to vaccination with the ability to evaluate cross-subtype neutralizing responses elicited by specific vaccinating antigens. Our findings may inform further pre-clinical studies involving immunization dosing regimens in mice and may help in the creation and selection of better antigens for vaccine design. These HA pseudotypes can be harnessed to meet strategic objectives that contribute to the strengthening of global influenza surveillance, expansion of seasonal influenza prevention and control policies, and strengthening pandemic preparedness and response.

scholarly journals Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin

Science ◽  
2018 ◽  
Vol 362 (6414) ◽  
pp. 598-602 ◽  
Author(s):  
Nick S. Laursen ◽  
Robert H. E. Friesen ◽  
Xueyong Zhu ◽  
Mandy Jongeneelen ◽  
Sven Blokland ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Influenza Infection ◽  
Cross Reactivity ◽  
Broadly Neutralizing Antibodies ◽  
Adeno Associated Virus ◽  
Influenza Hemagglutinin ◽  
Influenza Virus Hemagglutinin ◽  
Single Domain Antibodies

Broadly neutralizing antibodies against highly variable pathogens have stimulated the design of vaccines and therapeutics. We report the use of diverse camelid single-domain antibodies to influenza virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus–mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.

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