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Title: Vaccine-Induced Antibodies that Neutralize Group 1 and Group 2 Influenza A Viruses

Journal Article · · Cell
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  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases (NIAID)
  2. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases (NIAID); Vanderbilt Univ. Medical Center, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
  3. Frederick National Lab. for Cancer Research, MD (United States)
  4. National Inst. of Health (NIH), Bethesda, MD (United States). National Human Genome Research Inst. (NHGRI)
  5. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases (NIAID); Columbia Univ., New York, NY (United States)
+ Show Author Affiliations

Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and—in half the subjects—multidonor-class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); USDOE Office of Science (SC), Basic Energy Sciences (BES)
Contributing Organization:
NISC Comparative Sequencing Program
Grant/Contract Number:
HHSN261200800001E; W-31-109-Eng-38
OSTI ID:
1389087
Alternate ID(s):
OSTI ID: 1314264
Journal Information:
Cell, Vol. 166, Issue 3; ISSN 0092-8674
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 216 works
Citation information provided by
Web of Science

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Cited By (83)

Advances in Vaccines to Prevent Viral Respiratory Illnesses in Children journal August 2017
Functional interrogation and mining of natively paired human VH:VL antibody repertoires journal January 2018
A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein journal March 2018
Passive immunotherapy of viral infections: 'super-antibodies' enter the fray journal January 2018
Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses journal April 2019
How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin journal April 2018
Cross-lineage protection by human antibodies binding the influenza B hemagglutinin journal January 2019
Improvement of antibody functionality by structure-guided paratope engraftment journal February 2019
Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies journal August 2019
Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses journal February 2020
Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses journal February 2019
Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1 journal June 2018
Structural insights into the design of novel anti-influenza therapies journal February 2018
Use of Hemagglutinin Stem Probes Demonstrate Prevalence of Broadly Reactive Group 1 Influenza Antibodies in Human Sera journal June 2018
Structural analysis of influenza vaccine virus-like particles reveals a multicomponent organization journal July 2018
Repertoire Builder: high-throughput structural modeling of B and T cell receptors journal January 2019
Functional clustering of B cell receptors using sequence and structural features journal January 2019
Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing journal February 2020
Vaccine approaches conferring cross-protection against influenza viruses journal September 2017
Effector mechanisms of influenza-specific antibodies: neutralization and beyond journal September 2018
Passive immunization with influenza haemagglutinin specific monoclonal antibodies journal July 2018
A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases journal February 2018
Vaccine Generation of Protective Ebola Antibodies and Identification of Conserved B-Cell Signatures journal July 2018
Immunodominance and Antigenic Variation of Influenza Virus Hemagglutinin: Implications for Design of Universal Vaccine Immunogens journal April 2019
A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection journal December 2018
Influenza H3 and H1 hemagglutinins have different genetic barriers for resistance to broadly neutralizing stem antibodies posted_content December 2019
Tailored Design of Protein Nanoparticle Scaffolds for Multivalent Presentation of Viral Glycoprotein Antigens posted_content January 2020
Is It Possible to Develop a “Universal” Influenza Virus Vaccine?: Immunogenetic Considerations Underlying B-Cell Biology in the Development of a Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem journal June 2017
Tfh cells and HIV bnAbs, an immunodominance model of the HIV neutralizing antibody generation problem journal January 2017
A small-molecule fusion inhibitor of influenza virus is orally active in mice journal March 2019
A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses journal October 2019
Preferential induction of cross-group influenza A hemagglutinin stem–specific memory B cells after H7N9 immunization in humans journal July 2017
Prolonged evolution of the memory B cell response induced by a replicating adenovirus-influenza H5 vaccine journal April 2019
Origins and clonal convergence of gastrointestinal IgE + B cells in human peanut allergy journal March 2020
Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages journal February 2019
Protein Microarray Analysis of the Specificity and Cross-Reactivity of Influenza Virus Hemagglutinin-Specific Antibodies journal December 2018
Immune repertoire fingerprinting by principal component analysis reveals shared features in subject groups with common exposures journal December 2019
IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro journal January 2017
One‐step CRISPR /Cas9 method for the rapid generation of human antibody heavy chain knock‐in mice journal August 2018
Insights into the Structural Basis of Antibody Affinity Maturation from Next-Generation Sequencing journal February 2018
Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design journal August 2018
An Influenza HA and M2e Based Vaccine Delivered by a Novel Attenuated Salmonella Mutant Protects Mice against Homologous H1N1 Infection journal May 2017
Structural Vaccinology for Viral Vaccine Design journal April 2019
Antibody Cross-Reactivity in Antivenom Research journal September 2018
Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies journal January 2020
Observed Antibody Space: A Resource for Data Mining Next-Generation Sequencing of Antibody Repertoires journal September 2018
Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses. text January 2020
Large-Scale Analysis of 2,152 Dataset Reveals Key Features of B Cell Biology and the Antibody Repertoire journal January 2019
cAb-Rep: A Database of Curated Antibody Repertoires for Exploring Antibody Diversity and Predicting Antibody Prevalence journal October 2019
Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses. text January 2020
VRC34-Antibody Lineage Development Reveals How a Required Rare Mutation Shapes the Maturation of a Broad HIV-Neutralizing Lineage journal April 2020
A Broadly Reactive Human Anti-hemagglutinin Stem Monoclonal Antibody That Inhibits Influenza A Virus Particle Release journal March 2017
The Individual and Population Genetics of Antibody Immunity journal July 2017
Passive immunotherapy of viral infections: 'super-antibodies' enter the fray journal January 2018
How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin journal April 2018
Cross-lineage protection by human antibodies binding the influenza B hemagglutinin journal January 2019
Improvement of antibody functionality by structure-guided paratope engraftment journal February 2019
Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses journal February 2020
Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic journal December 2017
Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses journal February 2019
Different Repeat Annual Influenza Vaccinations Improve the Antibody Response to Drifted Influenza Strains journal July 2017
Structural analysis of influenza vaccine virus-like particles reveals a multicomponent organization journal July 2018
Complementary recognition of the receptor-binding site of highly pathogenic H5N1 influenza viruses by two human neutralizing antibodies journal October 2018
Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing journal February 2020
Restricted epitope specificity determined by variable region germline segment pairing in rodent antibody repertoires journal January 2020
Novel in vitro booster vaccination to rapidly generate antigen-specific human monoclonal antibodies journal July 2017
Influenza, evolution, and the next pandemic journal October 2018
Protect, Modify, Deprotect (PMD): A strategy for creating vaccines to elicit antibodies targeting a specific epitope posted_content December 2018
Antibodyomics: bioinformatics technologies for understanding B-cell immunity to HIV-1 journal January 2017
Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins journal September 2016
Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages journal February 2019
Protein Microarray Analysis of the Specificity and Cross-Reactivity of Influenza Virus Hemagglutinin-Specific Antibodies journal December 2018
Immune repertoire fingerprinting by principal component analysis reveals shared features in subject groups with common exposures journal December 2019
IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro journal January 2017
One‐step CRISPR /Cas9 method for the rapid generation of human antibody heavy chain knock‐in mice journal August 2018
Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses. text January 2020
Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design journal August 2018
Recombinant Influenza Vaccines: Saviors to Overcome Immunodominance journal January 2020
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Antibody Cross-Reactivity in Antivenom Research journal September 2018
Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies journal January 2020
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