Antigenic Peptides of Influenza Virus Hemagglutinin: Reactivity with Virus-Neutralizing Antibodies

Intervirology ◽  
1981 ◽  
Vol 15 (3) ◽  
pp. 145-153
Author(s):  
Yvonne M. Arcus ◽  
Arthur Knight
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Antigenic Peptides ◽  
Influenza Virus Hemagglutinin

scholarly journals A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin

2021 ◽  
Author(s):  
Jenna J. Guthmiller ◽  
Julianna Han ◽  
Henry A. Utset ◽  
Lei Li ◽  
Linda Yu-Ling Lan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Memory ◽  
Influenza Virus Vaccine ◽  
Virus Infections ◽  
Broadly Neutralizing Antibodies ◽  
Cell Repertoire ◽  
Influenza Virus Hemagglutinin

SummaryBroadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is “anchored” to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an underappreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.

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.

scholarly journals Dissection of Epitope-Specific Mechanisms of Neutralization of Influenza Virus by Intact IgG and Fab Fragments

2017 ◽  
Vol 92 (6) ◽  
Author(s):  
James A. Williams ◽  
Long Gui ◽  
Nancy Hom ◽  
Alexander Mileant ◽  
Kelly K. Lee
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Target Cells ◽  
Virus Infectivity ◽  
Fab Fragment ◽  
Fab Fragments ◽  
Influenza Virus Hemagglutinin ◽  
Fusion Glycoprotein ◽  
The Impact

ABSTRACTThe neutralizing antibody (nAb) response against the influenza virus hemagglutinin (HA) fusion glycoprotein is important for preventing viral infection, but we lack a comprehensive understanding of the mechanisms by which these antibodies act. Here we investigated the effect of nAb binding and the role of IgG bivalency in the inhibition of HA function for nAbs targeting distinct HA epitopes. HC19 targets the receptor binding pocket at the distal end of HA, while FI6v3 binds primarily to the HA2 fusion subunit toward the base of the stalk. Surprisingly, HC19 inhibited the ability of HA to induce lipid mixing by preventing the structural rearrangement of HA under fusion-activating conditions. These results suggest that nAbs such as HC19 not only act by blocking receptor binding but also inhibit key late-stage HA conformational changes required for fusion. Intact HC19 IgG was also shown to cross-link separate virus particles, burying large proportions of HA within aggregates where they are blocked from interacting with target membranes; Fabs yielded no such aggregation and displayed weaker neutralization than IgG, emphasizing the impact of bivalency on the ability to neutralize virus. In contrast, the stem-targeting nAb FI6v3 did not aggregate particles. The Fab fragment was significantly less effective than IgG in preventing both membrane disruption and fusion. We infer that interspike cross-linking within a given particle by FI6v3 IgG may be critical to its potent neutralization, as no significant neutralization occurred with Fabs. These results demonstrate that IgG bivalency enhances HA inhibition through functionally important modes not evident in pared-down Fab-soluble HA structures.IMPORTANCEThe influenza virus hemagglutinin (HA) fusion glycoprotein mediates entry into target cells and is the primary antigenic target of neutralizing antibodies (nAbs). Our current structural understanding of mechanisms of antibody (Ab)-mediated neutralization largely relies on the high-resolution characterization of antigen binding (Fab) fragments in complex with soluble, isolated antigen constructs by cryo-electron microscopy (EM) single-particle reconstruction or X-ray crystallography. Interactions between full-length IgG and whole virions have not been well characterized, and a gap remains in our understanding of how intact Abs neutralize virus and prevent infection. Using structural and biophysical approaches, we observed that Ab-mediated inhibition of HA function and neutralization of virus infectivity occur by multiple coexisting mechanisms, are largely dependent on the specific epitope that is targeted, and are highly dependent on the bivalent nature of IgG molecules.

scholarly journals Attenuated Vesicular Stomatitis Viruses as Vaccine Vectors

1999 ◽  
Vol 73 (5) ◽  
pp. 3723-3732 ◽  
Author(s):  
Anjeanette Roberts ◽  
Linda Buonocore ◽  
Ryan Price ◽  
John Forman ◽  
John K. Rose
Keyword(s):  
Influenza Virus ◽  
Vesicular Stomatitis Virus ◽  
Neutralizing Antibodies ◽  
Intranasal Administration ◽  
Complete Protection ◽  
Lethal Challenge ◽  
Virus Challenge ◽  
Influenza Virus Hemagglutinin ◽  
Vesicular Stomatitis ◽  
Ha Protein

ABSTRACT We showed previously that a single intranasal vaccination of mice with a recombinant vesicular stomatitis virus (VSV) expressing an influenza virus hemagglutinin (HA) protein provided complete protection from lethal challenge with influenza virus (A. Roberts, E. Kretzschmar, A. S. Perkins, J. Forman, R. Price, L. Buonocore, Y. Kawaoka, and J. K. Rose, J. Virol. 72:4704–4711, 1998). Because some pathogenesis was associated with the vector itself, in the present study we generated new VSV vectors expressing HA which are completely attenuated for pathogenesis in the mouse model. The first vector has a truncation of the cytoplasmic domain of the VSV G protein and expresses influenza virus HA (CT1-HA). This nonpathogenic vector provides complete protection from lethal influenza virus challenge after intranasal administration. A second vector with VSV G deleted and expressing HA (ΔG-HA) is also protective and nonpathogenic and has the advantage of not inducing neutralizing antibodies to the vector itself.

scholarly journals The Analysis of B-Cell Epitopes of Influenza Virus Hemagglutinin

Acta Naturae ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 13-20 ◽  
Author(s):  
D. N. Shcherbinin ◽  
S. V. Alekseeva ◽  
M. M. Shmarov ◽  
Yu. A. Smirnov ◽  
B. S. Naroditskiy ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cell ◽  
Broad Spectrum ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
B Cell Epitopes ◽  
Humoral Immune ◽  
Influenza Virus Hemagglutinin ◽  
Long Time ◽  
Single Domain Antibodies

Vaccination has been successfully used to prevent influenza for a long time. Influenza virus hemagglutinin (HA), which induces a humoral immune response in humans and protection against the flu, is the main antigenic component of modern influenza vaccines. However, new seasonal and pandemic influenza virus variants with altered structures of HA occasionally occur. This allows the pathogen to avoid neutralization with antibodies produced in response to previous vaccination. Development of a vaccine with the new variants of HA acting as antigens takes a long time. Therefore, during an epidemic, it is important to have passive immunization agents to prevent and treat influenza, which can be monoclonal or single-domain antibodies with universal specificity (broad-spectrum agents). We considered antibodies to conserved epitopes of influenza virus antigens as universal ones. In this paper, we tried to characterize the main B-cell epitopes of hemagglutinin and analyze our own and literature data on broadly neutralizing antibodies. We conducted a computer analysis of the best known conformational epitopes of influenza virus HAs using materials of different databases. The analysis showed that the core of the HA molecule, whose antibodies demonstrate pronounced heterosubtypic activity, can be used as a target for the search for and development of broad-spectrum antibodies to the influenza virus.

scholarly journals Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Kristina L. Prachanronarong ◽  
Aneth S. Canale ◽  
Ping Liu ◽  
Mohan Somasundaran ◽  
Shurong Hou ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Cultured Cells ◽  
Whole Genome ◽  
Resistance Mutations ◽  
Broadly Neutralizing Antibodies ◽  
Influenza Virus Hemagglutinin

ABSTRACTInfluenza A virus (IAV), a major cause of human morbidity and mortality, continuously evolves in response to selective pressures. Stem-directed, broadly neutralizing antibodies (sBnAbs) targeting the influenza virus hemagglutinin (HA) are a promising therapeutic strategy, but neutralization escape mutants can develop. We used an integrated approach combining viral passaging, deep sequencing, and protein structural analyses to define escape mutations and mechanisms of neutralization escapein vitrofor the F10 sBnAb. IAV was propagated with escalating concentrations of F10 over serial passages in cultured cells to select for escape mutations. Viral sequence analysis revealed three mutations in HA and one in neuraminidase (NA). Introduction of these specific mutations into IAV through reverse genetics confirmed their roles in resistance to F10. Structural analyses revealed that the selected HA mutations (S123G, N460S, and N203V) are away from the F10 epitope but may indirectly impact influenza virus receptor binding, endosomal fusion, or budding. The NA mutation E329K, which was previously identified to be associated with antibody escape, affects the active site of NA, highlighting the importance of the balance between HA and NA function for viral survival. Thus, whole-genome population sequencing enables the identification of viral resistance mutations responding to antibody-induced selective pressure.IMPORTANCEInfluenza A virus is a public health threat for which currently available vaccines are not always effective. Broadly neutralizing antibodies that bind to the highly conserved stem region of the influenza virus hemagglutinin (HA) can neutralize many influenza virus strains. To understand how influenza virus can become resistant or escape such antibodies, we propagated influenza A virusin vitrowith escalating concentrations of antibody and analyzed viral populations by whole-genome sequencing. We identified HA mutations near and distal to the antibody binding epitope that conferred resistance to antibody neutralization. Additionally, we identified a neuraminidase (NA) mutation that allowed the virus to grow in the presence of high concentrations of the antibody. Virus carrying dual mutations in HA and NA also grew under high antibody concentrations. We show that NA mutations mediate the escape of neutralization by antibodies against HA, highlighting the importance of a balance between HA and NA for optimal virus function.

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