Faculty Opinions recommendation of Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin.

2019 ◽  
Author(s):  
Michael Gold
Keyword(s):  
Influenza Infection ◽  
Influenza Hemagglutinin

scholarly journals Novel in vitro booster vaccination to rapidly generate antigen-specific human monoclonal antibodies

2017 ◽  
Vol 214 (8) ◽  
pp. 2471-2490 ◽  
Author(s):  
Irene Sanjuan Nandin ◽  
Carol Fong ◽  
Cecilia Deantonio ◽  
Juan A. Torreno-Pina ◽  
Simone Pecetta ◽  
...  
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Vaccine Development ◽  
Influenza Infection ◽  
Booster Vaccination ◽  
Human Memory ◽  
Influenza Hemagglutinin ◽  
Novel Approach ◽  
Antigenic Exposure

Vaccines remain the most effective tool to prevent infectious diseases. Here, we introduce an in vitro booster vaccination approach that relies on antigen-dependent activation of human memory B cells in culture. This stimulation induces antigen-specific B cell proliferation, differentiation of B cells into plasma cells, and robust antibody secretion after a few days of culture. We validated this strategy using cells from healthy donors to retrieve human antibodies against tetanus toxoid and influenza hemagglutinin (HA) from H1N1 and newly emergent subtypes such as H5N1 and H7N9. Anti-HA antibodies were cross-reactive against multiple subtypes, and some showed neutralizing activity. Although these antibodies may have arisen as a result of previous influenza infection, we also obtained gp120-reactive antibodies from non–HIV-infected donors, indicating that we can generate antibodies without prior antigenic exposure. Overall, our novel approach can be used to rapidly produce therapeutic antibodies and has the potential to assess the immunogenicity of candidate antigens, which could be exploited in future vaccine development.

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 Development and characterization of influenza M2 ectodomain and/or HA stalk-based DC-targeting vaccines for different influenza infections

2021 ◽  
Author(s):  
Xiaojian Yao ◽  
Titus Olukitibi ◽  
Zhujun Ao ◽  
Hiva Azizi ◽  
Mona Mahmoudi ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Matrix Protein ◽  
Influenza Infection ◽  
Extracellular Matrix Protein ◽  
Influenza Hemagglutinin ◽  
Viral Particles ◽  
Vesicular Stomatitis ◽  
Universal Influenza Vaccine ◽  
Mouse Study

A universal influenza vaccine is required for broad protection against influenza infection. Here, we revealed the efficacy of novel influenza vaccine candidates based on Ebola glycoprotein (EboGP) DC-targeting domain (EΔM) fusion protein technology. We fused influenza hemagglutinin stalk (HAcs) and extracellular matrix protein (M2e) or four copies of M2e (referred to as tetra M2e (tM2e)) with EΔM to generate EΔM-HM2e or EΔM-tM2e, respectively, and revealed that EΔM facilitates DC/macrophage targeting in vitro. In a mouse study, EΔM-HM2e- or EΔM-tM2e-pseudotyped viral particles (PVPs) induced significantly higher titers of anti-HA and/or anti-M2e antibodies. We also developed recombinant vesicular stomatitis virus (rVSV)-EΔM-HM2e and rVSV-EΔM-tM2e vaccines that resulted in rapid and potent induction of HA and/or M2 antibodies in mouse sera and mucosa. Importantly, vaccination protects mice from influenza H1N1 and H3N2 challenges. Taken together, our study suggests that recombinant rVSV-EΔM-HM2e and rVSV-EΔM-tM2e are efficacious and protective universal vaccines against influenza.

scholarly journals A prevalent focused human antibody response to the influenza hemagglutinin head interface

2020 ◽  
Author(s):  
Kevin R. McCarthy ◽  
Jiwon Lee ◽  
Akiko Watanabe ◽  
Masayuki Kuraoka ◽  
Lindsey R. Robinson-McCarthy ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antibody Response ◽  
Influenza Infection ◽  
Herd Immunity ◽  
Influenza Viruses ◽  
Human Antibody ◽  
Influenza Hemagglutinin ◽  
Protective Antibodies ◽  
Interface Structures ◽  
Major Target

ABSTRACTNovel animal influenza viruses emerge, initiate pandemics and become endemic seasonal variants that have evolved to escape from prevalent herd immunity. These processes often outpace vaccine-elicited protection. Focusing immune responses on conserved epitopes may impart durable immunity. We describe a focused, protective antibody response, abundant in memory and serum repertoires, to a conserved region at the influenza hemagglutinin head interface. Structures of eleven examples, eight reported here, from seven human donors demonstrate the convergence of responses on a single epitope. The eleven are genetically diverse, with one class having a common, IGκV1-39, light chain. All of the antibodies bind HAs from multiple serotypes. The lack of apparent genetic restriction and potential for elicitation by more than one serotype may explain their abundance. We define the head interface as a major target of broadly protective antibodies with the potential to influence the outcomes of influenza infection.

scholarly journals pH-Dependent Mechanisms of Influenza Infection Mediated by Hemagglutinin

2021 ◽  
Vol 8 ◽  
Author(s):  
Michael Caffrey ◽  
Arnon Lavie
Keyword(s):  
Small Molecules ◽  
Conformational Changes ◽  
Influenza Infection ◽  
Critical Role ◽  
Genetic Material ◽  
Therapeutic Strategies ◽  
Target Cells ◽  
Viral Membrane ◽  
Influenza Hemagglutinin ◽  
Membrane Bound

Influenza hemagglutinin (HA) is a viral membrane bound protein that plays a critical role in the viral life cycle by mediating entry into target cells. HA exploits the lowering of the pH in the endosomal compartment to initiate a series of conformational changes that promote access of the viral genetic material to the cytoplasm, and hence viral replication. In this review we will first discuss what is known about the structural properties of HA as a function of pH. Next, we will discuss the dynamics and intermediate states of HA. We will then discuss the specific residues that are thought to be titrated by the change in pH and possible mechanisms for the pH triggered conformational changes. Finally, we will discuss small molecules that disrupt the pH trigger and thus serve as potential therapeutic strategies to prevent influenza infection.

Influenza hemagglutinin peptides fused to interferon gamma and encapsulated in liposomes protects mice against influenza infection

Vaccine ◽  
2003 ◽  
Vol 21 (9-10) ◽  
pp. 932-939 ◽  
Author(s):  
L Faulkner ◽  
G Buchan ◽  
L Slobbe ◽  
E Lockhart ◽  
J Wales ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Influenza Infection ◽  
Influenza Hemagglutinin

scholarly journals Structure of avian influenza hemagglutinin in complex with a small molecule entry inhibitor

2020 ◽  
Vol 3 (8) ◽  
pp. e202000724
Author(s):  
Aleksandar Antanasijevic ◽  
Matthew A Durst ◽  
Han Cheng ◽  
Irina N Gaisina ◽  
Jasmine T Perez ◽  
...  
Keyword(s):  
Small Molecule ◽  
Specific Activity ◽  
Influenza Infection ◽  
Critical Role ◽  
Fusion Peptide ◽  
Nmr Studies ◽  
X Ray ◽  
X Ray Crystallography ◽  
Influenza Hemagglutinin ◽  
Group 1

HA plays a critical role in influenza infection and, thus HA is a potential target for antivirals. Recently, our laboratories have described a novel fusion inhibitor, termed CBS1117, with EC50 ∼3 μM against group 1 HA. In this work, we characterize the binding properties of CBS1117 to avian H5 HA by x-ray crystallography, NMR, and mutagenesis. The x-ray structure of the complex shows that the compound binds near the HA fusion peptide, a region that plays a critical role in HA-mediated fusion. NMR studies demonstrate binding of CBS1117 to H5 HA in solution and show extensive hydrophobic contacts between the compound and HA surface. Mutagenesis studies further support the location of the compound binding site proximal to the HA fusion peptide and identify additional amino acids that are important to compound binding. Together, this work gives new insights into the CBS1117 mechanism of action and can be exploited to further optimize this compound and better understand the group specific activity of small-molecule inhibitors of HA-mediated entry.

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