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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2020, Vol. 14 Issue (2) : 149-159    https://doi.org/10.1007/s11684-020-0764-y
REVIEW
Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head
Yulu Wang, Dan Hu, Yanling Wu(), Tianlei Ying()
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Abstract

Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates. Despite significant efforts to address influenza, it remains a major threat to human public health. This issue is partially due to the lack of antiviral drugs with potent antiviral activity and broad reactivity against all influenza virus strains and the rapid emergence of drug-resistant variants. Moreover, designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies is difficult. Some novel epitopes hidden in the hemagglutinin (HA) trimeric interface have been discovered recently, and a number of antibodies targeting these epitopes have been found to be capable of neutralizing a broad range of influenza isolates. These findings may have important implications for the development of universal influenza vaccines and antiviral drugs. In this review, we focused on the antibodies targeting these newly discovered epitopes in the HA domain of the influenza virus to promote the development of universal anti-influenza antibodies or vaccines and extend the discovery to other viruses with similar conformational changes in envelope proteins.

Keywords influenza virus      neutralizing antibody      hemagglutinin      globular head region      trimeric interface     
Corresponding Author(s): Yanling Wu,Tianlei Ying   
Just Accepted Date: 11 March 2020   Online First Date: 31 March 2020    Issue Date: 09 May 2020
 Cite this article:   
Yulu Wang,Dan Hu,Yanling Wu, et al. Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head[J]. Front. Med., 2020, 14(2): 149-159.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0764-y
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I2/149
Fig.1  Overview of influenza virus structure and epitopes recognized by neutralizing antibodies in the HA1 domain. The genomes of the influenza virus comprise eight gene segments, including polymerase basic 1 (PB1), polymerase basic 2 (PB2), polymerase acidic (PA), nucleoprotein (NP), matrix (M), nonstructural (NS), HA, and NA. The dominant glycoprotein on the viral surface, HA, mediates receptor binding, and membrane fusion is divided into HA1 and HA2. HA1 is the main target of neutralizing antibodies and antibody binding sites in the HA1 domain (indicated by different colors).
Fig.2  HA interface is the critical binding site for neutralizing antibodies. (A) Trimeric HA structure seen from the side and top in space filling. The HA trimer is dynamic, and the partially open structure is observed after a change in conformation, which resembles “breathing.” (B) The epitopes are presented by the representative structure of targeting HA-interfaced antibody-HA complexes (FluA-20, 8H10, and S5V2-29). The “breathing” process of the HA trimer exposes a concealed epitope, which can be recognized by protective and well-conserved antibodies. The 220 loop is targeted by antibodies FluA-20 and H3-S5V2-29 partially for 8H10.
Antibody Year Epitope Activity Phase
In vitro In vivo
Anti-stalk CR6261 [55] 2008 A highly conserved helical region in the membrane-proximal stem of HA1 and HA2 Neutralization group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16) In mice:
H2N2-1.7mg/kg-100% survival rate;
H2N3-1.7mg/kg-100% survival rate
In ferret:
H5N1-30mg/kg-100% survival rate
Phase 2
CR8020 [64] 2011 A highly conserved epitope in the HA stalk close to the virus membrane Neutralization group 2 (H3, H4, H7, H10, H14, H15) Mice challenges
H3N3-3mg/kg-100% survival rate;
H3N3-3mg/kg-100% survival rate;
H7N7-3mg/kg-100% survival rate
Phase 2
MEDI8852 [57] 2016 A highly conserved epitope encompassing a hydrophobic groove in the fusion domain and a large portion of the fusion peptide Neutralization group 1 (H1, H2, H5, H6, H9) and group 2 (H3, H7) Mice and ferret challenge studies
In mice:
H5N1-10 mg/kg-100% survival rate;
H7N9-10 mg/kg-100% survival rate
In ferret:
H5N1-12.5 mg/kg-86% survival rate
Phase 1b/2a
Anti-trimeric interface FluA-20 [87] 2019 An exceedingly conserved protective determinant in the influenza HA head domain trimer interface No neutralization but mediates ADCC against group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H16) and group 2 (H3, H4, H7, H10, H14, H15) Mice challenge studies:
H1N1-10 mg/kg-100% survival rate;
H3N2-10 mg/kg-80% survival rate;
H5N1-10 mg/kg-100% survival rate
Preclinical
S5V2-29 [17] 2019 The epitope, occluded in the pre-fusion form of HA, is at the contact surface between HA head domains No neutralization but the Fc-dependent protection against group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16) and group 2 (H3, H4, H7, H10, H14, H15) Mice challenge studies:
H3N2-100 μg-100% survival rate;
H1N1-100 μg-90% survival rate
Preclinical
Tab.1  Monoclonal antibodies specific for HA stalk and trimeric interface
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