#Human #Norovirus Neutralized by a #Monoclonal Antibody Targeting the HBGA Pocket (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Human Norovirus Neutralized by a Monoclonal Antibody Targeting the HBGA Pocket

Anna D. Koromyslova, Vasily A. Morozov, Lisa Hefele, Grant S. Hansman

DOI: 10.1128/JVI.02174-18

 

ABSTRACT

Temporal changes in the GII.4 human norovirus capsid sequences occasionally result in the emergence of genetic variants capable of causing new epidemics. The GII.4 persistence is believed to be associated with the recognition of numerous histo-blood group antigen (HBGA) types and antigenic drift. We found that one of the earliest known GII.4 isolate (1974) and a more recent epidemic GII.4 variant (2012) had varied norovirus-specific monoclonal antibody (MAb) reactivities, yet similar HBGA binding profiles. To better understand the binding interaction of one MAb (10E9) that had varied reactivities with these GII.4 variants, we determined the X-ray crystal structure of the NSW-2012 GII.4 P domain 10E9 Fab complex. We showed that the 10E9 Fab interacted with conserved and variable residues, which could be associated with antigenic drift. Interestingly, the 10E9 Fab binding pocket partially overlapped the HBGA pocket and had direct competition for conserved HBGA binding residues (i.e., Arg345 and Tyr444). Indeed, the 10E9 MAb blocked norovirus VLPs from binding to several sources of HBGAs. Moreover, the 10E9 antibody completely abolished virus replication in the human norovirus intestinal enteroid cell culture system. Our new findings provide first direct evidence that competition for GII.4 HBGA binding residues and steric obstruction could lead to norovirus neutralization. On the other hand, the 10E9 MAb recognized residues flanking the HBGA pocket, which are often substituted as the virus evolves. This mechanism of antigenic drift likely influences herd immunity and impedes the possibility of acquiring broadly reactive HBGA-blocking antibodies.

 

IMPORTANCE

The emergence of new epidemic GII.4 variants is thought to be associated with changes in antigenicity and HBGA binding capacity. Here, we show that HBGA binding profiles remain unchanged between 1974 and 2012 GII.4 variants, whereas these variants showed varying levels of reactivities against a panel of GII.4 MAbs. We identified a MAb that bound at the HBGA pocket and blocked norovirus VLPs from binding to HBGAs and neutralized norovirus virions in the cell culture system. Raised against GII.4 2006 strain this MAb was unreactive to GII.4 1987 isolate, but was able to neutralize newer 2012 strain, which has important implications for vaccine design. Altogether, these new findings suggested that the amino acid variations surrounding HBGA pocket lead to temporal changes in antigenicity without affecting the ability of GII.4 variants to bind HBGAs, which are known co-factors for infection.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Norovirus; Monoclonal antibodies.

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Role of the #Ebola #membrane in the protection conferred by the three- #mAb cocktail #MIL77 (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2018 Dec 4;8(1):17628. doi: 10.1038/s41598-018-35964-6.

Role of the Ebola membrane in the protection conferred by the three-mAb cocktail MIL77.

Cao P1, Bai H2, Wang X3, Che J4.

Author information: 1 Center for Drug Evaluation, CFDA, Beijing, People’s Republic of China. 2 Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, People’s Republic of China. 3 Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, People’s Republic of China. wangxh@bjsjth.cn. 4 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China. chejinjing80@126.com.

 

Abstract

MIL77, which has a higher manufacturing capacity than ZMapp, comprises MIL77-1, MIL77-2, and MIL77-3. The mechanisms by which these antibodies inhibit glycoprotein are unclear. Infection by viruses with lipid-bilayer envelopes occurs via the fusion of the viral membrane with the membrane of the target cell. Therefore, the interaction between the antibodies and the EBOV membrane is crucial. We examined the interactions between MIL77 and the viral membrane using SPR. MIL77-1 selectively binds to viral membranes, while MIL77-2 and MIL77-3 do not. MIL77-1’s ability to screen the more rigid domains of the membranes results in a locally increased concentration of the drug at the fusion site. Although MIL77-2 recognizes an epitope of GP, it is not necessary in the MIL77 cocktail. These results highlight the importance of EBOV membrane interactions in improving the efficiency of a neutralizing antibody. Furthermore, the viral membrane may be an important target of antibodies against EBOV.

PMID: 30514891 DOI: 10.1038/s41598-018-35964-6 Free full text

Keywords: Ebola; Monoclonal antibodies.

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Neutralizing #Monoclonal #Antibodies as Promising #Therapeutics against #MERS #Coronavirus Infection (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2018 Nov 30;10(12). pii: E680. doi: 10.3390/v10120680.

Neutralizing Monoclonal Antibodies as Promising Therapeutics against Middle East Respiratory Syndrome Coronavirus Infection.

Han HJ1, Liu JW2, Yu H3, Yu XJ4.

Author information: 1 School of Health Sciences, and State Key Laboratory of Virology,  Wuhan University, Wuhan 430071, China. nikihuijuhan@163.com. 2 School of Health Sciences, and State Key Laboratory of Virology, Wuhan University, Wuhan 430071, China. liujw_2012@163.com. 3 Fudan University School of Medicine, Shanghai 200032, China. howardyu89@163.com. 4 School of Health Sciences, and State Key Laboratory of Virology, Wuhan University, Wuhan 430071, China. yuxuejie@whu.edu.cn.

 

Abstract

Since emerging in 2012, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) has been a global public health threat with a high fatality rate and worldwide distribution. There are no approved vaccines or therapies for MERS until now. Passive immunotherapy with neutralizing monoclonal antibodies (mAbs) is an effective prophylactic and therapeutic reagent against emerging viruses. In this article, we review current advances in neutralizing mAbs against MERS-CoV. The receptor-binding domain (RBD) in the spike protein of MERS-CoV is a major target, and mouse, camel, or human-derived neutralizing mAbs targeting RBD have been developed. A major problem with neutralizing mAb therapy is mutant escape under selective pressure, which can be solved by combination of neutralizing mAbs targeting different epitopes. Neutralizing mAbs are currently under preclinical evaluation, and they are promising candidate therapeutic agents against MERS-CoV infection.

KEYWORDS: MERS-CoV; Middle East Respiratory Syndrome Virus; neutralizing monoclonal antibodies

PMID: 30513619 DOI: 10.3390/v10120680

Keywords: MERS-CoV; Monoclonal antibodies.

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Structure-function #analysis of neutralizing #antibodies to #H7N9 #influenza from naturally infected #humans (Nat Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Nat Microbiol. 2018 Nov 26. doi: 10.1038/s41564-018-0303-7. [Epub ahead of print]

Structure-function analysis of neutralizing antibodies to H7N9 influenza from naturally infected humans.

Huang KA1,2, Rijal P3, Jiang H4,5, Wang B6,7,8, Schimanski L3, Dong T3,6, Liu YM9, Chang P10, Iqbal M10, Wang MC11, Chen Z8,12, Song R8,12, Huang CC13, Yang JH14, Qi J4, Lin TY15,16, Li A7,8, Powell TJ3, Jan JT9, Ma C9, Gao GF17,18,19, Shi Y20,21,22, Townsend AR23,24.

Author information: 1 Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan. arthur1726@cgmh.org.tw. 2 School of Medicine, Chang Gung University, Taoyuan, Taiwan. arthur1726@cgmh.org.tw. 3 Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. 4 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. 5 College of Veterinary Medicine, China Agricultural University, Beijing, China. 6 Center for translational Immunology, Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, UK. 7 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China. 8 Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China. 9 Genomics Research Center, Academia Sinica, Taipei, Taiwan. 10 The Pirbright Institute, Pirbright, Woking, UK. 11 Department of Cardiovascular Surgery, Min-Sheng General Hospital, Taoyuan, Taiwan. 12 Clinical and Research Center of Infectious Diseases, The National Clinical Key Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. 13 Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 14 Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 15 Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 16 School of Medicine, Chang Gung University, Taoyuan, Taiwan. 17 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. gaof@im.ac.cn. 18 Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen, China. gaof@im.ac.cn. 19 Center for Influenza Research and Early-Warning, Chinese Academy of Sciences, Beijing, China. gaof@im.ac.cn. 20 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China. shiyi@im.ac.cn. 21 Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen, China. shiyi@im.ac.cn. 22 Center for Influenza Research and Early-Warning, Chinese Academy of Sciences, Beijing, China. shiyi@im.ac.cn. 23 Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. alain.townsend@imm.ox.ac.uk. 24 Center for translational Immunology, Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, UK. alain.townsend@imm.ox.ac.uk.

 

Abstract

Little is known about the specificities and neutralization breadth of the H7-reactive antibody repertoire induced by natural H7N9 infection in humans. We have isolated and characterized 73 H7-reactive monoclonal antibodies from peripheral B cells from four donors infected in 2013 and 2014. Of these, 45 antibodies were H7-specific, and 17 of these neutralized the virus, albeit with few somatic mutations in their variable domain sequences. An additional set of 28 antibodies, isolated from younger donors born after 1968, cross-reacted between H7 and H3 haemagglutinins in binding assays, and had accumulated significantly more somatic mutations, but were predominantly non-neutralizing in vitro. Crystal structures of three neutralizing and protective antibodies in complex with the H7 haemagglutinin revealed that they recognize overlapping residues surrounding the receptor-binding site of haemagglutinin. One of the antibodies, L4A-14, bound into the sialic acid binding site and made contacts with haemagglutinin residues that were conserved in the great majority of 2016-2017 H7N9 isolates. However, only 3 of the 17 neutralizing antibodies retained activity for the Yangtze River Delta lineage viruses isolated in 2016-2017 that have undergone antigenic change, which emphasizes the need for updated H7N9 vaccines.

PMID: 30478290 DOI: 10.1038/s41564-018-0303-7

Keywords: Avian Influenza; H7N9; Human; Monoclonal Antibodies.

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A broadly protective #therapeutic #antibody against #influenza B virus with two mechanisms of action (Nat Commun., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Nat Commun. 2017 Jan 19;8:14234. doi: 10.1038/ncomms14234.

A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action.

Chai N1, Swem LR1, Park S2, Nakamura G3, Chiang N3, Estevez A4, Fong R4, Kamen L5, Kho E5, Reichelt M6, Lin Z2, Chiu H7, Skippington E8, Modrusan Z9, Stinson J9, Xu M2, Lupardus P4, Ciferri C4, Tan MW1.

Author information: 1 Department of Infectious Diseases, Genentech, South San Francisco, California 94080, USA. 2 Department of Translational Immunology, Genentech, South San Francisco, California 94080, USA. 3 Department of Antibody Engineering, Genentech, South San Francisco, California 94080, USA. 4 Department of Structural Biology, Genentech, South San Francisco, California 94080, USA. 5 Department of BioAnalytical Sciences, Genentech, South San Francisco, California 94080, USA. 6 Department of Pathology, Genentech, South San Francisco, California 94080, USA. 7 Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California 94080, USA. 8 Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California 94080, USA. 9 Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA.

 

Abstract

Influenza B virus (IBV) causes annual influenza epidemics around the world. Here we use an in vivo plasmablast enrichment technique to isolate a human monoclonal antibody, 46B8 that neutralizes all IBVs tested in vitro and protects mice against lethal challenge of all IBVs tested when administered 72 h post infection. 46B8 demonstrates a superior therapeutic benefit over Tamiflu and has an additive antiviral effect in combination with Tamiflu. 46B8 binds to a conserved epitope in the vestigial esterase domain of hemagglutinin (HA) and blocks HA-mediated membrane fusion. After passage of the B/Brisbane/60/2008 virus in the presence of 46B8, we isolated three resistant clones, all harbouring the same mutation (Ser301Phe) in HA that abolishes 46B8 binding to HA at low pH. Interestingly, 46B8 is still able to protect mice against lethal challenge of the mutant viruses, possibly owing to its ability to mediate antibody-dependent cellular cytotoxicity (ADCC).

PMID: 28102191 PMCID: PMC5253702 DOI: 10.1038/ncomms14234 [Indexed for MEDLINE]  Free PMC Article

Keywords: Seasonal Influenza; Influenza B; Monoclonal Antibodies.

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Broad neutralizing #activity of a #human monoclonal #antibody against #H7N9 strains from 2013 to 2017 (Emerg Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Emerg Microbes Infect. 2018 Nov 14;7(1):179. doi: 10.1038/s41426-018-0182-2.

Broad neutralizing activity of a human monoclonal antibody against H7N9 strains from 2013 to 2017.

Chen C1, Liu Z1, Liu L1, Xiao Y1, Wang J2, Jin Q3,4.

Author information: 1 MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. 2 MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. jianminwang@ipbcams.ac.cn. 3 MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. zdsys@vip.sina.com. 4 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China. zdsys@vip.sina.com.

 

Abstract

H7N9 influenza virus has been circulating among humans for five epidemic waves since it was first isolated in 2013 in China. The recent increase in H7N9 infections during the fifth outbreak in China has caused concerns of a possible pandemic. In this study, we describe a previously characterized human monoclonal antibody, HNIgGA6, obtained by isolating rearranged heavy-chain and light-chain genes from patients who had recovered from H7N9 infections. HNIgGA6 recognized multiple HAs and neutralized the infectivity of 11 out of the 12 H7N9 strains tested, as well as three emerging HPAI H7N9 isolates. The only resistant strain was A/Shanghai/1/2013 (H7N9-SH1), which carries the avian receptor alleles 186V and 226Q in the sialic acid-binding pocket. The mAb broadly neutralized divergent H7N9 strains from 2013 to 2017 and represents a potential alternative treatment for H7N9 interventions.

PMID: 30425238 DOI: 10.1038/s41426-018-0182-2

Keywords: Avian Influenza; H7N9; Human; Monoclonal Antibodies; China.

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A Combination of Two #Human Monoclonal #Antibodies Prevents #Zika Virus Escape Mutations in Non-human #Primates (Cell Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Cell Rep. 2018 Nov 6;25(6):1385-1394.e7. doi: 10.1016/j.celrep.2018.10.031.

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates.

Keeffe JR1, Van Rompay KKA2, Olsen PC3, Wang Q4, Gazumyan A5, Azzopardi SA6, Schaefer-Babajew D5, Lee YE1, Stuart JB7, Singapuri A7, Watanabe J8, Usachenko J8, Ardeshir A8, Saeed M6, Agudelo M5, Eisenreich T5, Bournazos S9, Oliveira TY5, Rice CM6, Coffey LL7, MacDonald MR6, Bjorkman PJ1, Nussenzweig MC10, Robbiani DF11.

Author information: 1 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. 2 California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA; Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA. 3 Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil. 4 Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. 5 Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. 6 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. 7 Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA. 8 California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA. 9 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA. 10 Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: nussen@rockefeller.edu. 11 Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA. Electronic address: drobbiani@rockefeller.edu.

 

Abstract

Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV.

KEYWORDS: antibodies; antibody dependent enhancement; crystal structure; epitope; escape; flavivirus; macaques; prophylaxis; protection

PMID: 30403995 DOI: 10.1016/j.celrep.2018.10.031

Keywords: Zika Virus; Monoclonal antibodies; Animal models.

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