A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses

Hu, Hongxing; Voss, Jarrod; Zhang, Guoliang; Buchy, Philippe; Zuo, Teng; Wang, Lulan; Wang, Feng; Zhou, Fan; Wang, Guiqing; Tsai, Cheguo; Calder, Lesley J.; Gamblin, Steve; Zhang, Linqi; Denis, Vincent; Zhou, Boping; Skehel, J.J.; Zhou, Paul

doi:10.1128/jvi.06665-11

Cited by 61 publications

(76 citation statements)

References 53 publications

(59 reference statements)

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“…These Abs potently neutralize all clades and subclades of HPAI H5N1 viruses except subclade 7.2. Furthermore, they protect against lethal challenge of both homologous and heterologous H5N1 strains (26,27). More recently, we showed that 65C6 and 100F4 Abs also cross-neutralize newly emerging HPAI H5N6 and H5N8 reassortants.…”

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confidence: 78%

“…In addition, Abs against the globular head with different degrees of cross-reactivity have also been isolated (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Many of these Abs are virus strain specific and recognize epitopes located in the receptor binding site (RBS), but some Abs recognize conserved epitopes within or outside the RBS of diverse strains of different subtypes (17)(18)(19) or within a HA subtype (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). The antibody repertoire against epitopes located in the head is more diverse than those Abs targeting epitopes in the stem (31).…”

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confidence: 99%

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Divergent Requirement of Fc-Fcγ Receptor Interactions for In Vivo Protection against Influenza Viruses by Two Pan-H5 Hemagglutinin Antibodies

Wang

Ren

Jiang

et al. 2017

J Virol

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Recent studies have shown that Fc-Fc␥ receptor (Fc␥R) interactions are required for in vivo protection against influenza viruses by broadly reactive antihemagglutinin (HA) stem, but not virus strain-specific, anti-receptor binding site (RBS), antibodies (Abs). Since only a few Abs recognizing epitopes in the head region but outside the RBS have been tested against single-challenge virus strains, it remains unknown whether Fc-Fc␥R interactions are required for in vivo protection by Abs recognizing epitopes outside the RBS and whether the requirement is virus strain specific or epitope specific. In the present study, we therefore investigated the requirements for in vivo protection using two pan-H5 Abs, 65C6 and 100F4. We generated chimeric Abs, 65C6/IgG2a and 100F4/IgG2a, which preferentially engage activating Fc␥Rs, and isogenic forms, 65C6/D265A and 100F4/D265A, which do not bind Fc␥R. Virus neutralizing activity, binding, antibody-dependent cellular cytotoxicity (ADCC), and in vivo protection of these Abs were compared using three H5 strains, A/Shenzhen/406H/2006 (SZ06), A/chicken/Shanxi/2/2006 (SX06), and A/chicken/Netherlands/14015526/2014 (NE14). We found that all four chimeric Abs bound and neutralized the SZ06 and NE14 strains but poorly inhibited the SX06 strain. 65C6/IgG2a and 100F4/IgG2a, but not 65C6/D265A and 100F4/D265A, mediated ADCC against target cells expressing HA derived from all three virus strains. Interestingly, both 65C6/IgG2a and 65C6/D265A demonstrated comparable protection against all three virus strains in vivo; however, 100F4/IgG2a, but not 100F4/D265A, showed in vivo protection. Thus, we conclude that Fc-Fc␥R interactions are required for in vivo protection by 100F4, but not by 65C6, and therefore, protection is not virus strain specific but epitope specific.IMPORTANCE Abs play an important role in immune protection against influenza virus infection. Fc-Fc␥R interactions are required for in vivo protection by broadly neutralizing antistem, but not by virus strain-specific, anti-receptor binding site (RBS), Abs. Whether such interactions are necessary for protection by Abs that recognize epitopes outside RBS is not fully understood. In the present study, we investigated in vivo protection mechanisms against three H5 strains by two pan-H5 Abs, 65C6 and 100F4. We show that although these two Abs have similar neutralizing, binding, and ADCC activities against all three H5 strains in vitro, they have divergent requirements for Fc-Fc␥R interactions to protect against the three H5 strains in vivo. The FcFc␥R interactions are required for in vivo protection by 100F4, but not by 65C6. Thus, we conclude that Fc-Fc␥R interactions for in vivo protection by pan-H5 Abs is not strain specific, but epitope specific.KEYWORDS influenza viruses, in vivo protection, monoclonal antibodies

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confidence: 78%

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confidence: 99%

Divergent Requirement of Fc-Fcγ Receptor Interactions for In Vivo Protection against Influenza Viruses by Two Pan-H5 Hemagglutinin Antibodies

Wang

Ren

Jiang

et al. 2017

J Virol

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“…Significant abrogation of binding in western blot analysis was observed when WLLGNP was mutated to WRRGNP. Another human mAb, 100F4, neutralises multiple clades of H5N1 and binds outside the receptor binding subdomain of H5N1 HA [12,22]. Memory B cells from peripheral blood mononuclear cells of a patient who recovered from H5N1 infection were immortalised and culture supernatants were screened by HA pseudotype-based neutralisation assay.…”

Section: Generation Of Neutralising Mabs Binding To the Ve Subdomainmentioning

confidence: 99%

The Vestigial Esterase Domain of Haemagglutinin of H5N1 Avian Influenza A Virus: Antigenicity and Contribution to Viral Pathogenesis

Zheng

Paul

et al. 2018

Preprint

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Initial attempts to develop monoclonal antibodies as therapeutics to resolve influenza infections focused mainly on searching for antibodies with the potential to neutralise the virus in vitro with classical haemagglutination inhibition and micro-neutralisation assays. This led to the identification of many antibodies that bind to the head domain of haemagglutinin (HA) which generally have potent neutralisation capabilities that block viral entry or viral membrane fusion. However, this class of antibodies has a narrow breadth of protection in that they are usually strain specific. This led to the emphasis on stalk targeting antibodies which are able to bind a broad range of viral targets that span across different influenza subtypes.Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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“…Broad domain mapping for independent panels of anti-influenza mAbs are described from yeast libraries displaying fulllength, precursor influenza HA (HA0) or the HA1 and HA2 subunits separately (113,114). After confirming binding and domain localization, sublibraries of mutant HA fragments were generated by error-prone PCR for fine epitope mapping.…”

Section: Anti-influenza Mab Discovery Involving Yeast Displaymentioning

confidence: 99%

Phage and Yeast Display

Sheehan

Marasco

2015

Microbiol Spectr

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Despite the availability of antimicrobial drugs, the continued development of microbial resistance-established through escape mutations and the emergence of resistant strains-limits their clinical utility. The discovery of novel, therapeutic, monoclonal antibodies (mAbs) offers viable clinical alternatives in the treatment and prophylaxis of infectious diseases. Human mAb-based therapies are typically nontoxic in patients and demonstrate high specificity for the intended microbial target. This specificity prevents negative impacts on the patient microbiome and avoids driving the resistance of nontarget species. The in vitro selection of human antibody fragment libraries displayed on phage or yeast surfaces represents a group of well-established technologies capable of generating human mAbs. The advantage of these forms of microbial display is the large repertoire of human antibody fragments present during a single selection campaign. Furthermore, the in vitro selection environments of microbial surface display allow for the rapid isolation of antibodies-and their encoding genes-against infectious pathogens and their toxins that are impractical within in vivo systems, such as murine hybridomas. This article focuses on the technologies of phage display and yeast display, as these strategies relate to the discovery of human mAbs for the treatment and vaccine development of infectious diseases.

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A Human Antibody Recognizing a Conserved Epitope of H5 Hemagglutinin Broadly Neutralizes Highly Pathogenic Avian Influenza H5N1 Viruses

Cited by 61 publications

References 53 publications

Divergent Requirement of Fc-Fcγ Receptor Interactions for In Vivo Protection against Influenza Viruses by Two Pan-H5 Hemagglutinin Antibodies

Divergent Requirement of Fc-Fcγ Receptor Interactions for In Vivo Protection against Influenza Viruses by Two Pan-H5 Hemagglutinin Antibodies

The Vestigial Esterase Domain of Haemagglutinin of H5N1 Avian Influenza A Virus: Antigenicity and Contribution to Viral Pathogenesis

Phage and Yeast Display

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