Broadly protective human antibodies that target the active site of influenza virus neuraminidase

Stadlbauer, Daniel; Zhu, Xueyong; McMahon, Meagan; Turner, Jackson S.; Wohlbold, Teddy John; Schmitz, Aaron J.; Strohmeier, Shirin; Yu, Wenli; Nachbagauer, Raffael; Mudd, Philip A.; Wilson, Ian A.; Ellebedy, Ali H.; Krammer, Florian

doi:10.1126/science.aay0678

Cited by 189 publications

(223 citation statements)

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“…Excitingly, new antigenic targets are still being uncovered, providing new opportunities to apply this rational approach. For example, in influenza virus, very recent studies have 'rediscovered' neuraminidase (NA), as a promising target [52][53][54]. Furthermore, a newly identified class of epitopes on HA, namely those at the interface between the HA1 head subunits, are have also been found to be a target for broad protective activity [55][56][57].…”

Section: Resultsmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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Please cite this article as: Ward AB, Wilson IA, Innovations in structure-based antigen design and immune monitoring for next generation vaccines, J o u r n a l P r e -p r o o f Highligthts Immunofocusing as a strategy for structure-based vaccine design. Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. Structure-based vaccine design translated into the clinic. AbstractThe recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, hepatitis C and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate result of ever increasingly breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development.

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Section: Resultsmentioning

confidence: 99%

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Ward

Wilson

2020

Current Opinion in Immunology

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“…A single monoclonal antibody can neutralize decades of influenza virus isolates regardless of strain at nanomolar amounts. Neuraminidase inhibitory antibodies can inhibit viral spread, and replication at multiple stages of the virus life cycle [42]. Finally, many different studies show that NA inhibitory antibodies can decrease disease severity, virus transmission or provide sterilizing immunity [5, 14, 18-20, 24].…”

Section: Discussionmentioning

confidence: 99%

Neuraminidase antigenic drift of Influenza A virus H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

Powell

Pekosz

2020

Preprint

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27 In the 2014-2015 influenza season a novel neuraminidase (NA) genotype emerged in 28 the Johns Hopkins Center of Excellence for Influenza Research and Surveillance (JH 29 CEIRS) surveillance network as well as globally. This novel genotype encoded a 30 glycosylation site at position 245-247 in the NA protein from clade 3c.2a H3N2 viruses.31 In the years following the 2014-2015 season, this novel NA glycosylation genotype 32 quickly dominated the human H3N2 population of viruses. To assess the effect this 33 novel glycosylation has on virus fitness and antibody binding, recombinant viruses with 34 (NA Gly+) or without (NA Gly-) the novel NA glycosylation were created. Viruses with 35 the 245 NA Gly+ genotype grew to a significantly lower infectious virus titer on primary, 36 differentiated human nasal epithelial cells (hNEC) compared to viruses with the 245 NA 37 Gly-genotype, but growth was similar on immortalized cells. The 245 NA Gly+ blocked 38 human and rabbit monoclonal antibodies that target the enzymatic site from binding to 39 their epitope. Additionally, viruses with the 245 NA Gly+ genotype had significantly 40 lower enzymatic activity compared to viruses with the 245 NA Gly-genotype. Human 41 monoclonal antibodies that target residues near the 245 NA glycosylation were less 42 effective at inhibiting NA enzymatic activity and virus replication of viruses encoding an 43 NA Gly+ protein compared to ones encoding NA Gly-protein. Additionally, a 44 recombinant H6N2 virus with the 245 NA Gly+ protein was more resistant to enzymatic 45 inhibition from convalescent serum from H3N2-infected humans compared to viruses 46 with the 245 NA Gly-genotype. Finally, the 245 NA Gly+ protected from NA antibody 47 mediated virus neutralization. These results suggest that while the 245 NA Gly+ 48 decreases virus replication in hNECs and decreases enzymatic activity, the 49 glycosylation blocks the binding of monoclonal and human serum NA specific antibodies 50 that would otherwise inhibit enzymatic activity and virus replication. Influenza virus infects millions of people worldwide and leads to thousands of deaths 74 and millions in economic loss each year. During the 2014/2015 season circulating 75 human H3N2 viruses acquired a novel mutation in the neuraminidase (NA) protein. This 76 mutation has since fixed in human H3N2 viruses. This mutation at position 245 through 77 247 in the amino acid sequence of NA encoded an N-linked glycosylation. Here, we 78 studied how this N-linked glycosylation impacts virus fitness and protein function. We 79 found that this N-linked glycosylation on the NA protein decreased viral replication 80 fitness on human nasal epithelial cells (hNEC) but not immortalized Madin-Darby 81 Canine Kidney (MDCK) cells. We also determined this glycosylation decreases NA 82 enzymatic activity, enzyme kinetics and affinity for substrate. Furthermore, we show that 83 this N-linked glycosylation at position 245 blocks some NA specific inhibitory antibodies 84 from binding to the protein, inhibiting enzyma...

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“…DiLillio et al reported that the broadly neutralizing NA-reactive antibodies, 3C05, can induce protective immunity in vivo in an FcγR-dependent manner [100]. Recently, Stadlbauer et al showed that one monoclonal antibody generated from plasmablasts isolated from a human donor naturally infected with the H3N2 virus, designated 1G01, showed the broadest reactive spectrum to a variety of neuraminidases ranging from influenza A group 1 and group 2, to both influenza B virus lineages [113]. These antibodies exhibited multiple anti-viral activities including the blockade of virus particle release and ADCC.…”

Section: Adcc To Other Proteins In Influenza Virusmentioning

confidence: 99%

Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

Gao

Sheng

Sreenivasan

et al. 2020

Viruses

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Influenza causes millions of cases of hospitalizations annually and remains a public health concern on a global scale. Vaccines are developed and have proven to be the most effective countermeasures against influenza infection. Their efficacy has been largely evaluated by hemagglutinin inhibition (HI) titers exhibited by vaccine-induced neutralizing antibodies, which correlate fairly well with vaccine-conferred protection. Contrarily, non-neutralizing antibodies and their therapeutic potential are less well defined, yet, recent advances in anti-influenza antibody research indicate that non-neutralizing Fc-effector activities, especially antibody-dependent cellular cytotoxicity (ADCC), also serve as a critical mechanism in antibody-mediated anti-influenza host response. Monoclonal antibodies (mAbs) with Fc-effector activities have the potential for prophylactic and therapeutic treatment of influenza infection. Inducing mAbs mediated Fc-effector functions could be a complementary or alternative approach to the existing neutralizing antibody-based prevention and therapy. This review mainly discusses recent advances in Fc-effector functions, especially ADCC and their potential role in influenza countermeasures. Considering the complexity of anti-influenza approaches, future vaccines may need a cocktail of immunogens in order to elicit antibodies with broad-spectrum protection via multiple protective mechanisms.Viruses 2020, 12, 276 2 of 20 the infected cell, HA on the virion still interacts with the SA receptors on the host cell membrane. The tetrameric NA spike functions to release the viral progeny through cleaving α-ketosidic linkage between the SA and an adjacent sugar residue [5].α-ketosidic linkage between the SA and an adjacent sugar residue [5].The HA and NA proteins are also highly immunogenic and antibodies targeting both glycoproteins can be isolated after natural infection or vaccination. Through binding to viral surface proteins HA and NA, antibodies can block the essential steps in the virus replication cycle, thereby limiting the spread of infection. Due to the host immune pressure and error-prone RNA polymerase, HA and NA are very plastic and display difference in antigenic properties. According to the antigenic difference, influenza A virus can divide into 18 HA (H1-H18) and 11 NA (N1-N11) subtypes [6]. According to the Weekly U.S. Influenza Surveillance Report released by CDC, H1N1(pdm09) and B/Victoria lineage viruses are equally dominant and responsible for the majority of death cases during the 2019-2020 influenza season [7].

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Broadly protective human antibodies that target the active site of influenza virus neuraminidase

Cited by 189 publications

References 45 publications

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Neuraminidase antigenic drift of Influenza A virus H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

Influenza A Virus Antibodies with Antibody-Dependent Cellular Cytotoxicity Function

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