2023 |
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851. | Zhou, Panpan; Song, Ge; Liu, Hejun; Yuan, Meng; He, Wan-Ting; Beutler, Nathan; Zhu, Xueyong; Tse, Longping V; Martinez, David R; Schäfer, Alexandra; Anzanello, Fabio; Yong, Peter; Peng, Linghang; Dueker, Katharina; Musharrafieh, Rami; Callaghan, Sean; Capozzola, Tazio; Limbo, Oliver; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A; Smith, Davey M; Nemazee, David; Jardine, Joseph G; Safonova, Yana; Briney, Bryan; Rogers, Thomas F; Wilson, Ian A; Baric, Ralph S; Gralinski, Lisa E; Burton, Dennis R; Andrabi, Raiees: Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease. In: Immunity, vol. 56, no. 3, pp. 669–686.e7, 2023, ISSN: 1097-4180. (Type: Journal Article | Abstract | Links)
@article{pmid36889306, Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines.
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850. | Feng, Yupeng; Yuan, Meng; Powers, John M; Hu, Mengyun; Munt, Jennifer E; Arunachalam, Prabhu S; Leist, Sarah R; Bellusci, Lorenza; Adams, Lily E; Sundaramurthy, Sumana; Shirreff, Lisa M; Mallory, Michael L; Scooby, Trevor D; Moreno, Alberto; O'Hagan, Derek T; Kleanthous, Harry; Villinger, Francois J; Veesler, David; King, Neil P; Suthar, Mehul S; Khurana, Surender; Baric, Ralph S; Wilson, Ian A; Pulendran, Bali: Extremely potent pan-sarbecovirus neutralizing antibodies generated by immunization of macaques with an AS03-adjuvanted monovalent subunit vaccine against SARS-CoV-2. 2023. (Type: Miscellaneous | Abstract | Links)
@misc{pmid36711543, The rapid emergence of SARS-CoV-2 variants that evade immunity to vaccination has placed a global health imperative on the development of therapeutic countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent pan-sarbecovirus antibodies from non-human primates vaccinated with an AS03 adjuvanted subunit vaccine against SARS-CoV-2 that recognize conserved epitopes in the receptor binding domain (RBD) with femtomolar affinities. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells for at least one year following primary vaccination. 514 monoclonal antibodies (mAbs) were generated from antigen-specific memory B cells. Antibodies isolated at 5 to 12 months following vaccination displayed greater potency and breadth, relative to those identified at 1.4 months. Notably, 15 out of 338 (∼4.4%) antibodies isolated at 1.4∼6 months after the primary vaccination showed extraordinary neutralization potency against SARS-CoV-2 omicron BA.1, despite the absence of BA.1 neutralization in serum. Two of them, 25F9 and 20A7, neutralized authentic clade Ia sarbecoviruses (SARS-CoV, WIV-1, SHC014) and clade Ib sarbecoviruses (SARS-CoV-2 D614G, SARS-CoV-2 BA.1, Pangolin-GD) with half-maximal inhibition concentrations of (0.85 ng/ml, 3 ng/ml, 6 ng/ml, 6 ng/ml, 42 ng/ml, 6 ng/ml) and (13 ng/ml, 2 ng/ml, 18 ng/ml, 9 ng/ml, 6 ng/ml, 345 ng/ml), respectively. Furthermore, 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants of concern and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1 and XBB variants. X-ray crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved RBD sites. In vivo prophylactic protection of 25F9, 20A7 and 27A12 was confirmed in aged Balb/c mice. Notably, administration of 25F9 provided complete protection against SARS-CoV-2, SARS-CoV-2 BA.1, SARS-CoV, and SHC014 challenge, underscoring that these mAbs are promising pan-sarbecovirus therapeutic antibodies.nnONE SENTENCE SUMMARY: Extremely potent pan-sarbecovirus neutralizing antibodies.
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849. | Dacon, Cherrelle; Peng, Linghang; Lin, Ting-Hui; Tucker, Courtney; Lee, Chang-Chun D; Cong, Yu; Wang, Lingshu; Purser, Lauren; Cooper, Andrew J R; Williams, Jazmean K; Pyo, Chul-Woo; Yuan, Meng; Kosik, Ivan; Hu, Zhe; Zhao, Ming; Mohan, Divya; Peterson, Mary; Skinner, Jeff; Dixit, Saurabh; Kollins, Erin; Huzella, Louis; Perry, Donna; Byrum, Russell; Lembirik, Sanae; Murphy, Michael; Zhang, Yi; Yang, Eun Sung; Chen, Man; Leung, Kwanyee; Weinberg, Rona S; Pegu, Amarendra; Geraghty, Daniel E; Davidson, Edgar; Doranz, Benjamin J; Douagi, Iyadh; Moir, Susan; Yewdell, Jonathan W; Schmaljohn, Connie; Crompton, Peter D; Mascola, John R; Holbrook, Michael R; Nemazee, David; Wilson, Ian A; Tan, Joshua: Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses. In: Cell Host Microbe, vol. 31, no. 1, pp. 97–111.e12, 2023, ISSN: 1934-6069. (Type: Journal Article | Abstract | Links)
@article{pmid36347257, Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.
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2022 |
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848. | Willis, Jordan R; Berndsen, Zachary T; Ma, Krystal M; Steichen, Jon M; Schiffner, Torben; Landais, Elise; Liguori, Alessia; Kalyuzhniy, Oleksandr; Allen, Joel D; Baboo, Sabyasachi; Omorodion, Oluwarotimi; Diedrich, Jolene K; Hu, Xiaozhen; Georgeson, Erik; Phelps, Nicole; Eskandarzadeh, Saman; Groschel, Bettina; Kubitz, Michael; Adachi, Yumiko; Mullin, Tina-Marie; Alavi, Nushin B; Falcone, Samantha; Himansu, Sunny; Carfi, Andrea; Wilson, Ian A; Yates, John R; Paulson, James C; Crispin, Max; Ward, Andrew B; Schief, William R: Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors. In: Immunity, vol. 55, no. 11, pp. 2149–2167.e9, 2022, ISSN: 1097-4180. (Type: Journal Article | Abstract | Links)
@article{pmid36179689, Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy-chain complementarity-determining region 3 (HCDR3), suggesting that the rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy-chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bound inferred germlines for PCT64 and PG9 and had higher affinities for bnAbs, determined cryo-EM structures of ApexGT trimers complexed with inferred-germline and bnAb forms of PCT64 and PG9, and developed an mRNA-encoded cell-surface ApexGT trimer. These methods and immunogens have promise to assist HIV vaccine development.
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847. | Yuan, Meng; Wang, Yiquan; Lv, Huibin; Tan, Timothy J C; Wilson, Ian A; Wu, Nicholas C: Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2. In: Cell Rep, vol. 41, no. 7, pp. 111650, 2022, ISSN: 2211-1247. (Type: Journal Article | Abstract | Links)
@article{pmid36335937, As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key toward next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes a broad range of VOCs, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino acid residue 54 of IGHV2-5, which is located at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.
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846. | van Schooten, Jelle; Schorcht, Anna; Farokhi, Elinaz; Umotoy, Jeffrey C; Gao, Hongmei; van den Kerkhof, Tom L G M; Dorning, Jessica; Meesters, Tim G Rijkhold; van der Woude, Patricia; Burger, Judith A; Bijl, Tom; Ghalaiyini, Riham; de la Peña, Alba Torrents; Turner, Hannah L; Labranche, Celia C; Stanfield, Robyn L; Sok, Devin; Schuitemaker, Hanneke; Montefiori, David C; Burton, Dennis R; Ozorowski, Gabriel; Seaman, Michael S; Wilson, Ian A; Sanders, Rogier W; Ward, Andrew B; van Gils, Marit J: Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer. In: PLoS Pathog, vol. 18, no. 11, pp. e1010945, 2022, ISSN: 1553-7374. (Type: Journal Article | Abstract | Links)
@article{pmid36395347, Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely difficult to induce by vaccination. Defining the developmental pathways towards neutralization breadth can assist in the design of strategies to elicit protective bNAb responses by vaccination. Here, HIV-1 envelope glycoproteins (Env)-specific IgG+ B cells were isolated at various time points post infection from an HIV-1 infected elite neutralizer to obtain monoclonal antibodies (mAbs). Multiple antibody lineages were isolated targeting distinct epitopes on Env, including the gp120-gp41 interface, CD4-binding site, silent face and V3 region. The mAbs each neutralized a diverse set of HIV-1 strains from different clades indicating that the patient's remarkable serum breadth and potency might have been the result of a polyclonal mixture rather than a single bNAb lineage. High-resolution cryo-electron microscopy structures of the neutralizing mAbs (NAbs) in complex with an Env trimer generated from the same individual revealed that the NAbs used multiple strategies to neutralize the virus; blocking the receptor binding site, binding to HIV-1 Env N-linked glycans, and disassembly of the trimer. These results show that diverse NAbs can complement each other to achieve a broad and potent neutralizing serum response in HIV-1 infected individuals. Hence, the induction of combinations of moderately broad NAbs might be a viable vaccine strategy to protect against a wide range of circulating HIV-1 viruses.
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845. | Guerra, Denise; Beaumont, Tim; RadiÄ, Laura; Kerster, Gius; van der Straten, Karlijn; Yuan, Meng; Torres, Jonathan L; Lee, Wen-Hsin; Liu, Hejun; Poniman, Meliawati; Bontjer, Ilja; Burger, Judith A; Claireaux, Mathieu; Caniels, Tom G; Snitselaar, Jonne L; Bijl, Tom P L; Kruijer, Sabine; Ozorowski, Gabriel; Gideonse, David; Sliepen, Kwinten; Ward, Andrew B; Eggink, Dirk; de Bree, Godelieve J; Wilson, Ian A; Sanders, Rogier W; van Gils, Marit J: Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid36263063, The worldwide pandemic caused by SARS-CoV-2 has remained a human medical threat due to the continued evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants for therapeutic and prophylactic use. A stabilized autologous SARS-CoV-2 spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection. Five mAbs selected from those B cells showed considerable neutralizing potency against multiple variants of concern, with COVA309-35 being the most potent against the autologous virus, as well as against Omicron BA.1 and BA.2. When combining the COVA309 mAbs as cocktails or bispecific antibody formats, the breadth and potency was significantly improved against all tested variants. In addition, the mechanism of cross-neutralization of the COVA309 mAbs was elucidated by structural analysis. Altogether these data indicate that a Gamma-infected individual can develop broadly neutralizing antibodies.
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844. | He, Linling; Chaudhary, Anshul; Lin, Xiaohe; Sou, Cindy; Alkutkar, Tanwee; Kumar, Sonu; Ngo, Timothy; Kosviner, Ezra; Ozorowski, Gabriel; Stanfield, Robyn L; Ward, Andrew B; Wilson, Ian A; Zhu, Jiang: Author Correction: Single-component multilayered self-assembling nanoparticles presenting rationally designed glycoprotein trimers as Ebola virus vaccines. 2022, ISSN: 2041-1723. (Type: Miscellaneous | Links)
@misc{pmid36284102, |
843. | Krause, Robert; Snyman, Jumari; Shi-Hsia, Hwa; Muema, Daniel; Karim, Farina; Ganga, Yashica; Ngoepe, Abigail; Zungu, Yenzekile; Gazy, Inbal; Bernstein, Mallory; Khan, Khadija; Mazibuko, Matilda; Mthabela, Ntombifuthi; Ramjit, Dirhona; ; Limbo, Oliver; Jardine, Joseph; Sok, Devin; Wilson, Ian A; Hanekom, Willem; Sigal, Alex; Kløverpris, Henrik; Ndung'u, Thumbi; Leslie, Alasdair: HIV skews the SARS-CoV-2 B cell response towards an extrafollicular maturation pathway. In: Elife, vol. 11, 2022, ISSN: 2050-084X. (Type: Journal Article | Abstract | Links)
@article{pmid36300787, BACKGROUND: HIV infection dysregulates the B cell compartment, affecting memory B cell formation and the antibody response to infection and vaccination. Understanding the B cell response to SARS-CoV-2 in people living with HIV (PLWH) may explain the increased morbidity, reduced vaccine efficacy, reduced clearance, and intra-host evolution of SARS-CoV-2 observed in some HIV-1 coinfections.nnMETHODS: We compared B cell responses to COVID-19 in PLWH and HIV negative (HIV-ve) patients in a cohort recruited in Durban, South Africa, during the first pandemic wave in July 2020 using detailed flow cytometry phenotyping of longitudinal samples with markers of B cell maturation, homing, and regulatory features.nnRESULTS: This revealed a coordinated B cell response to COVID-19 that differed significantly between HIV-ve and PLWH. Memory B cells in PLWH displayed evidence of reduced germinal centre (GC) activity, homing capacity, and class-switching responses, with increased PD-L1 expression, and decreased Tfh frequency. This was mirrored by increased extrafollicular (EF) activity, with dynamic changes in activated double negative (DN2) and activated naïve B cells, which correlated with anti-RBD-titres in these individuals. An elevated SARS-CoV-2-specific EF response in PLWH was confirmed using viral spike and RBD bait proteins.nnCONCLUSIONS: Despite similar disease severity, these trends were highest in participants with uncontrolled HIV, implicating HIV in driving these changes. EF B cell responses are rapid but give rise to lower affinity antibodies, less durable long-term memory, and reduced capacity to adapt to new variants. Further work is needed to determine the long-term effects of HIV on SARS-CoV-2 immunity, particularly as new variants emerge.nnFUNDING: This work was supported by a grant from the Wellcome Trust to the Africa Health Research Institute (Wellcome Trust Strategic Core Award [grant number 201433/Z/16/Z]). Additional funding was received from the South African Department of Science and Innovation through the National Research Foundation (South African Research Chairs Initiative [grant number 64809]), and the Victor Daitz Foundation.
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842. | Liu, Hejun; Wilson, Ian A: Protective neutralizing epitopes in SARS-CoV-2. In: Immunol Rev, vol. 310, no. 1, pp. 76–92, 2022, ISSN: 1600-065X. (Type: Journal Article | Abstract | Links)
@article{pmid35599305, The COVID-19 pandemic has caused an unprecedented health crisis and economic burden worldwide. Its etiological agent SARS-CoV-2, a new virus in the coronavirus family, has infected hundreds of millions of people worldwide. SARS-CoV-2 has evolved over the past 2 years to increase its transmissibility as well as to evade the immunity established by previous infection and vaccination. Nevertheless, strong immune responses can be elicited by viral infection and vaccination, which have proved to be protective against the emergence of variants, particularly with respect to hospitalization or severe disease. Here, we review our current understanding of how the virus enters the host cell and how our immune system is able to defend against cell entry and infection. Neutralizing antibodies are a major component of our immune defense and have been extensively studied for SARS-CoV-2 and its variants. Structures of these neutralizing antibodies have provided valuable insights into epitopes that are protective against the original ancestral virus and the variants that have emerged. The molecular characterization of neutralizing epitopes as well as epitope conservation and resistance are important for design of next-generation vaccines and antibody therapeutics.
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841. | Tan, Timothy J C; Mou, Zongjun; Lei, Ruipeng; Ouyang, Wenhao O; Yuan, Meng; Song, Ge; Andrabi, Raiees; Wilson, Ian A; Kieffer, Collin; Dai, Xinghong; Matreyek, Kenneth A; Wu, Nicholas C: High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid36203547, Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All COVID-19 vaccines in the US encode spike with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering prefusion-stabilized spike immunogens involve tedious experimental work and heavily rely on structural information. Here, we established a systematic and unbiased method of identifying mutations that concomitantly improve expression and stabilize the prefusion conformation of the SARS-CoV-2 spike. Our method integrated a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, this method was applied to a region in the S2 domain that includes the first heptad repeat and central helix. Our results revealed that besides K986P and V987P, several mutations simultaneously improved expression and significantly lowered the fusogenicity of the spike. As prefusion stabilization is a common challenge for viral immunogen design, this work will help accelerate vaccine development against different viruses.
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840. | van Schooten, Jelle; Farokhi, Elinaz; Schorcht, Anna; van den Kerkhof, Tom L G M; Gao, Hongmei; van der Woude, Patricia; Burger, Judith A; Meesters, Tim G Rijkhold; Bijl, Tom; Ghalaiyini, Riham; Turner, Hannah L; Dorning, Jessica; van Schaik, Barbera D C; van Kampen, Antoine H C; Labranche, Celia C; Stanfield, Robyn L; Sok, Devin; Montefiori, David C; Burton, Dennis R; Seaman, Michael S; Ozorowski, Gabriel; Wilson, Ian A; Sanders, Rogier W; Ward, Andrew B; van Gils, Marit J: Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein. In: Nat Commun, vol. 13, no. 1, pp. 4515, 2022, ISSN: 2041-1723. (Type: Journal Article | Abstract | Links)
@article{pmid35922441, A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.
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839. | Dacon, Cherrelle; Tucker, Courtney; Peng, Linghang; Lee, Chang-Chun D; Lin, Ting-Hui; Yuan, Meng; Cong, Yu; Wang, Lingshu; Purser, Lauren; Williams, Jazmean K; Pyo, Chul-Woo; Kosik, Ivan; Hu, Zhe; Zhao, Ming; Mohan, Divya; Cooper, Andrew J R; Peterson, Mary; Skinner, Jeff; Dixit, Saurabh; Kollins, Erin; Huzella, Louis; Perry, Donna; Byrum, Russell; Lembirik, Sanae; Drawbaugh, David; Eaton, Brett; Zhang, Yi; Yang, Eun Sung; Chen, Man; Leung, Kwanyee; Weinberg, Rona S; Pegu, Amarendra; Geraghty, Daniel E; Davidson, Edgar; Douagi, Iyadh; Moir, Susan; Yewdell, Jonathan W; Schmaljohn, Connie; Crompton, Peter D; Holbrook, Michael R; Nemazee, David; Mascola, John R; Wilson, Ian A; Tan, Joshua: Broadly neutralizing antibodies target the coronavirus fusion peptide. In: Science, vol. 377, no. 6607, pp. 728–735, 2022, ISSN: 1095-9203. (Type: Journal Article | Abstract | Links)
@article{pmid35857439, The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.
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838. | Yuan, Meng; Zhu, Xueyong; He, Wan-Ting; Zhou, Panpan; Kaku, Chengzi I; Capozzola, Tazio; Zhu, Connie Y; Yu, Xinye; Liu, Hejun; Yu, Wenli; Hua, Yuanzi; Tien, Henry; Peng, Linghang; Song, Ge; Cottrell, Christopher A; Schief, William R; Nemazee, David; Walker, Laura M; Andrabi, Raiees; Burton, Dennis R; Wilson, Ian A: A broad and potent neutralization epitope in SARS-related coronaviruses. In: Proc Natl Acad Sci U S A, vol. 119, no. 29, pp. e2205784119, 2022, ISSN: 1091-6490. (Type: Journal Article | Abstract | Links)
@article{pmid35767670, Many neutralizing antibodies (nAbs) elicited to ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through natural infection and vaccination have reduced effectiveness to SARS-CoV-2 variants. Here, we show that therapeutic antibody ADG20 is able to neutralize SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize a broad range of VOCs, albeit with reduced potency against Omicron. Thus, this conserved and vulnerable site can be exploited for the design of universal vaccines and therapeutic antibodies.
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837. | Liu, Hejun; Kaku, Chengzi I; Song, Ge; Yuan, Meng; Andrabi, Raiees; Burton, Dennis R; Walker, Laura M; Wilson, Ian A: Human antibodies to SARS-CoV-2 with a recurring YYDRxG motif retain binding and neutralization to variants of concern including Omicron. In: Commun Biol, vol. 5, no. 1, pp. 766, 2022, ISSN: 2399-3642. (Type: Journal Article | Abstract | Links)
@article{pmid35906394, Studying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally identified a YYDRxG motif encoded by IGHD3-22 in CDR H3 that facilitates antibody targeting to a functionally conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences uncovered 100 such antibodies, many of which can neutralize SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to target sarbecoviruses including the Omicron variant. These findings suggest an epitope-targeting strategy to identify potent and broadly neutralizing antibodies for design of pan-sarbecovirus vaccines and antibody therapeutics.
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836. | He, Wan-Ting; Musharrafieh, Rami; Song, Ge; Dueker, Katharina; Tse, Longping V; Martinez, David R; Schäfer, Alexandra; Callaghan, Sean; Yong, Peter; Beutler, Nathan; Torres, Jonathan L; Volk, Reid M; Zhou, Panpan; Yuan, Meng; Liu, Hejun; Anzanello, Fabio; Capozzola, Tazio; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A; Smith, Davey M; Wilson, Ian A; Safonova, Yana; Ward, Andrew B; Rogers, Thomas F; Baric, Ralph S; Gralinski, Lisa E; Burton, Dennis R; Andrabi, Raiees: Targeted isolation of diverse human protective broadly neutralizing antibodies against SARS-like viruses. In: Nat Immunol, vol. 23, no. 6, pp. 960–970, 2022, ISSN: 1529-2916. (Type: Journal Article | Abstract | Links)
@article{pmid35654851, The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.
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835. | Wang, Yiquan; Yuan, Meng; Lv, Huibin; Peng, Jian; Wilson, Ian A; Wu, Nicholas C: A large-scale systematic survey reveals recurring molecular features of public antibody responses to SARS-CoV-2. In: Immunity, vol. 55, no. 6, pp. 1105–1117.e4, 2022, ISSN: 1097-4180. (Type: Journal Article | Abstract | Links)
@article{pmid35397794, Global research to combat the COVID-19 pandemic has led to the isolation and characterization of thousands of human antibodies to the SARS-CoV-2 spike protein, providing an unprecedented opportunity to study the antibody response to a single antigen. Using the information derived from 88 research publications and 13 patents, we assembled a dataset of ∼8,000 human antibodies to the SARS-CoV-2 spike protein from >200 donors. By analyzing immunoglobulin V and D gene usages, complementarity-determining region H3 sequences, and somatic hypermutations, we demonstrated that the common (public) responses to different domains of the spike protein were quite different. We further used these sequences to train a deep-learning model to accurately distinguish between the human antibodies to SARS-CoV-2 spike protein and those to influenza hemagglutinin protein. Overall, this study provides an informative resource for antibody research and enhances our molecular understanding of public antibody responses.
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834. | Lv, Huibin; So, Ray T Y; Teo, Qi Wen; Yuan, Meng; Liu, Hejun; Lee, Chang-Chun D; Yip, Garrick K; Ng, Wilson W; Wilson, Ian A; Peiris, Malik; Wu, Nicholas C; Mok, Chris Ka Pun: Neutralizing Antibody Response to Is Delayed in Sequential Heterologous Immunization. In: Viruses, vol. 14, no. 7, 2022, ISSN: 1999-4915. (Type: Journal Article | Abstract | Links)
@article{pmid35891363, Antigenic imprinting, which describes the bias of the antibody response due to previous immune history, can influence vaccine effectiveness. While this phenomenon has been reported for viruses such as influenza, there is little understanding of how prior immune history affects the antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting through immunization with two , the subgenus that includes SARS-CoV-2. Mice were immunized subsequently with two antigenically distinct strains, namely SARS-CoV-1 and SARS-CoV-2. We found that sequential heterologous immunization induced cross-reactive binding antibodies for both viruses and delayed the emergence of neutralizing antibody responses against the booster strain. Our results provide fundamental knowledge about the immune response to and important insights into the development of pan-sarbecovirus vaccines and guiding therapeutic interventions.
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833. | Xiang, Yufei; Huang, Wei; Liu, Hejun; Sang, Zhe; Nambulli, Sham; Tubiana, Jérôme; Williams, Kevin L; Duprex, W Paul; Schneidman-Duhovny, Dina; Wilson, Ian A; Taylor, Derek J; Shi, Yi: Superimmunity by pan-sarbecovirus nanobodies. In: Cell Rep, vol. 39, no. 13, pp. 111004, 2022, ISSN: 2211-1247. (Type: Journal Article | Abstract | Links)
@article{pmid35738279, Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observe superimmunity in a camelid extensively immunized with the SARS-CoV-2 receptor-binding domain (RBD). We rapidly isolate a large repertoire of specific ultra-high-affinity nanobodies that bind strongly to all known sarbecovirus clades using integrative proteomics. These pan-sarbecovirus nanobodies (psNbs) are highly effective against SARS-CoV and SARS-CoV-2 variants, including Omicron, with the best median neutralization potency at single-digit nanograms per milliliter. A highly potent, inhalable, and bispecific psNb (PiN-31) is also developed. Structural determinations of 13 psNbs with the SARS-CoV-2 spike or RBD reveal five epitope classes, providing insights into the mechanisms and evolution of their broad activities. The highly evolved psNbs target small, flat, and flexible epitopes that contain over 75% of conserved RBD surface residues. Their potencies are strongly and negatively correlated with the distance of the epitopes from the receptor binding sites.
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832. | Cao, Longxing; Coventry, Brian; Goreshnik, Inna; Huang, Buwei; Sheffler, William; Park, Joon Sung; Jude, Kevin M; Marković, Iva; Kadam, Rameshwar U; Verschueren, Koen H G; Verstraete, Kenneth; Walsh, Scott Thomas Russell; Bennett, Nathaniel; Phal, Ashish; Yang, Aerin; Kozodoy, Lisa; DeWitt, Michelle; Picton, Lora; Miller, Lauren; Strauch, Eva-Maria; DeBouver, Nicholas D; Pires, Allison; Bera, Asim K; Halabiya, Samer; Hammerson, Bradley; Yang, Wei; Bernard, Steffen; Stewart, Lance; Wilson, Ian A; Ruohola-Baker, Hannele; Schlessinger, Joseph; Lee, Sangwon; Savvides, Savvas N; Garcia, K Christopher; Baker, David: Design of protein-binding proteins from the target structure alone. In: Nature, vol. 605, no. 7910, pp. 551–560, 2022, ISSN: 1476-4687. (Type: Journal Article | Abstract | Links)
@article{pmid35332283, The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge. Here we describe a general solution to this problem that starts with a broad exploration of the vast space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate the broad applicability of this approach through the de novo design of binding proteins to 12 diverse protein targets with different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and, following experimental optimization, bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five closely match the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvements of both. Our approach enables the targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.
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831. | Torres, Jonathan L; Ozorowski, Gabriel; Andreano, Emanuele; Liu, Hejun; Copps, Jeffrey; Piccini, Giulia; Donnici, Lorena; Conti, Matteo; Planchais, Cyril; Planas, Delphine; Manganaro, Noemi; Pantano, Elisa; Paciello, Ida; Pileri, Piero; Bruel, Timothée; Montomoli, Emanuele; Mouquet, Hugo; Schwartz, Olivier; Sala, Claudia; Francesco, Raffaele De; Wilson, Ian A; Rappuoli, Rino; Ward, Andrew B: Structural insights of a highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody. In: Proc Natl Acad Sci U S A, vol. 119, no. 20, pp. e2120976119, 2022, ISSN: 1091-6490. (Type: Journal Article | Abstract | Links)
@article{pmid35549549, As the coronavirus disease 2019 (COVID-19) pandemic continues, there is a strong need for highly potent monoclonal antibodies (mAbs) that are resistant against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs). Here, we evaluate the potency of the previously described mAb J08 against these variants using cell-based assays and delve into the molecular details of the binding interaction using cryoelectron microscopy (cryo-EM) and X-ray crystallography. We show that mAb J08 has low nanomolar affinity against most VoCs and binds high on the receptor binding domain (RBD) ridge, away from many VoC mutations. These findings further validate the phase II/III human clinical trial underway using mAb J08 as a monoclonal therapy.
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830. | Yuan, Meng; Wang, Yiquan; Lv, Huibin; Wilson, Ian A; Wu, Nicholas C: Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid35611339, As SARS-CoV-2 variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key towards next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes all VOCs to date, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino-acid residue 54 of IGHV2-5, which locates at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.
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829. | Zhu, Xueyong; Han, Julianna; Sun, Weina; Puente-Massaguer, Eduard; Yu, Wenli; Palese, Peter; Krammer, Florian; Ward, Andrew B; Wilson, Ian A: Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface. In: Proc Natl Acad Sci U S A, vol. 119, no. 21, pp. e2200821119, 2022, ISSN: 1091-6490. (Type: Journal Article | Abstract | Links)
@article{pmid35594401, Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
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828. | Pfaff-Kilgore, Jennifer M; Davidson, Edgar; Kadash-Edmondson, Kathryn; Hernandez, Mayda; Rosenberg, Erin; Chambers, Ross; Castelli, Matteo; Clementi, Nicola; Mancini, Nicasio; Bailey, Justin R; Crowe, James E; Law, Mansun; Doranz, Benjamin J: Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening. In: Cell Rep, vol. 39, no. 8, pp. 110859, 2022, ISSN: 2211-1247. (Type: Journal Article | Abstract | Links)
@article{pmid35613596, The E1 and E2 envelope proteins of hepatitis C virus (HCV) form a heterodimer that drives virus-host membrane fusion. Here, we analyze the role of each amino acid in E1E2 function, expressing 545 individual alanine mutants of E1E2 in human cells, incorporating them into infectious viral pseudoparticles, and testing them against 37 different monoclonal antibodies (MAbs) to ascertain full-length translation, folding, heterodimer assembly, CD81 binding, viral pseudoparticle incorporation, and infectivity. We propose a model describing the role of each critical residue in E1E2 functionality and use it to examine how MAbs neutralize infection by exploiting functionally critical sites of vulnerability on E1E2. Our results suggest that E1E2 is a surprisingly fragile protein complex where even a single alanine mutation at 92% of positions disrupts its function. The amino-acid-level targets identified are highly conserved and functionally critical and can be exploited for improved therapies and vaccines.
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827. | Dacon, Cherrelle; Tucker, Courtney; Peng, Linghang; Lee, Chang-Chun D; Lin, Ting-Hui; Yuan, Meng; Cong, Yu; Wang, Lingshu; Purser, Lauren; Williams, Jazmean K; Pyo, Chul-Woo; Kosik, Ivan; Hu, Zhe; Zhao, Ming; Mohan, Divya; Cooper, Andrew; Peterson, Mary; Skinner, Jeff; Dixit, Saurabh; Kollins, Erin; Huzella, Louis; Perry, Donna; Byrum, Russell; Lembirik, Sanae; Zhang, Yi; Yang, Eun Sung; Chen, Man; Leung, Kwanyee; Weinberg, Rona S; Pegu, Amarendra; Geraghty, Daniel E; Davidson, Edgar; Douagi, Iyadh; Moir, Susan; Yewdell, Jonathan W; Schmaljohn, Connie; Crompton, Peter D; Holbrook, Michael R; Nemazee, David; Mascola, John R; Wilson, Ian A; Tan, Joshua: Broadly neutralizing antibodies target the coronavirus fusion peptide. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid35441178, The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development.nnONE-SENTENCE SUMMARY: Rare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.
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826. | Zhou, Panpan; Song, Ge; He, Wan-Ting; Beutler, Nathan; Tse, Longping V; Martinez, David R; Schäfer, Alexandra; Anzanello, Fabio; Yong, Peter; Peng, Linghang; Dueker, Katharina; Musharrafieh, Rami; Callaghan, Sean; Capozzola, Tazio; Yuan, Meng; Liu, Hejun; Limbo, Oliver; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A; Smith, Davey M; Nemazee, David; Jardine, Joseph G; Wilson, Ian A; Safonova, Yana; Rogers, Thomas F; Baric, Ralph S; Gralinski, Lisa E; Burton, Dennis R; Andrabi, Raiees: Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause severe disease. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid35291291, Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against coronaviruses that cause severe disease, for anticipating novel pandemic-causing viruses, and to respond more effectively to SARS-CoV-2 variants. The emergence of the Omicron variant of SARS-CoV-2 has illustrated the limitations of solely targeting the receptor binding domain (RBD) of the envelope Spike (S)-protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors that target a conserved S2 region in the fusion machinery on betacoronavirus spikes. Select bnAbs show broad protection against all three pathogenic betacoronaviruses, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, that have spilled over into humans in the past 20 years to cause severe disease. The bnAbs provide new opportunities for antibody-based interventions and key insights for developing pan-betacoronavirus vaccines.
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825. | Spruit, Cindy M; Zhu, Xueyong; Tomris, Ilhan; Ríos-Carrasco, María; Han, Alvin X; Broszeit, Frederik; van der Woude, Roosmarijn; Bouwman, Kim M; Luu, Michel M T; Matsuno, Keita; Sakoda, Yoshihiro; Russell, Colin A; Wilson, Ian A; Boons, Geert-Jan; de Vries, Robert P: -Glycolylneuraminic Acid Binding of Avian and Equine H7 Influenza A Viruses. In: J Virol, vol. 96, no. 5, pp. e0212021, 2022, ISSN: 1098-5514. (Type: Journal Article | Abstract | Links)
@article{pmid35044215, Influenza A viruses (IAV) initiate infection by binding to glycans with terminal sialic acids on the cell surface. Hosts of IAV variably express two major forms of sialic acid, -acetylneuraminic acid (NeuAc) and -glycolylneuraminic acid (NeuGc). NeuGc is produced in most mammals, including horses and pigs, but is absent in humans, ferrets, and birds. The only known naturally occurring IAV that exclusively bind NeuGc are extinct highly pathogenic equine H7N7 viruses. We determined the crystal structure of a representative equine H7 hemagglutinin (HA) in complex with NeuGc and observed high similarity in the receptor-binding domain with an avian H7 HA. To determine the molecular basis for NeuAc and NeuGc specificity, we performed systematic mutational analyses, based on the structural insights, on two distant avian H7 HAs and an H15 HA. We found that the A135E mutation is key for binding α2,3-linked NeuGc but does not abolish NeuAc binding. The additional mutations S128T, I130V, T189A, and K193R converted the specificity from NeuAc to NeuGc. We investigated the residues at positions 128, 130, 135, 189, and 193 in a phylogenetic analysis of avian and equine H7 HAs. This analysis revealed a clear distinction between equine and avian residues. The highest variability was observed at key position 135, of which only the equine glutamic acid led to NeuGc binding. These results demonstrate that genetically distinct H7 and H15 HAs can be switched from NeuAc to NeuGc binding and vice versa after the introduction of several mutations, providing insights into the adaptation of H7 viruses to NeuGc receptors. Influenza A viruses cause millions of cases of severe illness and deaths annually. To initiate infection and replicate, the virus first needs to bind to a structure on the cell surface, like a key fitting in a lock. For influenza A viruses, these "keys" (receptors) on the cell surface are chains of sugar molecules (glycans). The terminal sugar on these glycans is often either -acetylneuraminic acid (NeuAc) or -glycolylneuraminic acid (NeuGc). Most influenza A viruses bind NeuAc, but a small minority bind NeuGc. NeuGc is present in species like horses, pigs, and mice but not in humans, ferrets, and birds. Here, we investigated the molecular determinants of NeuGc specificity and the origin of viruses that bind NeuGc.
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824. | Yuan, Meng; Zhu, Xueyong; He, Wan-Ting; Zhou, Panpan; Kaku, Chengzi I; Capozzola, Tazio; Zhu, Connie Y; Yu, Xinye; Liu, Hejun; Yu, Wenli; Hua, Yuanzi; Tien, Henry; Peng, Linghang; Song, Ge; Cottrell, Christopher A; Schief, William R; Nemazee, David; Walker, Laura M; Andrabi, Raiees; Burton, Dennis R; Wilson, Ian A: A broad and potent neutralization epitope in SARS-related coronaviruses. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid35313576, Many neutralizing antibodies (nAbs) elicited to ancestral SARS-CoV-2 through natural infection and vaccination generally have reduced effectiveness to SARS-CoV-2 variants. Here we show therapeutic antibody ADG20 is able to neutralize all SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize all VOCs, albeit with reduced potency against Omicron. Thus, this highly conserved and vulnerable site can be exploited for design of universal vaccines and therapeutic antibodies.
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823. | Yan, Nicholas L; Nair, Reji; Chu, Alan; Wilson, Ian A; Johnson, Kristen A; Morgan, Gareth J; Kelly, Jeffery W: Amyloidogenic immunoglobulin light chain kinetic stabilizers comprising a simple urea linker module reveal a novel binding sub-site. In: Bioorg Med Chem Lett, vol. 60, pp. 128571, 2022, ISSN: 1464-3405. (Type: Journal Article | Abstract | Links)
@article{pmid35065233, In immunoglobulin light chain (LC) amyloidosis, the misfolding, or misfolding and misassembly of LC a protein or fragments thereof resulting from aberrant endoproteolysis, causes organ damage to patients. A small molecule "kinetic stabilizer" drug could slow or stop these processes and improve prognosis. We previously identified coumarin-based kinetic stabilizers of LCs that can be divided into four components, including a "linker module" and "distal substructure". Our prior studies focused on characterizing carbamate, hydantoin, and spirocyclic urea linker modules, which bind in a solvent-exposed site at the V-V domain interface of the LC dimer. Here, we report structure-activity relationship data on 7-diethylamino coumarin-based kinetic stabilizers. This substructure occupies the previously characterized "anchor cavity" and the "aromatic slit". The potencies of amide and urea linker modules terminating in a variety of distal substructures attached at the 3-position of this coumarin ring were assessed. Surprisingly, crystallographic data on a 7-diethylamino coumarin-based kinetic stabilizer reveals that the urea linker module and distal substructure attached at the 3-position bind a solvent-exposed region of the full-length LC dimer distinct from previously characterized sites. Our results further elaborate the small-molecule binding surface of LCs that could be occupied by potent and selective LC kinetic stabilizers.
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822. | Zhou, Panpan; Yuan, Meng; Song, Ge; Beutler, Nathan; Shaabani, Namir; Huang, Deli; He, Wan-Ting; Zhu, Xueyong; Callaghan, Sean; Yong, Peter; Anzanello, Fabio; Peng, Linghang; Ricketts, James; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A; Smith, Davey M; Nemazee, David; Teijaro, John R; Rogers, Thomas F; Wilson, Ian A; Burton, Dennis R; Andrabi, Raiees: A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection. In: Sci Transl Med, vol. 14, no. 637, pp. eabi9215, 2022, ISSN: 1946-6242. (Type: Journal Article | Abstract | Links)
@article{pmid35133175, Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a CoV disease 2019 (COVID-19) convalescent donor that exhibits broad reactivity with human β-CoVs. Here, we showed that CC40.8 targets the conserved S2 stem helix region of the CoV spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem peptide at 1.6-Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted that CC40.8-like bnAbs are relatively rare in human COVID-19 infection, and therefore, their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan-β-CoV vaccines.
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821. | Beutler, Nathan; Pholcharee, Tossapol; Oyen, David; Flores-Garcia, Yevel; MacGill, Randall S; Garcia, Elijah; Calla, Jaeson; Parren, Mara; Yang, Linlin; Volkmuth, Wayne; Locke, Emily; Regules, Jason A; Dutta, Sheetij; Emerling, Daniel; Early, Angela M; Neafsey, Daniel E; Winzeler, Elizabeth A; King, C Richter; Zavala, Fidel; Burton, Dennis R; Wilson, Ian A; Rogers, Thomas F: A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum. In: PLoS Pathog, vol. 18, no. 3, pp. e1010409, 2022, ISSN: 1553-7374. (Type: Journal Article | Abstract | Links)
@article{pmid35344575, Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved β-sheet face of the ctCSP (denoted β-ctCSP). Antibodies to the β-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of P. falciparum whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the β-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design.
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820. | He, Wan-Ting; Musharrafieh, Rami; Song, Ge; Dueker, Katharina; Tse, Longping V; Martinez, David R; Schäfer, Alexandra; Callaghan, Sean; Yong, Peter; Beutler, Nathan; Torres, Jonathan L; Volk, Reid M; Zhou, Panpan; Yuan, Meng; Liu, Hejun; Anzanello, Fabio; Capozzola, Tazio; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A; Smith, Davey M; Wilson, Ian A; Safonova, Yana; Ward, Andrew B; Rogers, Thomas F; Baric, Ralph S; Gralinski, Lisa E; Burton, Dennis R; Andrabi, Raiees: Targeted isolation of panels of diverse human protective broadly neutralizing antibodies against SARS-like viruses. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid35169804, The emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy . Development of broadly effective coronavirus vaccines that can mitigate these threats is needed . Notably, several recent studies have revealed that vaccination of recovered COVID-19 donors results in enhanced nAb responses compared to SARS-CoV-2 infection or vaccination alone . Here, we utilized a targeted donor selection strategy to isolate a large panel of broadly neutralizing antibodies (bnAbs) to sarbecoviruses from two such donors. Many of the bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and a substantial fraction also show notable binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against most SARS-CoV-2 VOCs and many neutralize the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in SARS-CoV-2 infection and vaccination . Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model. The generation of a large panel of potent bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a molecular basis for effective design of pan-sarbecovirus vaccines.
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819. | Reincke, S Momsen; Yuan, Meng; Kornau, Hans-Christian; Corman, Victor M; van Hoof, Scott; Sánchez-Sendin, Elisa; Ramberger, Melanie; Yu, Wenli; Hua, Yuanzi; Tien, Henry; Schmidt, Marie Luisa; Schwarz, Tatjana; Jeworowski, Lara Maria; Brandl, Sarah E; Rasmussen, Helle Foverskov; Homeyer, Marie A; Stöffler, Laura; Barner, Martin; Kunkel, Désirée; Huo, Shufan; Horler, Johannes; von Wardenburg, Niels; Kroidl, Inge; Eser, Tabea M; Wieser, Andreas; Geldmacher, Christof; Hoelscher, Michael; Gänzer, Hannes; Weiss, Günter; Schmitz, Dietmar; Drosten, Christian; Prüss, Harald; Wilson, Ian A; Kreye, Jakob: SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies. In: Science, vol. 375, no. 6582, pp. 782–787, 2022, ISSN: 1095-9203. (Type: Journal Article | Abstract | Links)
@article{pmid35076281, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type-elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.
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818. | Qiang, Min; Ma, Peixiang; Li, Yu; Liu, Hejun; Harding, Adam; Min, Chenyu; Wang, Fulian; Liu, Lili; Yuan, Meng; Ji, Qun; Tao, Pingdong; Shi, Xiaojie; Li, Zhean; Li, Teng; Wang, Xian; Zhang, Yu; Wu, Nicholas C; Lee, Chang-Chun D; Zhu, Xueyong; Gilbert-Jaramillo, Javier; Zhang, Chuyue; Saxena, Abhishek; Huang, Xingxu; Wang, Hou; James, William; Dwek, Raymond A; Wilson, Ian A; Yang, Guang; Lerner, Richard A: Neutralizing Antibodies to SARS-CoV-2 Selected from a Human Antibody Library Constructed Decades Ago. In: Adv Sci (Weinh), vol. 9, no. 1, pp. e2102181, 2022, ISSN: 2198-3844. (Type: Journal Article | Abstract | Links)
@article{pmid34716683, Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, a combinatorial human antibody library constructed 20 years before the coronavirus disease 2019 (COVID-19) pandemic is used to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these three antibodies contain over 13-22 SHMs, many of which are involved in specific interactions in their crystal structures with SARS-CoV-2 spike receptor binding domain. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of these antibodies with respect to their reactivity with SARS-CoV-2.
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817. | Zhou, Panpan; Yuan, Meng; Song, Ge; Beutler, Nathan; Shaabani, Namir; Huang, Deli; He, Wan-Ting; Zhu, Xueyong; Callaghan, Sean; Yong, Peter; Anzanello, Fabio; Peng, Linghang; Ricketts, James; Parren, Mara; Garcia, Elijah; Rawlings, Stephen A; Smith, Davey M; Nemazee, David; Teijaro, John R; Rogers, Thomas F; Wilson, Ian A; Burton, Dennis R; Andrabi, Raiees: A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection. 2022. (Type: Miscellaneous | Abstract | Links)
@misc{pmid33821273, Broadly neutralizing antibodies (bnAbs) to coronaviruses (CoVs) are valuable in their own right as prophylactic and therapeutic reagents to treat diverse CoVs and, importantly, as templates for rational pan-CoV vaccine design. We recently described a bnAb, CC40.8, from a coronavirus disease 2019 (COVID-19)-convalescent donor that exhibits broad reactivity with human beta-coronaviruses (β-CoVs). Here, we showed that CC40.8 targets the conserved S2 stem-helix region of the coronavirus spike fusion machinery. We determined a crystal structure of CC40.8 Fab with a SARS-CoV-2 S2 stem-peptide at 1.6 Å resolution and found that the peptide adopted a mainly helical structure. Conserved residues in β-CoVs interacted with CC40.8 antibody, thereby providing a molecular basis for its broad reactivity. CC40.8 exhibited in vivo protective efficacy against SARS-CoV-2 challenge in two animal models. In both models, CC40.8-treated animals exhibited less weight loss and reduced lung viral titers compared to controls. Furthermore, we noted CC40.8-like bnAbs are relatively rare in human COVID-19 infection and therefore their elicitation may require rational structure-based vaccine design strategies. Overall, our study describes a target on β-CoV spike proteins for protective antibodies that may facilitate the development of pan-β-CoV vaccines.nnSUMMARY: A human mAb isolated from a COVID-19 donor defines a protective cross-neutralizing epitope for pan-β-CoV vaccine design strategies.
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2021 |
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816. | Omorodion, Oluwarotimi; Wilson, Ian A: Structural and Biochemical Characterization of Cysteinylation in Broadly Neutralizing Antibodies to HIV-1. In: J Mol Biol, vol. 433, no. 24, pp. 167303, 2021, ISSN: 1089-8638. (Type: Journal Article | Abstract | Links)
@article{pmid34666044, Antibodies with exceptional breadth and potency have been elicited in some individuals during natural HIV-1 infection. Elicitation and affinity maturation of broadly neutralizing antibodies (bnAbs) is therefore the central goal of HIV-1 vaccine development. The functional properties of bnAbs also make them attractive as immunotherapeutic agents, which has led to their production and optimization for passive immunotherapy. This process requires in vitro manufacturing and monitoring of any heterogeneous expression, especially when subpopulations of antibodies are produced with varying levels of biological activity. Post-translational modification (PTM) of antibodies can contribute to heterogeneity and is the focus of this study. Specifically, we have investigated cysteinylation in a bnAb lineage (PCDN family) targeting the N332-glycan supersite on the surface envelope glycoprotein (Env) of HIV-1. This PTM is defined by capping of unpaired cysteine residues with molecular cysteine. Through chromatography and mass spectrometry, we were able to characterize subpopulations of cysteinylated and non-cysteinylated antibodies when expressed in mammalian cells. The crystal structures of two PCDN antibodies represent the first structures of a cysteinylated antibody and reveal that the cysteinylation in this case is located in CDRH3. Biophysical studies indicate that cysteinylation of these HIV-1 antibodies does not interfere with antigen binding, which has been reported to occur in other cysteinylated antibodies. As such, these studies highlight the need for further investigation of cysteinylation in anti-HIV and other bnAbs.
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815. | Strohmeier, Shirin; Amanat, Fatima; Zhu, Xueyong; McMahon, Meagan; Deming, Meagan E; Pasetti, Marcela F; Neuzil, Kathleen M; Wilson, Ian A; Krammer, Florian: A Novel Recombinant Influenza Virus Neuraminidase Vaccine Candidate Stabilized by a Measles Virus Phosphoprotein Tetramerization Domain Provides Robust Protection from Virus Challenge in the Mouse Model. In: mBio, vol. 12, no. 6, pp. e0224121, 2021, ISSN: 2150-7511. (Type: Journal Article | Abstract | Links)
@article{pmid34809451, Current seasonal influenza virus vaccines do not induce robust immune responses to neuraminidase. Several factors, including immunodominance of hemagglutinin over neuraminidase, instability of neuraminidase in vaccine formulations, and variable, nonstandardized amounts of neuraminidase in the vaccines, may contribute to this effect. However, vaccines that induce strong antineuraminidase immune responses would be beneficial, as they are highly protective. Furthermore, antigenic drift is slower for neuraminidase than for hemagglutinin, potentially providing broader coverage. Here, we designed stabilized recombinant versions of neuraminidase by replacing the N-terminal cytoplasmic domain, transmembrane, and extracellular stalk with tetramerization domains from the measles or Sendai virus phosphoprotein or from an Arabidopsis thaliana transcription factor. The measles virus tetramerization domain-based construct, termed N1-MPP, was chosen for further evaluation, as it retained antigenicity, neuraminidase activity, and structural integrity and provided robust protection against lethal virus challenge in the mouse model. We tested N1-MPP as a standalone vaccine, admixed with seasonal influenza virus vaccines, or given with seasonal influenza virus vaccines but in the other leg of the mouse. Admixture with different formulations of seasonal vaccines led to a weak neuraminidase response, suggesting a dominant effect of hemagglutinin over neuraminidase when administered in the same formulation. However, administration of neuraminidase alone or with seasonal vaccine administered in the alternate leg of the mouse induced robust antibody responses. Thus, this recombinant neuraminidase construct is a promising vaccine antigen that may enhance and broaden protection against seasonal influenza viruses. Influenza virus infections remain a high risk to human health, causing up to 650,000 deaths worldwide every year, with an enormous burden on the health care system. Since currently available seasonal vaccines are only partially effective and often mismatched to the circulating strains, a broader protective influenza virus vaccine is needed. Here, we generated a recombinant influenza virus vaccine candidate based on the more conserved neuraminidase surface glycoprotein in order to induce a robust and broader protective immune response against a variety of circulating influenza virus strains.
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814. | Yin, Victor; Lai, Szu-Hsueh; Caniels, Tom G; Brouwer, Philip J M; Brinkkemper, Mitch; Aldon, Yoann; Liu, Hejun; Yuan, Meng; Wilson, Ian A; Sanders, Rogier W; van Gils, Marit J; Heck, Albert J R: Probing Affinity, Avidity, Anticooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses. In: ACS Cent Sci, vol. 7, no. 11, pp. 1863–1873, 2021, ISSN: 2374-7943. (Type: Journal Article | Abstract | Links)
@article{pmid34845440, Determining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behavior of the original complexes. Here, we combine two single particle mass analysis techniques (mass photometry and charge-detection mass spectrometry) to enable the measurement of full IgG binding to the trimeric SARS-CoV-2 S ectodomain. Our experiments reveal that antibodies targeting the S-trimer typically prefer stoichiometries lower than the symmetry-predicted 3:1 binding. We determine that this behavior arises from the interplay of steric clashes and avidity effects that are not reflected in common antibody constructs (i.e., Fabs). Surprisingly, these substoichiometric complexes are fully effective at blocking ACE2 binding despite containing free receptor binding sites. Our results highlight the importance of studying antibody/antigen interactions using complete, multimeric constructs and showcase the utility of single particle mass analyses in unraveling these complex interactions.
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813. | Gebert, Luca F R; Law, Mansun; MacRae, Ian J: A structured RNA motif locks Argonaute2:miR-122 onto the 5' end of the HCV genome. In: Nat Commun, vol. 12, no. 1, pp. 6836, 2021, ISSN: 2041-1723. (Type: Journal Article | Abstract | Links)
@article{pmid34824224, microRNAs (miRNAs) form regulatory networks in metazoans. Viruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR-122 stabilizes the viral RNA and regulates viral translation. Here, we investigate the structural basis for these activities, taking into consideration that miRNAs function in complex with Argonaute (Ago) proteins. The crystal structure of the Ago2:miR-122:HCV complex reveals a structured RNA motif that traps Ago2 on the viral RNA, masking its 5' end from enzymatic attack. The trapped Ago2 can recruit host factor PCBP2, implicated in viral translation, while binding of a second Ago2:miR-122 competes with PCBP2, creating a potential molecular switch for translational control. Combined results reveal a viral RNA structure that modulates Ago2:miR-122 dynamics and repurposes host proteins to generate a functional analog of the mRNA cap-binding complex.
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812. | Wang, Yiquan; Yuan, Meng; Peng, Jian; Wilson, Ian A; Wu, Nicholas C: A large-scale systematic survey of SARS-CoV-2 antibodies reveals recurring molecular features. 2021. (Type: Miscellaneous | Abstract | Links)
@misc{pmid34873599, In the past two years, the global research in combating COVID-19 pandemic has led to isolation and characterization of numerous human antibodies to the SARS-CoV-2 spike. This enormous collection of antibodies provides an unprecedented opportunity to study the antibody response to a single antigen. From mining information derived from 88 research publications and 13 patents, we have assembled a dataset of ∼8,000 human antibodies to the SARS-CoV-2 spike from >200 donors. Analysis of antibody targeting of different domains of the spike protein reveals a number of common (public) responses to SARS-CoV-2, exemplified via recurring IGHV/IGK(L)V pairs, CDR H3 sequences, IGHD usage, and somatic hypermutation. We further present a proof-of-concept for prediction of antigen specificity using deep learning to differentiate sequences of antibodies to SARS-CoV-2 spike and to influenza hemagglutinin. Overall, this study not only provides an informative resource for antibody and vaccine research, but fundamentally advances our molecular understanding of public antibody responses to a viral pathogen.
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811. | Maisonnasse, Pauline; Aldon, Yoann; Marc, Aurélien; Marlin, Romain; Dereuddre-Bosquet, Nathalie; Kuzmina, Natalia A; Freyn, Alec W; Snitselaar, Jonne L; Gonçalves, Antonio; Caniels, Tom G; Burger, Judith A; Poniman, Meliawati; Bontjer, Ilja; Chesnais, Virginie; Diry, Ségolène; Iershov, Anton; Ronk, Adam J; Jangra, Sonia; Rathnasinghe, Raveen; Brouwer, Philip J M; Bijl, Tom P L; van Schooten, Jelle; Brinkkemper, Mitch; Liu, Hejun; Yuan, Meng; Mire, Chad E; van Breemen, Mariëlle J; Contreras, Vanessa; Naninck, Thibaut; Lemaître, Julien; Kahlaoui, Nidhal; Relouzat, Francis; Chapon, Catherine; Fang, Raphaël Ho Tsong; McDanal, Charlene; Osei-Twum, Mary; St-Amant, Natalie; Gagnon, Luc; Montefiori, David C; Wilson, Ian A; Ginoux, Eric; de Bree, Godelieve J; García-Sastre, Adolfo; Schotsaert, Michael; Coughlan, Lynda; Bukreyev, Alexander; van der Werf, Sylvie; Guedj, Jérémie; Sanders, Rogier W; van Gils, Marit J; Grand, Roger Le: COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models. In: Nat Commun, vol. 12, no. 1, pp. 6097, 2021, ISSN: 2041-1723. (Type: Journal Article | Abstract | Links)
@article{pmid34671037, Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.
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810. | Cho, Hyeseon; Gonzales-Wartz, Kristina Kay; Huang, Deli; Yuan, Meng; Peterson, Mary; Liang, Janie; Beutler, Nathan; Torres, Jonathan L; Cong, Yu; Postnikova, Elena; Bangaru, Sandhya; Talana, Chloe Adrienna; Shi, Wei; Yang, Eun Sung; Zhang, Yi; Leung, Kwanyee; Wang, Lingshu; Peng, Linghang; Skinner, Jeff; Li, Shanping; Wu, Nicholas C; Liu, Hejun; Dacon, Cherrelle; Moyer, Thomas; Cohen, Melanie; Zhao, Ming; Lee, Frances Eun-Hyung; Weinberg, Rona S; Douagi, Iyadh; Gross, Robin; Schmaljohn, Connie; Pegu, Amarendra; Mascola, John R; Holbrook, Michael; Nemazee, David; Rogers, Thomas F; Ward, Andrew B; Wilson, Ian A; Crompton, Peter D; Tan, Joshua: Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern. In: Sci Transl Med, vol. 13, no. 616, pp. eabj5413, 2021, ISSN: 1946-6242. (Type: Journal Article | Abstract | Links)
@article{pmid34519517, The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.
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809. | Lv, Huibin; Tsang, Owen Tak-Yin; So, Ray T Y; Wang, Yiquan; Yuan, Meng; Liu, Hejun; Yip, Garrick K; Teo, Qi Wen; Lin, Yihan; Liang, Weiwen; Wang, Jinlin; Ng, Wilson W; Wilson, Ian A; Peiris, J S Malik; Wu, Nicholas C; Mok, Chris K P: Homologous and heterologous serological response to the N-terminal domain of SARS-CoV-2 in humans and mice. In: Eur J Immunol, vol. 51, no. 9, pp. 2296–2305, 2021, ISSN: 1521-4141. (Type: Journal Article | Abstract | Links)
@article{pmid34089541, The increasing numbers of infected cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses serious threats to public health and the global economy. Most SARS-CoV-2 neutralizing antibodies target the receptor binding domain (RBD) and some the N-terminal domain (NTD) of the spike protein, which is the major antigen of SARS-CoV-2. While the antibody response to RBD has been extensively characterized, the antigenicity and immunogenicity of the NTD protein are less well studied. Using 227 plasma samples from COVID-19 patients, we showed that SARS-CoV-2 NTD-specific antibodies could be induced during infection. As compared to the results of SARS-CoV-2 RBD, the serological response of SARS-CoV-2 NTD is less cross-reactive with SARS-CoV, a pandemic strain that was identified in 2003. Furthermore, neutralizing antibodies are rarely elicited in a mice model when NTD is used as an immunogen. We subsequently demonstrate that NTD has an altered antigenicity when expressed alone. Overall, our results suggest that while NTD offers a supplementary strategy for serology testing, it may not be suitable as an immunogen for vaccine development.
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808. | Yuan, Meng; Huang, Deli; Lee, Chang-Chun D; Wu, Nicholas C; Jackson, Abigail M; Zhu, Xueyong; Liu, Hejun; Peng, Linghang; van Gils, Marit J; Sanders, Rogier W; Burton, Dennis R; Reincke, S Momsen; Prüss, Harald; Kreye, Jakob; Nemazee, David; Ward, Andrew B; Wilson, Ian A: Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants. In: Science, vol. 373, no. 6556, pp. 818–823, 2021, ISSN: 1095-9203. (Type: Journal Article | Abstract | Links)
@article{pmid34016740, Neutralizing antibodies (nAbs) elicited against the receptor binding site (RBS) of the spike protein of wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are generally less effective against recent variants of concern. RBS residues Glu, Lys, and Asn are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on angiotensin-converting enzyme 2 binding, as well as the effects of two of these mutations (K417N and E484K) on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternative binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.
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807. | Schoenle, Marta V; Li, Yang; Yuan, Meng; Clarkson, Michael W; Wilson, Ian A; Peti, Wolfgang; Page, Rebecca: NMR Based SARS-CoV-2 Antibody Screening. In: J Am Chem Soc, vol. 143, no. 21, pp. 7930–7934, 2021, ISSN: 1520-5126. (Type: Journal Article | Abstract | Links)
@article{pmid34018723, The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells is a complex process that involves (1) recognition of the host entry receptor, angiotensin-converting enzyme 2 (ACE2), by the SARS-CoV-2 spike protein receptor binding domain (RBD), and (2) the subsequent fusion of the viral and cell membranes. Our long-term immune-defense is the production of antibodies (Abs) that recognize the SARS-CoV-2 RBD and successfully block viral infection. Thus, to understand immunity against SARS-CoV-2, a comprehensive molecular understanding of how human SARS-CoV-2 Abs recognize the RBD is needed. Here, we report the sequence-specific backbone assignment of the SARS-CoV-2 RBD and, furthermore, demonstrate that biomolecular NMR spectroscopy chemical shift perturbation (CSP) mapping successfully and rapidly identifies the molecular epitopes of RBD-specific mAbs. By incorporating NMR-based CSP mapping with other molecular techniques to define RBD-mAb interactions and then correlating these data with neutralization efficacy, structure-based approaches for developing improved vaccines and COVID-19 mAb-based therapies will be greatly accelerated.
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806. | McKitrick, Tanya R; Bernard, Steffen M; Noll, Alexander J; Collins, Bernard C; Goth, Christoffer K; McQuillan, Alyssa M; Heimburg-Molinaro, Jamie; Herrin, Brantley R; Wilson, Ian A; Cooper, Max D; Cummings, Richard D: Novel lamprey antibody recognizes terminal sulfated galactose epitopes on mammalian glycoproteins. In: Commun Biol, vol. 4, no. 1, pp. 674, 2021, ISSN: 2399-3642. (Type: Journal Article | Abstract | Links)
@article{pmid34083726, The terminal galactose residues of N- and O-glycans in animal glycoproteins are often sialylated and/or fucosylated, but sulfation, such as 3-O-sulfated galactose (3-O-SGal), represents an additional, but poorly understood modification. To this end, we have developed a novel sea lamprey variable lymphocyte receptor (VLR) termed O6 to explore 3-O-SGal expression. O6 was engineered as a recombinant murine IgG chimera and its specificity and affinity to the 3-O-SGal epitope was defined using a variety of approaches, including glycan and glycoprotein microarray analyses, isothermal calorimetry, ligand-bound crystal structure, FACS, and immunohistochemistry of human tissue macroarrays. 3-O-SGal is expressed on N-glycans of many plasma and tissue glycoproteins, but recognition by O6 is often masked by sialic acid and thus exposed by treatment with neuraminidase. O6 recognizes many human tissues, consistent with expression of the cognate sulfotransferases (GAL3ST-2 and GAL3ST-3). The availability of O6 for exploring 3-O-SGal expression could lead to new biomarkers for disease and aid in understanding the functional roles of terminal modifications of glycans and relationships between terminal sulfation, sialylation and fucosylation.
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805. | Tan, Timothy J C; Yuan, Meng; Kuzelka, Kaylee; Padron, Gilberto C; Beal, Jacob R; Chen, Xin; Wang, Yiquan; Rivera-Cardona, Joel; Zhu, Xueyong; Stadtmueller, Beth M; Brooke, Christopher B; Wilson, Ian A; Wu, Nicholas C: Sequence signatures of two public antibody clonotypes that bind SARS-CoV-2 receptor binding domain. In: Nat Commun, vol. 12, no. 1, pp. 3815, 2021, ISSN: 2041-1723. (Type: Journal Article | Abstract | Links)
@article{pmid34155209, Since the COVID-19 pandemic onset, the antibody response to SARS-CoV-2 has been extensively characterized. Antibodies to the receptor binding domain (RBD) on the spike protein are frequently encoded by IGHV3-53/3-66 with a short complementarity-determining region (CDR) H3. Germline-encoded sequence motifs in heavy chain CDRs H1 and H2 have a major function, but whether any common motifs are present in CDR H3, which is often critical for binding specificity, is not clear. Here, we identify two public clonotypes of IGHV3-53/3-66 RBD antibodies with a 9-residue CDR H3 that pair with different light chains. Distinct sequence motifs on CDR H3 are present in the two public clonotypes that seem to be related to differential light chain pairing. Additionally, we show that Y58F is a common somatic hypermutation that results in increased binding affinity of IGHV3-53/3-66 RBD antibodies with a short CDR H3. These results advance understanding of the antibody response to SARS-CoV-2.
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804. | Tan, Joshua; Cho, Hyeseon; Pholcharee, Tossapol; Pereira, Lais S; Doumbo, Safiatou; Doumtabe, Didier; Flynn, Barbara J; Schön, Arne; Kanatani, Sachie; Aylor, Samantha O; Oyen, David; Vistein, Rachel; Wang, Lawrence; Dillon, Marlon; Skinner, Jeff; Peterson, Mary; Li, Shanping; Idris, Azza H; Molina-Cruz, Alvaro; Zhao, Ming; Olano, Lisa Renee; Lee, Patricia J; Roth, Alison; Sinnis, Photini; Barillas-Mury, Carolina; Kayentao, Kassoum; Ongoiba, Aissata; Francica, Joseph R; Traore, Boubacar; Wilson, Ian A; Seder, Robert A; Crompton, Peter D: Functional human IgA targets a conserved site on malaria sporozoites. In: Sci Transl Med, vol. 13, no. 599, 2021, ISSN: 1946-6242. (Type: Journal Article | Abstract | Links)
@article{pmid34162751, Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as , is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.
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803. | Kumar, Sonu; Lin, Xiaohe; Ngo, Timothy; Shapero, Benjamin; Sou, Cindy; Allen, Joel D; Copps, Jeffrey; Zhang, Lei; Ozorowski, Gabriel; He, Linling; Crispin, Max; Ward, Andrew B; Wilson, Ian A; Zhu, Jiang: Neutralizing Antibodies Induced by First-Generation gp41-Stabilized HIV-1 Envelope Trimers and Nanoparticles. In: mBio, vol. 12, no. 3, pp. e0042921, 2021, ISSN: 2150-7511. (Type: Journal Article | Abstract | Links)
@article{pmid34156262, The immunogenicity of gp41-stabilized HIV-1 BG505 envelope (Env) trimers and nanoparticles (NPs) was recently assessed in mice and rabbits. Here, we combined Env-specific B-cell sorting and repertoire sequencing to identify neutralizing antibodies (NAbs) from immunized animals. A panel of mouse NAbs was isolated from mice immunized with a 60-meric I3-01 NP presenting 20 stabilized trimers. Three mouse NAbs potently neutralized BG505.T332N by recognizing a glycan epitope centered in the C3/V4 region on BG505 Env, as revealed by electron microscopy (EM), X-ray crystallography, and epitope mapping. A set of rabbit NAbs was isolated from rabbits immunized with a soluble trimer and a 24-meric ferritin NP presenting 8 trimers. Neutralization assays against BG505.T332N variants confirmed that potent rabbit NAbs targeted previously described glycan holes on BG505 Env and accounted for a significant portion of the autologous NAb response in both the trimer and ferritin NP groups. Last, we examined NAb responses that were induced by non-BG505 Env immunogens. We determined a 3.4-Å-resolution crystal structure for the clade C transmitted/founder (T/F) Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend in gp41. This clade C Env, in a soluble trimer form and in a multivalent form with 8 trimers attached to ferritin NP, and the gp41-stabilized clade A Q482-d12 Env trimer elicited distinct NAb responses in rabbits, with notable differences in neutralization breadth. Although eliciting a broad NAb response remains a major challenge, our study provides valuable information on an HIV-1 vaccine design strategy that combines gp41 stabilization and NP display. Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env. This study validates the gp41 stabilization strategy for HIV-1 Env vaccine design and highlights the challenge in eliciting a broad NAb response.
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802. | Yechezkel, Itai; Law, Mansun; Tzarum, Netanel: From Structural Studies to HCV Vaccine Design. In: Viruses, vol. 13, no. 5, 2021, ISSN: 1999-4915. (Type: Journal Article | Abstract | Links)
@article{pmid34064532, Hepatitis C virus (HCV) is a serious and growing public health problem despite recent developments of antiviral therapeutics. To achieve global elimination of HCV, an effective cross-genotype vaccine is needed. The failure of previous vaccination trials to elicit an effective cross-reactive immune response demands better vaccine antigens to induce a potent cross-neutralizing response to improve vaccine efficacy. HCV E1 and E2 envelope (Env) glycoproteins are the main targets for neutralizing antibodies (nAbs), which aid in HCV clearance and protection. Therefore, a molecular-level understanding of the nAb responses against HCV is imperative for the rational design of cross-genotype vaccine antigens. Here we summarize the recent advances in structural studies of HCV Env and Env-nAb complexes and how they improve our understanding of immune recognition of HCV. We review the structural data defining HCV neutralization epitopes and conformational plasticity of the Env proteins, and the knowledge applicable to rational vaccine design.
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