@article{pmid37841584,

title = {Broad SARS-CoV-2 neutralization by monoclonal and bispecific antibodies derived from a Gamma-infected individual},

author = {Denise Guerra and Tim Beaumont and Laura Radić and Gius Kerster and Karlijn van der Straten and Meng Yuan and Jonathan L Torres and Wen-Hsin Lee and Hejun Liu and Meliawati Poniman and Ilja Bontjer and Judith A Burger and Mathieu Claireaux and Tom G Caniels and Jonne L Snitselaar and Tom P L Bijl and Sabine Kruijer and Gabriel Ozorowski and David Gideonse and Kwinten Sliepen and Andrew B Ward and Dirk Eggink and Godelieve J de Bree and Ian A Wilson and Rogier W Sanders and Marit J van Gils},

doi = {10.1016/j.isci.2023.108009},

issn = {2589-0042},

year  = {2023},

date = {2023-10-01},

journal = {iScience},

volume = {26},

number = {10},

pages = {108009},

abstract = {The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has remained a medical threat due to the 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. A stabilized 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, with COVA309-35 being the most potent against the autologous virus, as well as Omicron BA.1 and BA.2, and COVA309-22 having binding and neutralization activity against Omicron BA.4/5, BQ.1.1, and XBB.1. When combining the COVA309 mAbs as cocktails or bispecific antibodies, the breadth and potency were improved. 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37703367,

title = {Chimeric hemagglutinin split vaccines elicit broadly cross-reactive antibodies and protection against group 2 influenza viruses in mice},

author = {Eduard Puente-Massaguer and Kirill Vasilev and Annika Beyer and Madhumathi Loganathan and Benjamin Francis and Michael J Scherm and Guha Asthagiri Arunkumar and Irene González-Domínguez and Xueyong Zhu and Ian A Wilson and Lynda Coughlan and Weina Sun and Peter Palese and Florian Krammer},

doi = {10.1126/sciadv.adi4753},

issn = {2375-2548},

year  = {2023},

date = {2023-09-01},

journal = {Sci Adv},

volume = {9},

number = {37},

pages = {eadi4753},

abstract = {Seasonal influenza virus vaccines are effective when they are well matched to circulating strains. Because of antigenic drift/change in the immunodominant hemagglutinin (HA) head domain, annual vaccine reformulations are necessary to maintain a match with circulating strains. In addition, seasonal vaccines provide little to no protection against newly emerging pandemic strains. Sequential vaccination with chimeric HA (cHA) constructs has been proven to direct the immune response toward the immunosubdominant but more conserved HA stalk domain. In this study, we show that immunization with group 2 cHA split vaccines in combination with the CpG 1018 adjuvant elicits broadly cross-reactive antibodies against all group 2 HAs, as well as systemic and local antigen-specific T cell responses. Antibodies elicited after sequential vaccination are directed to conserved regions of the HA such as the stalk and the trimer interface and also to the N2 neuraminidase (NA). Immunized mice were fully protected from challenge with a broad panel of influenza A viruses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37722054,

title = {The smallest functional antibody fragment: Ultralong CDR H3 antibody knob regions potently neutralize SARS-CoV-2},

author = {Ruiqi Huang and Gabrielle Warner Jenkins and Yunjeong Kim and Robyn L Stanfield and Amrinder Singh and Maria Martinez-Yamout and Gerard J Kroon and Jonathan L Torres and Abigail M Jackson and Abigail Kelley and Namir Shaabani and Baisen Zeng and Michael Bacica and Wen Chen and Christopher Warner and Jasmina Radoicic and Joongho Joh and Krishani Dinali Perera and Huldah Sang and Tae Kim and Jianxiu Yao and Fangzhu Zhao and Devin Sok and Dennis R Burton and Jeff Allen and William Harriman and Waithaka Mwangi and Donghoon Chung and John R Teijaro and Andrew B Ward and H Jane Dyson and Peter E Wright and Ian A Wilson and Kyeong-Ok Chang and Duncan McGregor and Vaughn V Smider},

doi = {10.1073/pnas.2303455120},

issn = {1091-6490},

year  = {2023},

date = {2023-09-01},

journal = {Proc Natl Acad Sci U S A},

volume = {120},

number = {39},

pages = {e2303455120},

abstract = {Cows produce antibodies with a disulfide-bonded antigen-binding domain embedded within ultralong heavy chain third complementarity determining regions. This "knob" domain is analogous to natural cysteine-rich peptides such as knottins in that it is small and stable but can accommodate diverse loops and disulfide bonding patterns. We immunized cattle with SARS-CoV-2 spike and found ultralong CDR H3 antibodies that could neutralize several viral variants at picomolar IC potencies in vitro and could protect from disease in vivo. The independent CDR H3 peptide knobs were expressed and maintained the properties of the parent antibodies. The knob interaction with SARS-CoV-2 spike was revealed by electron microscopy, X-ray crystallography, NMR spectroscopy, and mass spectrometry and established ultralong CDR H3-derived knobs as the smallest known recombinant independent antigen-binding fragment. Unlike other vertebrate antibody fragments, these knobs are not reliant on the immunoglobulin domain and have potential as a new class of therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37777966,

title = {Widespread impact of immunoglobulin V-gene allelic polymorphisms on antibody reactivity},

author = {Meng Yuan and Ziqi Feng and Huibin Lv and Natalie So and Ivana R Shen and Timothy J C Tan and Qi Wen Teo and Wenhao O Ouyang and Logan Talmage and Ian A Wilson and Nicholas C Wu},

doi = {10.1016/j.celrep.2023.113194},

issn = {2211-1247},

year  = {2023},

date = {2023-09-01},

journal = {Cell Rep},

volume = {42},

number = {10},

pages = {113194},

abstract = {The ability of the human immune system to generate antibodies to any given antigen can be strongly influenced by immunoglobulin V-gene allelic polymorphisms. However, previous studies have provided only limited examples. Therefore, the prevalence of this phenomenon has been unclear. By analyzing >1,000 publicly available antibody-antigen structures, we show that many V-gene allelic polymorphisms in antibody paratopes are determinants for antibody binding activity. Biolayer interferometry experiments further demonstrate that paratope allelic polymorphisms on both heavy and light chains often abolish antibody binding. We also illustrate the importance of minor V-gene allelic polymorphisms with low frequency in several broadly neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus. Overall, this study not only highlights the pervasive impact of V-gene allelic polymorphisms on antibody binding but also provides mechanistic insights into the variability of antibody repertoires across individuals, which in turn have important implications for vaccine development and antibody discovery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37279624,

title = {Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis},

author = {Nicholas L Yan and Gareth J Morgan and H Michael Petrassi and Ian A Wilson and Jeffery W Kelly},

doi = {10.1016/j.cbpa.2023.102319},

issn = {1879-0402},

year  = {2023},

date = {2023-08-01},

journal = {Curr Opin Chem Biol},

volume = {75},

pages = {102319},

abstract = {Immunoglobulin light chain amyloidosis (AL) is a cancer of plasma cells that secrete unstable full-length immunoglobulin light chains. These light chains misfold and aggregate, often with aberrant endoproteolysis, leading to organ toxicity. AL is currently treated by pharmacological elimination of the clonal plasma cells. Since it remains difficult to completely kill these cells in the majority of patients, we seek a complementary drug that inhibits light chain aggregation, which should diminish organ toxicity. We discovered a small-molecule binding site on full-length immunoglobulin light chains by structurally characterizing hit stabilizers emerging from a high-throughput screen seeking small molecules that protect full-length light chains from conformational excursion-linked endoproteolysis. The x-ray crystallographic characterization of 7 structurally distinct hit native-state stabilizers provided a structure-based blueprint, reviewed herein, to design more potent stabilizers. This approach enabled us to transform hits with micromolar affinity into stabilizers with nanomolar dissociation constants that potently prevent light chain aggregation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37506693,

title = {Human anti-N1 monoclonal antibodies elicited by pandemic H1N1 virus infection broadly inhibit HxN1 viruses in vitro and in vivo},

author = {Lena Hansen and Meagan McMahon and Hannah L Turner and Xueyong Zhu and Jackson S Turner and Gabriel Ozorowski and Daniel Stadlbauer and Juha Vahokoski and Aaron J Schmitz and Amena A Rizk and Wafaa B Alsoussi and Shirin Strohmeier and Wenli Yu and José Alberto Choreño-Parra and Luis Jiménez-Alvarez and Alfredo Cruz-Lagunas and Joaquín Zúñiga and Philip A Mudd and Rebecca J Cox and Ian A Wilson and Andrew B Ward and Ali H Ellebedy and Florian Krammer},

doi = {10.1016/j.immuni.2023.07.004},

issn = {1097-4180},

year  = {2023},

date = {2023-08-01},

journal = {Immunity},

volume = {56},

number = {8},

pages = {1927--1938.e8},

abstract = {Neuraminidase (NA) is one of the two influenza virus surface glycoproteins, and antibodies that target it are an independent correlate of protection. However, our current understanding of NA antigenicity is incomplete. Here, we describe human monoclonal antibodies (mAbs) from a patient with a pandemic H1N1 virus infection in 2009. Two mAbs exhibited broad reactivity and inhibited NA enzyme activity of seasonal H1N1 viruses circulating before and after 2009, as well as viruses with avian or swine N1s. The mAbs provided robust protection from lethal challenge with human H1N1 and avian H5N1 viruses in mice, and both target an epitope on the lateral face of NA. In summary, we identified two broadly protective NA antibodies that share a novel epitope, inhibited NA activity, and provide protection against virus challenge in mice. Our work reaffirms that NA should be included as a target in future broadly protective or universal influenza virus vaccines.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37534714,

title = {An Engineered Human-Antibody Fragment with Fentanyl Pan-Specificity That Reverses Carfentanil-Induced Respiratory Depression},

author = {Lisa M Eubanks and Tossapol Pholcharee and David Oyen and Yoshihiro Natori and Bin Zhou and Ian A Wilson and Kim D Janda},

doi = {10.1021/acschemneuro.3c00455},

issn = {1948-7193},

year  = {2023},

date = {2023-08-01},

journal = {ACS Chem Neurosci},

volume = {14},

number = {16},

pages = {2849--2856},

abstract = {The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short-acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored to synthetic opioids and help prevent post-treatment renarcotization. The ultrapotent analog carfentanil is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display, producing C10-S66K. This monoclonal antibody displays high affinity to carfentanil, fentanyl, and other analogs and reversed carfentanil-induced respiratory depression. Additionally, X-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37582161,

title = {Broadening a SARS-CoV-1-neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution},

author = {Fangzhu Zhao and Meng Yuan and Celina Keating and Namir Shaabani and Oliver Limbo and Collin Joyce and Jordan Woehl and Shawn Barman and Alison Burns and Quoc Tran and Xueyong Zhu and Michael Ricciardi and Linghang Peng and Jessica Smith and Deli Huang and Bryan Briney and Devin Sok and David Nemazee and John R Teijaro and Ian A Wilson and Dennis R Burton and Joseph G Jardine},

doi = {10.1126/scisignal.abk3516},

issn = {1937-9145},

year  = {2023},

date = {2023-08-01},

journal = {Sci Signal},

volume = {16},

number = {798},

pages = {eabk3516},

abstract = {The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for strategies to rapidly develop neutralizing monoclonal antibodies that can function as prophylactic and therapeutic agents and to help guide vaccine design. Here, we demonstrate that engineering approaches can be used to refocus an existing antibody that neutralizes one virus but not a related virus. Through a rapid affinity maturation strategy, we engineered CR3022, a SARS-CoV-1-neutralizing antibody, to bind to the receptor binding domain of SARS-CoV-2 with >1000-fold increased affinity. The engineered CR3022 neutralized SARS-CoV-2 and provided prophylactic protection from viral challenge in a small animal model of SARS-CoV-2 infection. Deep sequencing throughout the engineering process paired with crystallographic analysis of engineered CR3022 elucidated the molecular mechanisms by which the antibody can accommodate sequence differences in the epitopes between SARS-CoV-1 and SARS-CoV-2. This workflow provides a blueprint for the rapid broadening of neutralization of an antibody from one virus to closely related but resistant viruses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37419097,

title = {Major classes of neutralizing antibodies evaded by the SARS-CoV-2 Omicron variant},

author = {Meng Yuan and Ian A Wilson},

doi = {10.1016/j.str.2023.06.005},

issn = {1878-4186},

year  = {2023},

date = {2023-07-01},

journal = {Structure},

volume = {31},

number = {7},

pages = {755--757},

abstract = {Understanding how SARS-CoV-2 evades neutralizing antibodies is crucial for the development of therapeutic antibodies and universal vaccines. In this issue of Structure, Patel et al. elucidate mechanisms of SARS-CoV-2 escape from two major antibody classes. Cryoelectron microscopy (cryo-EM) structures of these antibodies with the SARS-CoV-2 spike formed the basis of their findings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37507365,

title = {Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection},

author = {Gregory M Martin and Jonathan L Torres and Tossapol Pholcharee and David Oyen and Yevel Flores-Garcia and Grace Gibson and Re'em Moskovitz and Nathan Beutler and Diana D Jung and Jeffrey Copps and Wen-Hsin Lee and Gonzalo Gonzalez-Paez and Daniel Emerling and Randall S MacGill and Emily Locke and C Richter King and Fidel Zavala and Ian A Wilson and Andrew B Ward},

doi = {10.1038/s41467-023-40151-x},

issn = {2041-1723},

year  = {2023},

date = {2023-07-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {4546},

abstract = {The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37276407,

title = {Fully synthetic platform to rapidly generate tetravalent bispecific nanobody-based immunoglobulins},

author = {Laetitia Misson Mindrebo and Hejun Liu and Gabriel Ozorowski and Quoc Tran and Jordan Woehl and Irene Khalek and Jessica M Smith and Shawn Barman and Fangzhu Zhao and Celina Keating and Oliver Limbo and Megan Verma and Jingjia Liu and Robyn L Stanfield and Xueyong Zhu and Hannah L Turner and Devin Sok and Po-Ssu Huang and Dennis R Burton and Andrew B Ward and Ian A Wilson and Joseph G Jardine},

doi = {10.1073/pnas.2216612120},

issn = {1091-6490},

year  = {2023},

date = {2023-06-01},

journal = {Proc Natl Acad Sci U S A},

volume = {120},

number = {24},

pages = {e2216612120},

abstract = {Nanobodies bind a target antigen with a kinetic profile similar to a conventional antibody, but exist as a single heavy chain domain that can be readily multimerized to engage antigen via multiple interactions. Presently, most nanobodies are produced by immunizing camelids; however, platforms for animal-free production are growing in popularity. Here, we describe the development of a fully synthetic nanobody library based on an engineered human V3-23 variable gene and a multispecific antibody-like format designed for biparatopic target engagement. To validate our library, we selected nanobodies against the SARS-CoV-2 receptor-binding domain and employed an on-yeast epitope binning strategy to rapidly map the specificities of the selected nanobodies. We then generated antibody-like molecules by replacing the V and V domains of a conventional antibody with two different nanobodies, designed as a molecular clamp to engage the receptor-binding domain biparatopically. The resulting bispecific tetra-nanobody immunoglobulins neutralized diverse SARS-CoV-2 variants with potencies similar to antibodies isolated from convalescent donors. Subsequent biochemical analyses confirmed the accuracy of the on-yeast epitope binning and structures of both individual nanobodies, and a tetra-nanobody immunoglobulin revealed that the intended mode of interaction had been achieved. This overall workflow is applicable to nearly any protein target and provides a blueprint for a modular workflow for the development of multispecific molecules.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37384622,

title = {Antigen pressure from two founder viruses induces multiple insertions at a single antibody position to generate broadly neutralizing HIV antibodies},

author = {Collin Joyce and Sasha Murrell and Ben Murrell and Oluwarotimi Omorodion and Lorena S Ver and Nancy Carrico and Raiza Bastidas and Rebecca Nedellec and Michael Bick and Jordan Woehl and Fangzhu Zhao and Alison Burns and Shawn Barman and Michael Appel and Alejandra Ramos and Lalinda Wickramasinghe and Kemal Eren and Thomas Vollbrecht and Davey M Smith and Sergei L Kosakovsky Pond and Ryan McBride and Charli Worth and Facundo Batista and Devin Sok and  and Pascal Poignard and Bryan Briney and Ian A Wilson and Elise Landais and Dennis R Burton},

doi = {10.1371/journal.ppat.1011416},

issn = {1553-7374},

year  = {2023},

date = {2023-06-01},

journal = {PLoS Pathog},

volume = {19},

number = {6},

pages = {e1011416},

abstract = {Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population "arms" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37163615,

title = {Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine},

author = {Yupeng Feng and Meng Yuan and John M Powers and Mengyun Hu and Jennifer E Munt and Prabhu S Arunachalam and Sarah R Leist and Lorenza Bellusci and JungHyun Kim and Kaitlin R Sprouse and Lily E Adams and Sumana Sundaramurthy and Xueyong Zhu and Lisa M Shirreff and Michael L Mallory and Trevor D Scobey and Alberto Moreno and Derek T O'Hagan and Harry Kleanthous and Francois J Villinger and David Veesler and Neil P King and Mehul S Suthar and Surender Khurana and Ralph S Baric and Ian A Wilson and Bali Pulendran},

doi = {10.1126/scitranslmed.adg7404},

issn = {1946-6242},

year  = {2023},

date = {2023-05-01},

journal = {Sci Transl Med},

volume = {15},

number = {695},

pages = {eadg7404},

abstract = {The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has placed an imperative on the development of countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent monoclonal antibodies (mAbs) that neutralized multiple sarbecoviruses from macaques vaccinated with AS03-adjuvanted monovalent subunit vaccines. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells (MBCs) for at least 1 year after primary vaccination. Antibodies generated from these antigen-specific MBCs at 5 to 12 months after vaccination displayed greater potency and breadth relative to those identified at 1.4 months. Fifteen of the 338 (about 4.4%) antibodies isolated at 1.4 to 6 months after the primary vaccination showed potency against SARS-CoV-2 BA.1, despite the absence of serum BA.1 neutralization. 25F9 and 20A7 neutralized authentic clade 1 sarbecoviruses (SARS-CoV, WIV-1, SHC014, SARS-CoV-2 D614G, BA.1, and Pangolin-GD) and vesicular stomatitis virus-pseudotyped clade 3 sarbecoviruses (BtKY72 and PRD-0038). 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1, and XBB. Crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved sites within the RBD. Prophylactic protection of 25F9, 20A7, and 27A12 was confirmed in mice, and administration of 25F9 particularly provided complete protection against SARS-CoV-2, BA.1, SARS-CoV, and SHC014 challenge. These data underscore the extremely potent and broad activity of these mAbs against sarbecoviruses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37198165,

title = {Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9},

author = {Gregory M Martin and Monica L Fernández-Quintero and Wen-Hsin Lee and Tossapol Pholcharee and Lisa Eshun-Wilson and Klaus R Liedl and Marie Pancera and Robert A Seder and Ian A Wilson and Andrew B Ward},

doi = {10.1038/s41467-023-38509-2},

issn = {2041-1723},

year  = {2023},

date = {2023-05-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {2815},

abstract = {A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure of the highly potent anti-PfCSP antibody L9 in complex with recombinant PfCSP. We found that L9 Fab binds multivalently to the minor (NPNV) repeat domain, which is stabilized by a unique set of affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed a critical role of the L9 light chain in integrity of the homotypic interface, which likely impacts PfCSP affinity and protective efficacy. These findings reveal the molecular mechanism of the unique NPNV selectivity of L9 and emphasize the importance of anti-homotypic affinity maturation in protective immunity against P. falciparum.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36862518,

title = {Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants},

author = {Siriruk Changrob and Peter J Halfmann and Hejun Liu and Jonathan L Torres and Joshua J C McGrath and Gabriel Ozorowski and Lei Li and G Dewey Wilbanks and Makoto Kuroda and Tadashi Maemura and Min Huang and Nai-Ying Zheng and Hannah L Turner and Steven A Erickson and Yanbin Fu and Atsuhiro Yasuhara and Gagandeep Singh and Brian Monahan and Jacob Mauldin and Komal Srivastava and Viviana Simon and Florian Krammer and D Noah Sather and Andrew B Ward and Ian A Wilson and Yoshihiro Kawaoka and Patrick C Wilson},

doi = {10.1172/JCI166844},

issn = {1558-8238},

year  = {2023},

date = {2023-04-01},

journal = {J Clin Invest},

volume = {133},

number = {8},

abstract = {The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) that was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo challenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, this epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may inform target-driven vaccine designs against future SARS-CoV-2 variants.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37031217,

title = {Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimmers as HIV-1 vaccine candidates},

author = {Yi-Nan Zhang and Jennifer Paynter and Aleksandar Antanasijevic and Joel D Allen and Mor Eldad and Yi-Zong Lee and Jeffrey Copps and Maddy L Newby and Linling He and Deborah Chavez and Pat Frost and Anna Goodroe and John Dutton and Robert Lanford and Christopher Chen and Ian A Wilson and Max Crispin and Andrew B Ward and Jiang Zhu},

doi = {10.1038/s41467-023-37742-z},

issn = {2041-1723},

year  = {2023},

date = {2023-04-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {1985},

abstract = {Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37037866,

title = {High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike},

author = {Timothy J C Tan and Zongjun Mou and Ruipeng Lei and Wenhao O Ouyang and Meng Yuan and Ge Song and Raiees Andrabi and Ian A Wilson and Collin Kieffer and Xinghong Dai and Kenneth A Matreyek and Nicholas C Wu},

doi = {10.1038/s41467-023-37786-1},

issn = {2041-1723},

year  = {2023},

date = {2023-04-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {2003},

abstract = {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 establish 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 integrates a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, we apply this method to a region in the S2 domain that includes the first heptad repeat and central helix. Our results reveal that besides K986P and V987P, several mutations simultaneously improve expression and significantly lower 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37044090,

title = {Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions},

author = {Tom G Caniels and Max Medina-Ramírez and Jinsong Zhang and Anita Sarkar and Sonu Kumar and Alex LaBranche and Ronald Derking and Joel D Allen and Jonne L Snitselaar and Joan Capella-Pujol and Iván Del Moral Sánchez and Anila Yasmeen and Marilyn Diaz and Yoann Aldon and Tom P L Bijl and Sravani Venkatayogi and Joshua S Martin Beem and Amanda Newman and Chuancang Jiang and Wen-Hsin Lee and Maarten Pater and Judith A Burger and Mariëlle J van Breemen and Steven W de Taeye and Kimmo Rantalainen and Celia LaBranche and Kevin O Saunders and David Montefiori and Gabriel Ozorowski and Andrew B Ward and Max Crispin and John P Moore and Per Johan Klasse and Barton F Haynes and Ian A Wilson and Kevin Wiehe and Laurent Verkoczy and Rogier W Sanders},

doi = {10.1016/j.xcrm.2023.101003},

issn = {2666-3791},

year  = {2023},

date = {2023-04-01},

journal = {Cell Rep Med},

volume = {4},

number = {4},

pages = {101003},

abstract = {Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36175661,

title = {Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection},

author = {Chang-Ki Oh and Tomohiro Nakamura and Nathan Beutler and Xu Zhang and Juan Piña-Crespo and Maria Talantova and Swagata Ghatak and Dorit Trudler and Lauren N Carnevale and Scott R McKercher and Malina A Bakowski and Jolene K Diedrich and Amanda J Roberts and Ashley K Woods and Victor Chi and Anil K Gupta and Mia A Rosenfeld and Fiona L Kearns and Lorenzo Casalino and Namir Shaabani and Hejun Liu and Ian A Wilson and Rommie E Amaro and Dennis R Burton and John R Yates and Cyrus Becker and Thomas F Rogers and Arnab K Chatterjee and Stuart A Lipton},

doi = {10.1038/s41589-022-01149-6},

issn = {1552-4469},

year  = {2023},

date = {2023-03-01},

journal = {Nat Chem Biol},

volume = {19},

number = {3},

pages = {275--283},

abstract = {Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36889306,

title = {Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease},

author = {Panpan Zhou and Ge Song and Hejun Liu and Meng Yuan and Wan-Ting He and Nathan Beutler and Xueyong Zhu and Longping V Tse and David R Martinez and Alexandra Schäfer and Fabio Anzanello and Peter Yong and Linghang Peng and Katharina Dueker and Rami Musharrafieh and Sean Callaghan and Tazio Capozzola and Oliver Limbo and Mara Parren and Elijah Garcia and Stephen A Rawlings and Davey M Smith and David Nemazee and Joseph G Jardine and Yana Safonova and Bryan Briney and Thomas F Rogers and Ian A Wilson and Ralph S Baric and Lisa E Gralinski and Dennis R Burton and Raiees Andrabi},

doi = {10.1016/j.immuni.2023.02.005},

issn = {1097-4180},

year  = {2023},

date = {2023-03-01},

journal = {Immunity},

volume = {56},

number = {3},

pages = {669--686.e7},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36347257,

title = {Rare, convergent antibodies targeting the stem helix broadly neutralize diverse betacoronaviruses},

author = {Cherrelle Dacon and Linghang Peng and Ting-Hui Lin and Courtney Tucker and Chang-Chun D Lee and Yu Cong and Lingshu Wang and Lauren Purser and Andrew J R Cooper and Jazmean K Williams and Chul-Woo Pyo and Meng Yuan and Ivan Kosik and Zhe Hu and Ming Zhao and Divya Mohan and Mary Peterson and Jeff Skinner and Saurabh Dixit and Erin Kollins and Louis Huzella and Donna Perry and Russell Byrum and Sanae Lembirik and Michael Murphy and Yi Zhang and Eun Sung Yang and Man Chen and Kwanyee Leung and Rona S Weinberg and Amarendra Pegu and Daniel E Geraghty and Edgar Davidson and Benjamin J Doranz and Iyadh Douagi and Susan Moir and Jonathan W Yewdell and Connie Schmaljohn and Peter D Crompton and John R Mascola and Michael R Holbrook and David Nemazee and Ian A Wilson and Joshua Tan},

doi = {10.1016/j.chom.2022.10.010},

issn = {1934-6069},

year  = {2023},

date = {2023-01-01},

journal = {Cell Host Microbe},

volume = {31},

number = {1},

pages = {97--111.e12},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36179689,

title = {Human immunoglobulin repertoire analysis guides design of vaccine priming immunogens targeting HIV V2-apex broadly neutralizing antibody precursors},

author = {Jordan R Willis and Zachary T Berndsen and Krystal M Ma and Jon M Steichen and Torben Schiffner and Elise Landais and Alessia Liguori and Oleksandr Kalyuzhniy and Joel D Allen and Sabyasachi Baboo and Oluwarotimi Omorodion and Jolene K Diedrich and Xiaozhen Hu and Erik Georgeson and Nicole Phelps and Saman Eskandarzadeh and Bettina Groschel and Michael Kubitz and Yumiko Adachi and Tina-Marie Mullin and Nushin B Alavi and Samantha Falcone and Sunny Himansu and Andrea Carfi and Ian A Wilson and John R Yates and James C Paulson and Max Crispin and Andrew B Ward and William R Schief},

doi = {10.1016/j.immuni.2022.09.001},

issn = {1097-4180},

year  = {2022},

date = {2022-11-01},

journal = {Immunity},

volume = {55},

number = {11},

pages = {2149--2167.e9},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36335937,

title = {Molecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2},

author = {Meng Yuan and Yiquan Wang and Huibin Lv and Timothy J C Tan and Ian A Wilson and Nicholas C Wu},

doi = {10.1016/j.celrep.2022.111650},

issn = {2211-1247},

year  = {2022},

date = {2022-11-01},

journal = {Cell Rep},

volume = {41},

number = {7},

pages = {111650},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36395347,

title = {Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer},

author = {Jelle van Schooten and Anna Schorcht and Elinaz Farokhi and Jeffrey C Umotoy and Hongmei Gao and Tom L G M van den Kerkhof and Jessica Dorning and Tim G Rijkhold Meesters and Patricia van der Woude and Judith A Burger and Tom Bijl and Riham Ghalaiyini and Alba Torrents de la Peña and Hannah L Turner and Celia C Labranche and Robyn L Stanfield and Devin Sok and Hanneke Schuitemaker and David C Montefiori and Dennis R Burton and Gabriel Ozorowski and Michael S Seaman and Ian A Wilson and Rogier W Sanders and Andrew B Ward and Marit J van Gils},

doi = {10.1371/journal.ppat.1010945},

issn = {1553-7374},

year  = {2022},

date = {2022-11-01},

journal = {PLoS Pathog},

volume = {18},

number = {11},

pages = {e1010945},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36300787,

title = {HIV skews the SARS-CoV-2 B cell response towards an extrafollicular maturation pathway},

author = {Robert Krause and Jumari Snyman and Hwa Shi-Hsia and Daniel Muema and Farina Karim and Yashica Ganga and Abigail Ngoepe and Yenzekile Zungu and Inbal Gazy and Mallory Bernstein and Khadija Khan and Matilda Mazibuko and Ntombifuthi Mthabela and Dirhona Ramjit and  and Oliver Limbo and Joseph Jardine and Devin Sok and Ian A Wilson and Willem Hanekom and Alex Sigal and Henrik Kløverpris and Thumbi Ndung'u and Alasdair Leslie},

doi = {10.7554/eLife.79924},

issn = {2050-084X},

year  = {2022},

date = {2022-10-01},

journal = {Elife},

volume = {11},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35599305,

title = {Protective neutralizing epitopes in SARS-CoV-2},

author = {Hejun Liu and Ian A Wilson},

doi = {10.1111/imr.13084},

issn = {1600-065X},

year  = {2022},

date = {2022-09-01},

journal = {Immunol Rev},

volume = {310},

number = {1},

pages = {76--92},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35922441,

title = {Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein},

author = {Jelle van Schooten and Elinaz Farokhi and Anna Schorcht and Tom L G M van den Kerkhof and Hongmei Gao and Patricia van der Woude and Judith A Burger and Tim G Rijkhold Meesters and Tom Bijl and Riham Ghalaiyini and Hannah L Turner and Jessica Dorning and Barbera D C van Schaik and Antoine H C van Kampen and Celia C Labranche and Robyn L Stanfield and Devin Sok and David C Montefiori and Dennis R Burton and Michael S Seaman and Gabriel Ozorowski and Ian A Wilson and Rogier W Sanders and Andrew B Ward and Marit J van Gils},

doi = {10.1038/s41467-022-32208-0},

issn = {2041-1723},

year  = {2022},

date = {2022-08-01},

journal = {Nat Commun},

volume = {13},

number = {1},

pages = {4515},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35857439,

title = {Broadly neutralizing antibodies target the coronavirus fusion peptide},

author = {Cherrelle Dacon and Courtney Tucker and Linghang Peng and Chang-Chun D Lee and Ting-Hui Lin and Meng Yuan and Yu Cong and Lingshu Wang and Lauren Purser and Jazmean K Williams and Chul-Woo Pyo and Ivan Kosik and Zhe Hu and Ming Zhao and Divya Mohan and Andrew J R Cooper and Mary Peterson and Jeff Skinner and Saurabh Dixit and Erin Kollins and Louis Huzella and Donna Perry and Russell Byrum and Sanae Lembirik and David Drawbaugh and Brett Eaton and Yi Zhang and Eun Sung Yang and Man Chen and Kwanyee Leung and Rona S Weinberg and Amarendra Pegu and Daniel E Geraghty and Edgar Davidson and Iyadh Douagi and Susan Moir and Jonathan W Yewdell and Connie Schmaljohn and Peter D Crompton and Michael R Holbrook and David Nemazee and John R Mascola and Ian A Wilson and Joshua Tan},

doi = {10.1126/science.abq3773},

issn = {1095-9203},

year  = {2022},

date = {2022-08-01},

journal = {Science},

volume = {377},

number = {6607},

pages = {728--735},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35767670,

title = {A broad and potent neutralization epitope in SARS-related coronaviruses},

author = {Meng Yuan and Xueyong Zhu and Wan-Ting He and Panpan Zhou and Chengzi I Kaku and Tazio Capozzola and Connie Y Zhu and Xinye Yu and Hejun Liu and Wenli Yu and Yuanzi Hua and Henry Tien and Linghang Peng and Ge Song and Christopher A Cottrell and William R Schief and David Nemazee and Laura M Walker and Raiees Andrabi and Dennis R Burton and Ian A Wilson},

doi = {10.1073/pnas.2205784119},

issn = {1091-6490},

year  = {2022},

date = {2022-07-01},

journal = {Proc Natl Acad Sci U S A},

volume = {119},

number = {29},

pages = {e2205784119},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35906394,

title = {Human antibodies to SARS-CoV-2 with a recurring YYDRxG motif retain binding and neutralization to variants of concern including Omicron},

author = {Hejun Liu and Chengzi I Kaku and Ge Song and Meng Yuan and Raiees Andrabi and Dennis R Burton and Laura M Walker and Ian A Wilson},

doi = {10.1038/s42003-022-03700-6},

issn = {2399-3642},

year  = {2022},

date = {2022-07-01},

journal = {Commun Biol},

volume = {5},

number = {1},

pages = {766},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35654851,

title = {Targeted isolation of diverse human protective broadly neutralizing antibodies against SARS-like viruses},

author = {Wan-Ting He and Rami Musharrafieh and Ge Song and Katharina Dueker and Longping V Tse and David R Martinez and Alexandra Schäfer and Sean Callaghan and Peter Yong and Nathan Beutler and Jonathan L Torres and Reid M Volk and Panpan Zhou and Meng Yuan and Hejun Liu and Fabio Anzanello and Tazio Capozzola and Mara Parren and Elijah Garcia and Stephen A Rawlings and Davey M Smith and Ian A Wilson and Yana Safonova and Andrew B Ward and Thomas F Rogers and Ralph S Baric and Lisa E Gralinski and Dennis R Burton and Raiees Andrabi},

doi = {10.1038/s41590-022-01222-1},

issn = {1529-2916},

year  = {2022},

date = {2022-06-01},

journal = {Nat Immunol},

volume = {23},

number = {6},

pages = {960--970},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35397794,

title = {A large-scale systematic survey reveals recurring molecular features of public antibody responses to SARS-CoV-2},

author = {Yiquan Wang and Meng Yuan and Huibin Lv and Jian Peng and Ian A Wilson and Nicholas C Wu},

doi = {10.1016/j.immuni.2022.03.019},

issn = {1097-4180},

year  = {2022},

date = {2022-06-01},

journal = {Immunity},

volume = {55},

number = {6},

pages = {1105--1117.e4},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35891363,

title = {Neutralizing Antibody Response to  Is Delayed in Sequential Heterologous Immunization},

author = {Huibin Lv and Ray T Y So and Qi Wen Teo and Meng Yuan and Hejun Liu and Chang-Chun D Lee and Garrick K Yip and Wilson W Ng and Ian A Wilson and Malik Peiris and Nicholas C Wu and Chris Ka Pun Mok},

doi = {10.3390/v14071382},

issn = {1999-4915},

year  = {2022},

date = {2022-06-01},

journal = {Viruses},

volume = {14},

number = {7},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35738279,

title = {Superimmunity by pan-sarbecovirus nanobodies},

author = {Yufei Xiang and Wei Huang and Hejun Liu and Zhe Sang and Sham Nambulli and Jérôme Tubiana and Kevin L Williams and W Paul Duprex and Dina Schneidman-Duhovny and Ian A Wilson and Derek J Taylor and Yi Shi},

doi = {10.1016/j.celrep.2022.111004},

issn = {2211-1247},

year  = {2022},

date = {2022-06-01},

journal = {Cell Rep},

volume = {39},

number = {13},

pages = {111004},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35332283,

title = {Design of protein-binding proteins from the target structure alone},

author = {Longxing Cao and Brian Coventry and Inna Goreshnik and Buwei Huang and William Sheffler and Joon Sung Park and Kevin M Jude and Iva Marković and Rameshwar U Kadam and Koen H G Verschueren and Kenneth Verstraete and Scott Thomas Russell Walsh and Nathaniel Bennett and Ashish Phal and Aerin Yang and Lisa Kozodoy and Michelle DeWitt and Lora Picton and Lauren Miller and Eva-Maria Strauch and Nicholas D DeBouver and Allison Pires and Asim K Bera and Samer Halabiya and Bradley Hammerson and Wei Yang and Steffen Bernard and Lance Stewart and Ian A Wilson and Hannele Ruohola-Baker and Joseph Schlessinger and Sangwon Lee and Savvas N Savvides and K Christopher Garcia and David Baker},

doi = {10.1038/s41586-022-04654-9},

issn = {1476-4687},

year  = {2022},

date = {2022-05-01},

journal = {Nature},

volume = {605},

number = {7910},

pages = {551--560},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35549549,

title = {Structural insights of a highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody},

author = {Jonathan L Torres and Gabriel Ozorowski and Emanuele Andreano and Hejun Liu and Jeffrey Copps and Giulia Piccini and Lorena Donnici and Matteo Conti and Cyril Planchais and Delphine Planas and Noemi Manganaro and Elisa Pantano and Ida Paciello and Piero Pileri and Timothée Bruel and Emanuele Montomoli and Hugo Mouquet and Olivier Schwartz and Claudia Sala and Raffaele De Francesco and Ian A Wilson and Rino Rappuoli and Andrew B Ward},

doi = {10.1073/pnas.2120976119},

issn = {1091-6490},

year  = {2022},

date = {2022-05-01},

journal = {Proc Natl Acad Sci U S A},

volume = {119},

number = {20},

pages = {e2120976119},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35594401,

title = {Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface},

author = {Xueyong Zhu and Julianna Han and Weina Sun and Eduard Puente-Massaguer and Wenli Yu and Peter Palese and Florian Krammer and Andrew B Ward and Ian A Wilson},

doi = {10.1073/pnas.2200821119},

issn = {1091-6490},

year  = {2022},

date = {2022-05-01},

journal = {Proc Natl Acad Sci U S A},

volume = {119},

number = {21},

pages = {e2200821119},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35613596,

title = {Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening},

author = {Jennifer M Pfaff-Kilgore and Edgar Davidson and Kathryn Kadash-Edmondson and Mayda Hernandez and Erin Rosenberg and Ross Chambers and Matteo Castelli and Nicola Clementi and Nicasio Mancini and Justin R Bailey and James E Crowe and Mansun Law and Benjamin J Doranz},

doi = {10.1016/j.celrep.2022.110859},

issn = {2211-1247},

year  = {2022},

date = {2022-05-01},

journal = {Cell Rep},

volume = {39},

number = {8},

pages = {110859},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35044215,

title = {-Glycolylneuraminic Acid Binding of Avian and Equine H7 Influenza A Viruses},

author = {Cindy M Spruit and Xueyong Zhu and Ilhan Tomris and María Ríos-Carrasco and Alvin X Han and Frederik Broszeit and Roosmarijn van der Woude and Kim M Bouwman and Michel M T Luu and Keita Matsuno and Yoshihiro Sakoda and Colin A Russell and Ian A Wilson and Geert-Jan Boons and Robert P de Vries},

doi = {10.1128/jvi.02120-21},

issn = {1098-5514},

year  = {2022},

date = {2022-03-01},

journal = {J Virol},

volume = {96},

number = {5},

pages = {e0212021},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}