Yaroslav Tsybovsky

Leidos (United States)

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Peter D. Kwong

Columbia University

John R. Mascola

National Institute of Allergy and Infectious Diseases

Tongqing Zhou

National Institute of Allergy and Infectious Diseases

Baoshan Zhang

National Institute of Allergy and Infectious Diseases

Adam S. Olia

National Institute of Allergy and Infectious Diseases

Tyler Stephens

Frederick National Laboratory for Cancer Research

Barney S. Graham

National Institute of Allergy and Infectious Diseases

Shuishu Wang

National Institute of Allergy and Infectious Diseases

Masaru Kanekiyo

National Institute of Allergy and Infectious Diseases

Adrian B. McDermott

National Institutes of Health

Cooperative Institutions

National Institutes of Health

510

National Institute of Allergy and Infectious Diseases

470

Institut de Recherche Vaccinale

University of Washington

Harvard University

Columbia University

Howard Hughes Medical Institute

Scripps Research Institute

University of Pennsylvania

Johns Hopkins University

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Self-assembling SARS-CoV-2 spike-HBsAg nanoparticles elicit potent and durable neutralizing antibody responses via genetic delivery

npj Vaccines (2023)

Cuiping Liu Lingshu Wang Jonah S. Merriam Wei Shi Eun Sung Yang

Abstract While several COVID-19 vaccines have been in use, more effective and durable vaccines are needed to combat the ongoing COVID-19 pandemic. Here, we report highly immunogenic self-assembling SARS-CoV-2 spike-HBsAg nanoparticles displaying a six-proline-stabilized WA1 (wild type, WT) spike S6P on a HBsAg core. These S6P-HBsAgs bound diverse domain-specific SARS-CoV-2 monoclonal antibodies. In mice with and without a HBV pre-vaccination, DNA immunization with S6P-HBsAgs elicited significantly more potent and durable neutralizing antibody (nAb) responses against diverse SARS-CoV-2 strains than that of soluble S2P or S6P, or full-length S2P with its coding sequence matching mRNA-1273. The nAb responses elicited by S6P-HBsAgs persisted substantially longer than by soluble S2P or S6P and appeared to be enhanced by HBsAg pre-exposure. These data show that genetic delivery of SARS-CoV-2 S6P-HBsAg nanoparticles can elicit greater and more durable nAb responses than non-nanoparticle forms of stabilized spike. Our findings highlight the potential of S6P-HBsAgs as next generation genetic vaccine candidates against SARS-CoV-2.

spike protein

10.1038/s41541-023-00707-w

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Citations (7)

Crystal structure of photoreceptor dehydrogenase from Drosophila melanogaster

ACS Chemical Biology (2016)

Lukas Hofmann Yaroslav Tsybovsky Siddhartha Banerjee

Melanogaster

Crystal (programming language)

10.2210/pdb5ilg/pdb

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Citations (0)

HKU5 bat merbecoviruses use divergent mechanisms to engage bat and mink ACE2 as entry receptors

bioRxiv (Cold Spring Harbor Laboratory) (2025)

Mia Madel Alfajaro Emma L. Keeler Ning Li Nicholas J Cantanzaro I‐Ting Teng

Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness. While Middle East respiratory syndrome coronavirus (MERS-CoV) uses DPP4 for entry, the receptors of many MERS-related betacoronaviruses remain unknown. The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells. Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy (cryo-EM) analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2, revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use and underscore the need for continued surveillance of bat and mustelid species.

10.1101/2025.02.12.637862

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Advances in purification of SARS-CoV-2 spike ectodomain protein using high-throughput screening and non-affinity methods

Scientific Reports (2022)

Nicole Cibelli Gabriel F. Arias McKenzie Figur Shireen Khayat Kristin Leach

The spike (S) glycoprotein of the pandemic virus, SARS-CoV-2, is a critically important target of vaccine design and therapeutic development. A high-yield, scalable, cGMP-compliant downstream process for the stabilized, soluble, native-like S protein ectodomain is necessary to meet the extensive material requirements for ongoing research and development. As of June 2021, S proteins have exclusively been purified using difficult-to-scale, low-yield methodologies such as affinity and size-exclusion chromatography. Herein we present the first known non-affinity purification method for two S constructs, S_dF_2P and HexaPro, expressed in the mammalian cell line, CHO-DG44. A high-throughput resin screen on the Tecan Freedom EVO200 automated bioprocess workstation led to identification of ion exchange resins as viable purification steps. The chromatographic unit operations along with industry-standard methodologies for viral clearances, low pH treatment and 20 nm filtration, were assessed for feasibility. The developed process was applied to purify HexaPro from a CHO-DG44 stable pool harvest and yielded the highest yet reported amount of pure S protein. Our results demonstrate that commercially available chromatography resins are suitable for cGMP manufacturing of SARS-CoV-2 Spike protein constructs. We anticipate our results will provide a blueprint for worldwide biopharmaceutical production laboratories, as well as a starting point for process intensification.

Ectodomain

spike protein

10.1038/s41598-022-07485-w

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Development of Neutralization Breadth against Diverse HIV‐1 by Increasing Ab–Ag Interface on V2

Advanced Science (2022)

Nan Gao Yanxin Gai Lina Meng Chu Wang Wei Wang

Abstract Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV‐1 can be highly informative for HIV‐1 vaccine development. A lineage of J038 bnAbs is now obtained from a long‐term SHIV‐infected macaque. J038 neutralizes 54% of global circulating HIV‐1 strains. Its binding induces a unique “up” conformation for one of the V2 loops in the trimeric envelope glycoprotein and is heavily dependent on glycan, which provides nearly half of the binding surface. Their unmutated common ancestor neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody‐Env contact areas surrounding the core region contacted by germline‐encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for elicitation and maturation of V2‐targeting bnAbs.

Lineage (genetic)

Immune escape

Simian immunodeficiency virus

10.1002/advs.202200063

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Citations (5)

Design of soluble HIV-1 envelope trimers free of covalent gp120-gp41 bonds with prevalent native-like conformation

Cell Reports (2024)

Peng Zhang Jason Gorman Yaroslav Tsybovsky Maolin Lu Qingbo Liu

Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature between gp120 and gp41 constrains intersubunit mobility and may alter antigenicity. Here, we report an alternative strategy to generate stabilized soluble Env trimers free of covalent gp120-gp41 bonds. Stabilization was achieved by introducing an intrasubunit disulfide bond between the inner and outer domains of gp120, defined as interdomain lock (IDL). Correctly folded IDL trimers displaying a native-like antigenic profile were produced for HIV-1 Envs of different clades. Importantly, the IDL design abrogated CD4 binding while not affecting recognition by potent neutralizing antibodies to the CD4-binding site. By cryoelectron microscopy, IDL trimers were shown to adopt a closed prefusion configuration, while single-molecule fluorescence resonance energy transfer documented a high prevalence of native-like conformation. Thus, IDL trimers may be promising candidates as vaccine immunogens.

Antigenicity

Trimer

10.1016/j.celrep.2024.114518

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Citations (2)

The ATP-Binding Cassette Transporter ABCA4: Structural and Functional Properties and Role in Retinal Disease

Advances in experimental medicine and biology (2010)

Yaroslav Tsybovsky Robert S. Molday Krzysztof Palczewski

ABCA4

Stargardt disease

10.1007/978-1-4419-5635-4_8

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Citations (181)

Extraordinary Titer and Broad Anti-SARS-CoV-2 Neutralization Induced by Stabilized RBD Nanoparticles from Strain BA.5

Vaccines (2023)

Zhantong Wang Baoshan Zhang Li Ou Qi Qiu Lingshu Wang

The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a primary target of neutralizing antibodies and a key component of licensed vaccines. Substantial mutations in RBD, however, enable current variants to escape immunogenicity generated by vaccination with the ancestral (WA1) strain. Here, we produce and assess self-assembling nanoparticles displaying RBDs from WA1 and BA.5 strains by using the SpyTag:SpyCatcher system for coupling. We observed both WA1- and BA.5-RBD nanoparticles to degrade substantially after a few days at 37 °C. Incorporation of nine RBD-stabilizing mutations, however, increased yield ~five-fold and stability such that more than 50% of either the WA1- or BA.5-RBD nanoparticle was retained after one week at 37 °C. Murine immunizations revealed that the stabilized RBD-nanoparticles induced ~100-fold higher autologous neutralization titers than the prefusion-stabilized (S2P) spike at a 2 μg dose. Even at a 25-fold lower dose where S2P-induced neutralization titers were below the detection limit, the stabilized BA.5-RBD nanoparticle induced homologous titers of 12,795 ID50 and heterologous titers against WA1 of 1767 ID50. Assessment against a panel of β-coronavirus variants revealed both the stabilized BA.5-RBD nanoparticle and the stabilized WA1-BA.5-(mosaic)-RBD nanoparticle to elicit much higher neutralization breadth than the stabilized WA1-RBD nanoparticle. The extraordinary titer and high neutralization breadth elicited by stabilized RBD nanoparticles from strain BA.5 make them strong candidates for next-generation COVID-19 vaccines.

Heterologous

Strain (injury)

10.3390/vaccines12010037

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Citations (4)

Isolation and Structure of an Antibody that Fully Neutralizes Isolate SIVmac239 Reveals Functional Similarity of SIV and HIV Glycan Shields

Immunity (2019)

Jason Gorman Rosemarie D. Mason Leonard Nettey Nicole Cavett Gwo‐Yu Chuang

Simian immunodeficiency virus

10.1016/j.immuni.2019.09.007

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Citations (15)