Olubukola M. Abiona

Case Western Reserve University

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Barney S. Graham

National Institute of Allergy and Infectious Diseases

Kizzmekia S. Corbett

National Institute of Allergy and Infectious Diseases

Ralph S. Baric

University of North Carolina at Chapel Hill

John R. Mascola

National Institute of Allergy and Infectious Diseases

Lingshu Wang

National Institute of Allergy and Infectious Diseases

Jason S. McLellan

The University of Texas at Austin

Anne P. Werner

National Institute of Allergy and Infectious Diseases

Yaroslav Tsybovsky

Leidos (United States)

Yi Zhang

Fudan University

Daniel Wrapp

The University of Texas at Austin

Cooperative Institutions

National Institutes of Health

169

National Institute of Allergy and Infectious Diseases

125

Centers for Disease Control and Prevention

Institut de Recherche Vaccinale

Riverside University Health System - Medical Center

Synergy America (United States)

University of North Carolina at Chapel Hill

Rhode Island Department of Health

Moderna Therapeutics (United States)

Providence College

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SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Kizzmekia S. Corbett Darin K. Edwards Sarah R. Leist Olubukola M. Abiona Seyhan Boyoglu-Barnum

A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins. Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial with a trajectory towards Phase 3 efficacy evaluation.

Immunogen

Betacoronavirus

2019-20 coronavirus outbreak

10.1101/2020.06.11.145920

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Citations (133)

Activity Dependent Modulation of Granule Cell Survival in the Accessory Olfactory Bulb at Puberty

Frontiers in Neuroanatomy (2017)

Livio Oboti Sara Trova Roberta Schellino Marilena Marraudino Natalie R. Harris

The vomeronasal system (VNS) is specialized in the detection of salient chemical cues triggering social and neuroendocrine responses. Such responses are not always stereotyped, instead, they vary depending on age, sex and reproductive state, yet the mechanisms underlying this variability are unclear. Here, by analyzing neuronal survival in the first processing nucleus of the VNS, namely the accessory olfactory bulb (AOB), through multiple bromodeoxyuridine (BrdU) birthdating protocols, we show that exposure of female mice to male soiled bedding material affects the integration of newborn granule interneurons mainly after puberty. This effect is induced by urine compounds produced by mature males, as bedding soiled by younger males was ineffective. The granule cell increase induced by mature male odor exposure is not prevented by pre-pubertal ovariectomy, indicating a lesser role of circulating estrogens in this plasticity. Interestingly, the intake of adult male urine-derived cues by the female vomeronasal organ (VNO) increases during puberty, suggesting a direct correlation between sensory activity and AOB neuronal plasticity. Thus, as odor exposure increases the responses of newly born cells to the experienced stimuli, the addition of new GABAergic inhibitory cells to the AOB might contribute to the shaping of vomeronasal processing of male cues after puberty. Consistently, only after puberty, female mice are capable to discriminate individual male odors through the VNS.

Vomeronasal organ

Granule cell

Bromodeoxyuridine

10.3389/fnana.2017.00044

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Citations (15)

Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

New England Journal of Medicine (2020)

Kizzmekia S. Corbett Barbara J. Flynn Kathryn E. Foulds Joseph R. Francica Seyhan Boyoglu-Barnum

Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.).

10.1056/nejmoa2024671

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Citations (1,041)

SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

Nature (2020)

Kizzmekia S. Corbett Darin K. Edwards Sarah R. Leist Olubukola M. Abiona Seyhan Boyoglu-Barnum

Preparedness

2019-20 coronavirus outbreak

10.1038/s41586-020-2622-0

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Citations (1,401)

LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model of SARS-CoV-2 infection

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Bryan E. Jones Patricia Brown‐Augsburger Kizzmekia S. Corbett Kathryn Westendorf Julian Davies

Abstract SARS-CoV-2 poses a public health threat for which therapeutic agents are urgently needed. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract. These data demonstrate that high-throughput screening can lead to the identification of a potent antiviral antibody that protects against SARS-CoV-2 infection. One Sentence Summary LY-CoV555, an anti-spike antibody derived from a convalescent COVID-19 patient, potently neutralizes SARS-CoV-2 and protects the upper and lower airways of non-human primates against SARS-CoV-2 infection.

Rhesus macaque

10.1101/2020.09.30.318972

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Citations (160)

SARS-CoV-2 vaccines elicit durable immune responses in infant rhesus macaques

Science Immunology (2021)

Carolina Garrido Alan D. Curtis Maria Dennis Sachi Pathak Hongmei Gao

The inclusion of infants in the SARS-CoV-2 vaccine roll-out is important to prevent severe complications of pediatric SARS-CoV-2 infections and to limit transmission and could possibly be implemented via the global pediatric vaccine schedule. However, age-dependent differences in immune function require careful evaluation of novel vaccines in the pediatric population. Toward this goal, we assessed the safety and immunogenicity of two SARS-CoV-2 vaccines. Two groups of 8 infant rhesus macaques (RMs) were immunized intramuscularly at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. Both vaccines elicited high magnitude IgG binding to RBD, N terminus domain, S1, and S2, ACE2 blocking activity, and high neutralizing antibody titers, all peaking at week 6. S-specific memory B cells were detected by week 4 and S-specific T cell responses were dominated by the production of IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. The immune responses for the mRNA-LNP vaccine were of a similar magnitude to those elicited by the Moderna mRNA-1273 vaccine in adults. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines were well-tolerated and highly immunogenic in infant RMs, providing proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity that might decrease the transmission of SARS-CoV-2 and mitigate the ongoing health and socioeconomic impacts of COVID-19.

Rhesus macaque

10.1126/sciimmunol.abj3684

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Citations (40)

Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

Science (2021)

Lingshu Wang Tongqing Zhou Yi Zhang Eun Sung Yang Chaim A. Schramm

Defenses against SARS-CoV-2 variants Our key defense against the COVID-19 pandemic is neutralizing antibodies against the SARS-CoV-2 virus elicited by natural infection or vaccination. Recent emerging viral variants have raised concern because of their potential to escape antibody neutralization. Wang et al . identified four antibodies from early-outbreak convalescent donors that are potent against 23 variants, including variants of concern, and characterized their binding to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yuan et al . examined the impact of emerging mutations in the receptor-binding domain of the spike protein on binding to the host receptor ACE2 and to a range of antibodies. These studies may be helpful for developing more broadly effective vaccines and therapeutic antibodies. —VV

Coronavirus

spike protein

Antibody-dependent enhancement

Pandemic

10.1126/science.abh1766

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Citations (194)

Prefusion 2019-nCoV spike glycoprotein with a single receptor-binding domain up

Daniel Wrapp N. Wang Kevin Corbett Jory A. Goldsmith Cheng‐I Hsieh

Coronavirus

10.2210/pdb6vsb/pdb

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Citations (7)

Stabilized coronavirus spike stem elicits a broadly protective antibody

Cell Reports (2021)

Ching‐Lin Hsieh Anne P. Werner Sarah R. Leist Laura J. Stevens Ester Falconer

Highlights•Structure-guided design generates MERS-CoV spike stabilized stem (SS) antigens•Cross-reactive CoV-spike-stem-specific monoclonal antibodies•Structures of the Fab22-spike complexes reveal a conserved, protective epitope•Passive transfer of IgG22 protects mice against MERS-CoV and SARS-CoV-2 challengeSummaryCurrent coronavirus (CoV) vaccines primarily target immunodominant epitopes in the S1 subunit, which are poorly conserved and susceptible to escape mutations, thus threatening vaccine efficacy. Here, we use structure-guided protein engineering to remove the S1 subunit from the Middle East respiratory syndrome (MERS)-CoV spike (S) glycoprotein and develop stabilized stem (SS) antigens. Vaccination with MERS SS elicits cross-reactive β-CoV antibody responses and protects mice against lethal MERS-CoV challenge. High-throughput screening of antibody-secreting cells from MERS SS-immunized mice led to the discovery of a panel of cross-reactive monoclonal antibodies. Among them, antibody IgG22 binds with high affinity to both MERS-CoV and severe acute respiratory syndrome (SARS)-CoV-2 S proteins, and a combination of electron microscopy and crystal structures localizes the epitope to a conserved coiled-coil region in the S2 subunit. Passive transfer of IgG22 protects mice against both MERS-CoV and SARS-CoV-2 challenge. Collectively, these results provide a proof of principle for cross-reactive CoV antibodies and inform the development of pan-CoV vaccines and therapeutic antibodies.Graphical abstract

Coronavirus

spike protein

2019-20 coronavirus outbreak

10.1016/j.celrep.2021.109929

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Nanoparticle display of prefusion coronavirus spike elicits S1-focused cross-reactive protection across divergent subgroups

Research Square (Research Square) (2022)

Geoffrey B. Hutchinson Olubukola M. Abiona Cynthia T. Ziwawo Anne P. Werner Daniel Ellis

Multivalent antigen display is a fast-growing area of interest towards broadly protective vaccines. Current nanoparticle-based vaccine candidates demonstrate the ability to confer antibody-mediated immunity against divergent strains of notably mutable viruses. In coronaviruses, this work is predominantly aimed at targeting conserved epitopes of the receptor-binding domain. However, targeting other conserved non-RBD epitopes could further limit the potential for antigenic escape. To further explore new potential targets, we engineered protein nanoparticles displaying CoV_S-2P trimers derived from MERS-CoV, SARS-CoV-1, SARS-CoV-2, hCoV-HKU1, and hCoV-OC43 and assessed their immunogenicity in mice. Monotypic SARS-1_S-2P nanoparticles elicited cross-neutralizing antibodies against MERS_S and protected against MERS-CoV challenge. MERS and SARS-I53_dn5 nanoparticles elicited S1-focused antibodies, revealing a conserved site on the NTD. Moreover, mosaic nanoparticles co-displaying distinct CoV_S-2P trimers elicited antibody responses to distant cross-group antigens while protecting against MERS challenge despite diminished valency of MERS_S-2P. Our findings will inform further efforts towards the development of pan-coronavirus vaccines.

Coronavirus

spike protein

10.21203/rs.3.rs-2199814/v1

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Citations (2)