ROTOTYPE ATHOGEN APPROACH TO ANDEMIC PREPAREDNESS · Pallesen, J., Wang, N., Corbe tt, K., … Gr...
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4/1/2020 1 PROTOTYPE P ATHOGEN APPROACH TO P ANDEMIC PREPAREDNESS HIV→PNEUMOVIRUS→PARAMYXOVIRUS→CORONAVIRUS ADVAC Alumni 2 April 2020 Barney S. Graham, MD, PhD Deputy Director Vaccine Research Center, NIAID, NIH • Hanta virus • Nipah/Hendra • West Nile virus • SARS • Influenza • Chikungunya • Ebola • MERS • Zika • EV‐D68 • SARS‐CoV‐2 Recent Zoonotic and Vector-borne Viral Threats Process Development cGMP Manufacturing Clinical Trials Basic Research GLP Analysis • AIDS/HIV • Influenza • Ebola/Marburg • RSV • Malaria • Tuberculosis • EID • West Nile virus, Zika • Chikungunya • W/E/V equine encephalitis viruses • MERS‐CoV, SARS, and other CoV • Nipah and other paramyxoviruses • EV‐D68 and other picornaviruses • Smallpox Vectors Nucleic acid VLPs Proteins and nanoparticles Monoclonal antibodies NIAID Vaccine Research Center 1 2 3
Transcript of ROTOTYPE ATHOGEN APPROACH TO ANDEMIC PREPAREDNESS · Pallesen, J., Wang, N., Corbe tt, K., … Gr...
4/1/2020
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PROTOTYPE PATHOGEN APPROACH TOPANDEMIC PREPAREDNESS
HIV→PNEUMOVIRUS→PARAMYXOVIRUS→CORONAVIRUS
ADVAC Alumni2 April 2020
Barney S. Graham, MD, PhD Deputy DirectorVaccine Research Center, NIAID, NIH
• Hanta virus• Nipah/Hendra• West Nile virus• SARS• Influenza• Chikungunya• Ebola• MERS• Zika• EV‐D68• SARS‐CoV‐2
Recent Zoonotic and Vector-borne Viral Threats
Process Development
cGMP Manufacturing
Clinical Trials
Basic Research
GLP Analysis
• AIDS/HIV• Influenza• Ebola/Marburg• RSV• Malaria• Tuberculosis• EID
• West Nile virus, Zika• Chikungunya• W/E/V equine encephalitis viruses• MERS‐CoV, SARS, and other CoV• Nipah and other paramyxoviruses• EV‐D68 and other picornaviruses• Smallpox
Vectors
Nucleic acid
VLPs
Proteins and nanoparticles
Monoclonal antibodies
NIAID Vaccine Research Center
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Public health burden of re-emerging & emerging viruses
Vaccine Challenges
• Vaccines for unmet needs
• Emerging viruses• Improving
licensed vaccines
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Traditional Approaches
• Licensed vaccines/antibiotics• Passive surveillance• Contact tracing• Quarantine
New Technologies are Transforming Vaccinology
• Structure-based vaccine design
• Single-cell sorting, sequencing, and bioinformatics
– Rapid isolation of human mAbs
– Definition of antibody lineages
– Analysis of immune responses
• Protein engineering of self-assembling nanoparticles
• Rapid DNA synthesis
• Recombinant DNA and genetic engineering technology
– Rapid cell line development
– Animal model development
• Nucleic acid and vector-based delivery of vaccine antigen
Structural analysis of antigenic sites on viral surface glycoproteins
Isolation of human monoclonal antibodies from single B cells
Sequencing B cells to define clonal lineages; TCR & BCR-specific transcriptome
Sequencing for viral diversity and escape mutations
Epitope-specific phenotyping
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New Technologies Facilitate an Engineering Approach
New Technologies
• Structural biology• Protein engineering• Single cell sorting and analysis• High throughput sequencing• Rapid isolation of human mAbs• Antibody lineage analysis• Rapid diagnostic tools• Systems biology
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Vaccine Challenges
• Vaccines for unmet needs
• Emerging viruses• Improving
licensed vaccines
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Synthetic Vaccinology
…ATGCGACT…Historical knowledge about virus
biology and structure. Understanding antigenic targets
and basis for immunity
Design and SynthesisSurveillance and Discovery
Digital transfer of information
Isolation of virus and extraction and sequencing of genome
Synthesis of key genes encoding vaccine antigens and other reagents
Virus‐infected person from new outbreak
Gene Synthesis and Platform Technologies
Graham & Sullivan. Nature Immunology 20187
Graham, Mascola, Fauci. Novel Vaccine Technologies: Essential Components of an Adequate Response to Emerging Viral Diseases JAMA 2018
Platform Technologies Shorten Manufacturing Timelines
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100 days → ~50 days
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Structure-guided Stabilization of HKU1 CoV Spike
V1060PL1061P
MERS S‐2P ‐ V1060P & L1061P
2-P Mutation Stabilizes MERS and SARS CoV S
Pallesen, J., Wang, N., Corbett, K., … Graham BS, Ward A, McLellan et. al. PNAS 2017
Improved expression, prefusion structure, immunogenicity
Postfusion SPrefusion S
MERS S‐2P stabilizes prefusion trimers by EM
50‐fold greater expression than WT
2P mutations effectively stabilize multiple CoV prefusion S
Pallesen, J.*, Wang, N.*, Corbett, K.*, et. al. PNAS. 2017.
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2P mutations effectively stabilize multiple CoV prefusion S
EM Reconstruction by Robert Kirchdoerfer (Ward lab | Scripps)
Endemic Human CoVs Porcine CoV Potentially
Emerging CoV
Immunogenicity of MERS S-2P in Mice
Pallesen, J., Wang, N., Corbett, K., et. al. PNAS 2017 | EM by Yaroslav Tsybovsky 17
Stabilized MERS Spike-2P Protects hDPP4 Knock-in Mice from Lethal Challenge
Adam Cockrell, Ralph Baric, Kizzmekia Corbett 18
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MERS S-2P mRNA elicits better neutralizing antibodies than MERS S-WT mRNA
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Dose Titration MERS S-2P vs. MERS S WT mRNA
S WT
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Immunonogen Group
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Dr. Kizzmekia Corbett in collaboration with Moderna Therapeutics
Summary
• S from multiple CoV strains can be stabilized in the prefusion conformation using homologous 2P mutations
• Stabilized prefusion S trimers are more immunogenic and protective than WT trimers or monomeric subunits
• May be a general solution for beta‐CoV vaccine antigen design
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CORONAVIRUS BIOLOGY AND NOMENCLATURE
Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo‐EM structure of the 2019‐nCoV spike in the prefusion conformation. Science. 2020 Feb 19:eabb2507. doi: 10.1126/science.abb2507.
corona = crown or circle of light
Spike Protein
Cells in Human BodyCoronavirus
Vaccine Target: Coronavirus Spike Protein• Coronavirus spike protein is on the viral surface and mediates attachment to cells to start the infection process• Ideal vaccines target coronavirus spikes in order to block viral infection
Spike Protein
Cells in Human Body
Human ACE2 Receptor
Vaccine Target: Coronavirus Spike Protein• Coronavirus spike protein attaches to ACE2 protein to start infection
Cells in Human BodyCoronavirus Cells in Human Body
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Cells in Human Body
Vaccine Target: Coronavirus Spike Protein• Vaccine‐induced antibodies will block the interaction and function of CoV spike protein
Coronavirus Cells in Human Body
Antibodies
Jan 10, 2020
2019-nCoV sequences published
Spike structure
published in Science
Feb 19, 2020
Feb 20, 2020
DMID submits IND
Modernaships vaccine
to DMID
Feb 21, 20202013-2019
Extensive work on MERS and
other CoV
DMID initiates
clinical and regulatory process
Jan 23, 2020
Modernareceives
sequence for GMP production
Jan 14, 2020
UT-Austin solves spike
structure
Feb 10, 2020Jan 6, 2020
Wuhan outbreak may
be CoV
COVID-19 VACCINE DEVELOPMENT2013-2019 2020
1st report of respiratory virus
outbreak in Wuhan, China
Dec 31, 2019
2021
Jan 13, 2020
VRC decides on vaccine sequence
with Moderna
2019-nCoVconstructs
ordered
Jan 11, 2020
First nCoVspike ELISA
for cross-reactivity
Feb 1, 2020
Modernavials vaccine
Feb 7, 2020
VRC makes nCoV spike
protein
Jan 31, 2020
VRC vaccinates
mice
Feb 4, 2020
Immunogenicity confirmed in
mice
Feb 18, 2020 Mar 2, 2020
FDA safe-to-proceed
Phase 1 Clinical trial Starts
March 16, 2020
SARS-CoV-2 Outbreak
90 days 100 daysPrevious fastest timelineZIKV DNA vaccine
24 days3 days 38 days
COVID-19 Vaccine Consortium
COVID‐19 Vaccine
Development
NIAID OD:
USG organization
Communications
Diplomatic Relations
NIAID VRC
Vaccine design
Assay development
Preclinical evaluation
Human immunology
Pathogenesis NIAID DMID:
IND
VTEU clinical trial sites
Advanced development
NIAID DIR
RML animal NHP model
CDC
Virus isolation
Diagnostics
Sample sharing
US Dept of State
NIAID office of Global Affairs
Negotiations with WHO and China
DOD WRAIR:
Prior MERS study and collaborators
FDA CBER:
Regulatory oversight and adviceBARDA/ASPR:
Development support, USG organizational leadership
Moderna
GMP mRNA
Abcellera
mAb discovery
CEPI
Funding
WHO
Multiple Advisory and WG committees and
coordination
UNC:
Molecular clone and mouse model
UT Austin
Spike structure
UW IPD
Nanoparticle display
Vanderbilt
Live virus PRNT
Government
IndustryNon‐profitPublic health organizationsAcademia
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Structure of Prefusion RSV F Glycoprotein
PostfusionPrefusion
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Generalized Application to Other Fusion Proteins
Graham, Gilman, McLellan, Annual Review of Medicine 2019
• New technologies are transforming vaccinology providing solutions for long-standing problems and emerging viral diseases
• Combining atomic level antigen design with computationally designed nanoparticles and platform manufacturing approaches provides a modular, engineering approach to achieve generalizable solutions for vaccine antigen design
• The advent of precision vaccinology with rapid platform manufacturing makes a prototype pathogen approach for pandemic preparedness feasible
Summary
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NIAID Vaccine Research Center
NIAID Anthony Fauci Hilary MarstonCristina CassettiAudray HarrisTheodore Pierson
VPLTracy Ruckwardt Masaru KanekiyoKaitlyn Morabito Michelle CrankKizzmekia Corbett Seyhan Boyoglu‐BarnumLauren Chang Rebecca GillespieEmily Phung Adrian CreangaMan Chen Syed MoinDeepika Nair Julia LederhoferOlubukola Abiona Geoffrey HutchinsonAzad Kumar Brian FisherAlex Derrien‐Coleman Cynthia ZiwawoAnthony Dipiazza Osnat RosenRebecca Loomis Karin BokErez Bar Haim Saavan ChintalacheruvuMonique Young LaTanya Chapman
VRCJohn Mascola Mario Roederer Richard Koup Daniel DouekSarah Andrews Robert SederPeter Kwong Nancy SullivanJeffrey Boyington Judy Stein/Will AdamsAbe Mittelman Marybeth Daucher
Julie Ledgerwood & Clinical Trial ProgramAdrian McDermott & Vaccine Immunology ProgramDiane Scorpio & Animal Care ProgramJason Gall & Vaccine Production Program David Lindsay& Vaccine Clinical Material ProgramKevin Carlton & Project Management
Viral Pathogenesis Laboratory
Neil KingDavid BakerDaniel EllisBrooke FialaGeorge UedaJorge FallasRashmi RavichandranLauren Carter
VRC Immunology CoresKathy FouldsAmy NoeDillon FlebbeNadesh NjiShing-Fen KaoValerie FiccaMadhu PrabhakaranJoshua BrandDavid Ambrozak
Strategic Planning & DevelopmentJason GallJudith SteinWill Adams Kevin CarltonMythreyi Shastri
Funding:DB, NPK
Yaroslav TsybovskyTyler Stephens
Acknowledgements
UT AustinJason McLellanMorgan GilmanNianshuang WangMike BattlesDaniel Wrapp
UNCRalph BaricAdam Cockrell
ScrippsAndrew WardJesper PallesenRobert KirchdoerferChristopher CottrellHannah Turner
VanderbiltMark DenisonJim Chappel
NIAID VRC Clinical Trials Program
Nina BerkowitzTeam Lead, Protocol Operations
IngeliseGordonClinical Operations Manager
Sarah PlummerChief, Clinical Development Unit
Martin GaudinskiMedical Director
Grace ChenDeputy Chief
Charla AndrewsPreeti ApteAlison BeckEugeania BurchMaria Burgos FlorezCristina CarterEmily CoatesPam CostnerJosephine CoxJennifer Cunningham
Aba EshunCarmencita GravesMercy GuechCynthia Starr HendelSomia HickmanRenunda HicksLaSonji HolmanKate HouserRebecca LampleyBrenda Larkin
Lam LeFloreliz MendozaLaura NovikMark O’CallahanAbidemi OlaIris PittmanRo RothwellJamie SaundersEllie SeoSandra Sitar
Stephanie TaylorCora Trelles Cartagena Olga TrofymenkoOlga VasilenkoXiaolin WangWil WhalenAlicia WidgePernell Williams Galina Yamshchikov
Julie LedgerwoodChief, Clinical Trials Program
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