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RAPID (AND PRECISE) COVID-19 DEVELOPMENT: AN EXAMPLE OF PROTOTYPE PATHOGEN PREPAREDNESS

“Humanity has but three great enemies: , famine, and war; of these by far the greatest, by far the most terrible, is fever.”

Sir William Osler, M.D.

21st Annual Well Characterized Biological Products (WCBP) Conference January 25, 2021

Barney S. Graham, MD, PhD Deputy Director , NIAID, NIH Zoonotic and -borne Viral Threats

• Hanta • Nipah/Hendra • • SARS • Influenza • • • MERS • Zika • EV-D68 • SARS-CoV-2 Public health burden of re-emerging & emerging

Traditional Approaches

• Licensed /antibiotics Vaccine • Passive surveillance Challenges • Contact tracing • Quarantine • Vaccines for unmet needs • Emerging viruses • Improving licensed vaccines

3 Technology Advances Make New Vaccines Possible

Viral Vaccines Major Conceptual and Technological Advances Structural analysis of Cell Molecular New technical antigenic sites on viral Discovery of immunity culture biology advances surface glycoproteins RSV? Structural biology SARS-CoV-216 -based antigen delivery Isolation of human monoclonal HPV from single B cells 14 Rapid gene synthesis Varicella X Manufacturing Japanese 12 Human mAb isolation Hepatitis A 10 High throughput Hepatitis B sequencing Rubella Single cell analysis 8 Mumps including B cell lineages Adenovirus Nanoparticle display Epitope-specific phenotyping Measles 6 Poliovirus Custom animal models Sequencing for viral diversity and escape mutations Influenza 4 …omics & glycobiology Cell Biology 2 Smallpox Imaging 0

1800 1820 1840 1860 1880 1900 1920 1940 1960 1980 2000 2020 2040 2060 2080 Sequencing B cells to define clonal lineages; TCR & BCR-specific transcriptome

4 New Technologies Facilitate an Engineering Approach

Vaccine New Challenges Technologies

• Vaccines for • Structural biology unmet needs • Protein engineering • Emerging viruses • Single cell sorting and analysis • Improving • High throughput sequencing licensed vaccines • Rapid isolation of human mAbs • lineage analysis • Rapid diagnostic tools • Systems biology • Gene-based delivery • Rapid gene synthesis • Platform manufacturing 5 New Technologies are Transforming Vaccinology

• Structure-based vaccine design Structural analysis of antigenic sites on viral • Single-cell sorting, sequencing, and bioinformatics surface glycoproteins – Rapid isolation of human mAbs Isolation of human monoclonal – Definition of antibody lineages antibodies from single B cells – Analysis of immune responses • Protein engineering of self-assembling nanoparticles • Rapid DNA synthesis

• Recombinant DNA and genetic engineering technology Epitope-specific phenotyping

– Rapid cell line development Sequencing for viral diversity and escape mutations – Animal model development • Nucleic acid and vector-based delivery of vaccine antigen

Sequencing B cells to define clonal lineages; TCR & BCR-specific transcriptome 6 Viral Families that Infect Humans (with licensed vaccine)

Family Prototype(s) Other Viruses of Concern Paramyxo Measles, Mumps , Cedar virus, PIV1–PIV3

Western equine encephalitis virus, Eastern equine encephalitis virus, Venezuelan equine Toga/alpha Rubella, Chikungunya encephalitis virus, Mayaro virus, virus, , O’nyong’nyong virus, , Getah virus,

Reo Rotavirus New , , Nelson Bay orthoreoviruses Orthomyxo Influenza A, B Multiple subtypes of influenza A virus, , Thogoto virus, Adeno Adenovirus 4, 7 Adenovirus 14 or 81 or other serotypes Rhabdo Rabies VSV Picorna Polio 1,2,3, Hepatitis A EV71, EV-D68, rhinoviruses, Ljungan virus Papilloma HPV 6, 11, 16, 18 Other HPV serotypes Pox Variola virus Hepadna Hepatitis B Herpes Varicella CMV, EBV, HSV-1, HSV-2, HHV-6, HHV-7, HHV-8 HCV, , St. Louis encephalitis virus, West Nile virus, , virus, Murray Valley encephalitis virus, Rocio encephalitis virus, Kyasanur forest virus, Yellow Fever, TBE, JEV, Flavi , Russian spring and summer encephalitis virus, Central European -borne Dengue encephalitis virus, Wesselsbron virus, Bussuquara virus, Cacipacore virus, Ilheus virus, Iguape virus, Hepe Hepatitis E Graham & Sullivan. Nature Immunology 2018 Viral Families that Infect Humans (no licensed vaccine)

Family Prototype(s) Other Viruses of Concern

Pneumo RSV, MPV

Filo Ebola, Marburg

Retro HIV-1 HTLV-1

Corona SARS, MERS SARS-like viruses in bats

Parvo B19, Bocavirus

Calici Norovirus

Polyoma JC, BK SV40, Merkel cell virus

Junin virus, Guanarito virus, Chapare virus, Sabia virus, Flexal virus, lymphocytic choriomeningitis virus, Arena Lassa, Machupo Lujo virus

Crimean Congo hemorrhagic fever virus, California encephalitis virus, Batai virus, , Dobrava-Belgrade virus, Erve virus, Puumala virus, Seoul virus, Tahyna virus, severe fever with Hanta, Rift Valley Order syndrome virus, virus, Cache Valley virus, Jamestown Canyon virus, snowshoe hare virus, Heartland virus, Oropouche virus, Andes

Astro

Arteri Simian hemorrhagic fever virus (Not yet reported to infect humans)

Graham & Sullivan. Nature Immunology 2018 Defining and prioritizing the tasks

~120 known viruses known to infect humans with potential for increasing human-to-human transmission and virulence ~30 distinct viral families and subfamilies known to infect humans

12 virus families without a representative vaccine WHO priorities – Lassa, Nipah, MERS/SARS CoV, , Crimean Congo Hemorrhagic fever, Zika, Ebola and Marburg, Pathogen X CEPI priorities – Lassa, Nipah, MERS-CoV Pandemic Preparedness Scientific Organization

Class I Paramyxo Core Functions Class II Pneumo Core functions: Intramural Sequencing/synthesis Toga/Alpha Corona programs and extramural Protein production Flavi/hepatitis C Astro Structure/Antigen design Bunyavirales order contracts connected to Arena Antigen display/delivery intramural and extramural Retro Animal modeling Orthomyxo basic research laboratories Pathogenesis and organ- Filo specific immunology B cell biology/serology Viral Research Groups: T cell biology/flow cytometry Organized by viral fusion Single cell analysis Non-enveloped protein type; combined Class III and others Computational biology Picorna (EV-D68) resources of intramural and Herpes Bioinformatics Polyoma extramural investigators Pox Process development Papilloma Rhabdo Pilot manufacturing Calici Hepadna Phase I clinical trials Adeno (Arterivirus) Parvo Reo Hepe NIAID Vaccine Research Center

Basic Research Process Development Nucleic acid

Vectors

VLPs

• AIDS/HIV • Influenza Proteins and cGMP Manufacturing nanoparticles • Ebola/Marburg • RSV • Malaria Monoclonal antibodies • Tuberculosis • EID GLP Analysis • 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 Clinical Trials • Smallpox AS Fauci/NIAID

Vaccine Development Strategies for Pandemic Preparedness

• Platform Novel Vaccine Technologies Essential Components of an Adequate Response • Plug-and-play to Emerging Viral Diseases BS Graham, JR Mascola, AS Fauci • Priority-pathogen • Selected pathogens of concern • Prototype-pathogen • Systematic preparedness • All virus families of concern Structure of Prefusion RSV F Glycoprotein

Prefusion Postfusion

15 Preserving Apical Epitopes Improves Immunogenicity

~2-fold ~14-fold

Host Cell Post-F Vaccine Pre-F Vaccine Clinical Trial (Hum Vacc & Immuno June 2019) (Science August 2019)

Virus Class I Fusion Glycoproteins

• Functional homology • Distinct shapes and topography • Shared motifs and domains

Graham, Gilman, McLellan, Annual Review of Medicine 2019 17 Phylogenetic Tree Paramyxovirus Surface Proteins

Fusion Protein (F) Attachment Protein (G/HN/H) • Mediates viral entry • Viral tropism and host restriction • Trimeric type 1 transmembrane • Tetrameric structure – dimer of dimers • Transition from pre-F to post-F • Type 2 TM and may be shed

“stalk”

Post-F Pre-F

Chang A., et al. Viruses. 2012. Stabilizing Paramyxovirus Pre-F Preserves NT- sensitive Epitopes and Improves Protein Expression

S191P Measles L172F

Proline (Pro) Cavity-filling (Cav)

L104C

I114C 488 Disulfide (DS) GCN4 (TD)

Pre-F Hexameric G Pre-F/G Nipah Pre-F Mumps G head

TD

TD G3 G1

G2

Pre-F TD G TD G Pre-F TD G

Guillaume Stewart-Jones, Rebecca Loomis et al. Frontiers Immunology 2020 Jun 11;11:842. doi: 10.3389/fimmu.2020.00842. 20

Coronavirus Origins and Phylogeny

CoV

- MERS Structure-guided Stabilization of HKU1 CoV Spike

2017

2016

PP Stabilized CoV Spike Protein Improve Expression

Pallesen, J.*, Wang, N.*, Corbett, K.*, et. al. PNAS. 2017. 2P mutations effectively stabilize multiple CoV prefusion S

Potentially Endemic Human CoVs Porcine CoV Emerging CoV

EM ReconstructionPallesen, J.*, Wang, by Robert N.*, KirchdoerferCorbett, K.*, (Wardet. al. PNAS.lab | Scripps) 2017. MERS S-2P protects against mouse-adapted MERS CoV challenge in hDPP4 transgenic mice

Week 0 1 2 3 4 5 6 7

25

Deadliest Pandemics in History

COVID-19 caused by SARS-CoV-2 declared a pandemic by WHO on March 11, 2020

>2.1M

Week of Jan 18, 2021 (Ongoing)

SARS-CoV-2 Identified as cause of COVID-19

80 nm

Camille Ehre. NEJM 2020; 383:969 Global COVID-19 Vaccine Landscape

64 Vaccine Candidates in Clinical 173 Vaccine Candidates Evaluation (11 Phase 3 registered) in Pre-clinical Evaluation

Nucleic acid Nanoparticle display of * structurally defined proteins Whole-inactivated virus * Live-attenuated virus * Recombinant Vectors Recombinant Vectors Recombinant or chimeric viruses Recombinant or chimeric Virus-like particles viruses

Recombinant proteins Recombinant proteins * or subdomains or subdomains Peptides Source: WHO 19 Jan 2021 30 Years of Work Led to Rapid COVID-19 Vaccine Development

They spent 12 years solving a puzzle. It yielded the first COVID-19 vaccines.

Long before anyone knew of SARS-CoV-2, a small band of government and university scientists uncovered a prototypical key that unlocked life-saving immunizations. Readiness for Rapid CoV Countermeasure Development

Pre-existing public-private and academic partnerships Prior responses to PHEIC

Precision vaccinology Platform manufacturing including structure- technologies based vaccine design and protein engineering for RSV and CoV Prototype Pathogen Approach for Pandemic Preparedness and Response

Human discovery RSV vaccine- enhanced disease pathogenesis COVID-19 VACCINE & MAB DEVELOPMENT

2013-2019 2020 SARS-CoV-2 Outbreak

2013-2019 Jan 6, 2020 Jan 31, 2020 Feb 3, 2020 Feb 27, 2020 Apr 20, 2020 Jun 17, 2020 Aug 3, 2020

Abcellera Lilly begins Phase 2 mAb555 Phase 3 Extensive work Wuhan VRC makes UT-Austin begins sorting manufacturing trial begins mAb555 trial on MERS, other outbreak may nCoV spike solves spike (BLAZE-1) begins CoV, and other be CoV protein structure Fusion proteins

Dec 31, 2019 Jan 10, 2020 Feb 1, 2020 Feb 18, 2020 Mar 16, 2020 June 1, 2020 Jul 27, 2020 Sept 16, 2020

1st report of 2019-nCoV First nCoV Immunogenicity Phase 1 clinical Lilly Phase 3 respiratory virus sequences spike ELISA confirmed in Phase 1 trial for mAb555 announces Clinical vaccine outbreak in published for cross- mice Clinical vaccine efficacy trial starts Wuhan, China reactivity trial starts result in BLAZE-1

mRNA-1273 – 6.5 months to phase 3

mAb555 – 5 months to phase 3

33 High Quality Protein is the Beginning for Everything

Therapy Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults

Vaccines * * Diagnostics X * * * Rapid Platform Manufacturing and Precision Antigen Design

General Strategy for Pandemic Response

mRNA Prototype Pathogen Preparedness Structure-based vaccine design Protein engineering Nanoparticle display High throughput sequencing Rapid human mAb isolation Antibody lineage analysis Rapid synthesis of biologicals Gene-based antigen delivery mRNA immunization strategy

Protein expression affected by mRNA chemistry and manufacturing process

Nelson et al. Sci Adv 2020 A Binding Antibodies B Binding Antibodies C Binding Antibodies mRNA-1273 Immunized BALB/c mRNA-1273 Immunized C57BL/6 mRNA-1273 Immunized B6C3

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10 F P 101 101 Safety 100 100 PBS 0.01 0.1 1 PBS 0.01 0.1 1 mRNA-1273 mRNA-1273 Dose (mg) Dose (mg) Nature Aug 6 NEJM July 28 NEJM July 14 NEJM Sept 29 37 Durability of Antibody Response

Widge et al. NEJM 2020 Cumulative Incidence of COVID-19 (mITT)

Baden et al. NEJM 2020 Dec 30; NEJMoa2035389 FDA VRPAC Votes 21-0-1 for EUA Approval

December 17, 2020

December 22, 2020 Vaccinating Frontline Workers

Week of December 27, 2020 Conclusions

• Rapid pandemic response based on: • Prior fundamental basic and translational research • Both precision and speed • Pre-established public-private partnership • mRNA-1273 Phase 3 interim VE~95% • mAb555 therapeutic EUA approved • Prototype pathogen preparedness is feasible

RML Austin Athman Ryan Kissinger Antia Mora

42 COVID-19 Response: A VRC-wide Effort Olubukola Abiona Jason Gall Rosemarie Mason Chaim Schramm Cassandra Almasri Lucio Gama Adrian McDermott Diana Scorpio Gabriela Alvarado Rebecca Gillespie Krisha McKee Robert Seder Obrimpong Amoa-Awua Ingelise Gordon John Misasi Wei Shi David Ambrozak Barney Graham Juan Moliva Erica Smit Charla Andrews Martin Gaudinski Damee Moon Nancy Sullivan Sarah Andrews Christina Harris Ian Moore Phillip Swanson Eli Boritz Christian Hatcher Kaitlyn Morabito Alison Taylor Seyhan Boyoglu-Barnum Ashley Heimann Sandeep Narpala I-Ting Teng Evan Cale Marie Hirsch Richard Nguyen John-Paul Todd Kevin Carlton Geoffrey Hutchinson Nadesh Nji Yaroslav Tsybovsky Lauren Chang Masaru Kanekiyo Amy Noe Lingshu Wang Azad Kumar Laura Novik Anne Werner Adrian Crenaga Peter Kwong Sarah O’Connell Alicia Widge Katie Cunnane Wing-Pui Kong Sijy O’Dell Eun Sung Yang Marybeth Daucher Richard Koup Amarendra Pegu Christina Yap Anthony DiPiazza Evan Lamb Yuliya Petrova Baoshan Zhang Mitzi Donaldson Emily Phung Yi Zhang Daniel Douek Kwanyee Leung Madhu Prabhakaran Tongqing Zhou Naomi Douek Bob C. Lin Amy Ransier Cynthia Ziwawo Britta Flach Catherine Liu Mario Roederer Dylan Flebbe Rebecca Loomis Tracy Ruckwardt Barbara Flynn Lindsay Longobardi Noemia Santana Lima Katherine Foulds Mark Louder Stephen Schmidt Joseph Francica John Mascola Alec Schrager