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Covid-19 Vaccine Development: an Example of Prototype Pathogen Preparedness

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Covid-19 Vaccine Development: an Example of Prototype Pathogen Preparedness RAPID (AND PRECISE) COVID-19 VACCINE DEVELOPMENT: AN EXAMPLE OF PROTOTYPE PATHOGEN PREPAREDNESS “Humanity has but three great enemies: fever, 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 Vaccine Research Center, NIAID, NIH Zoonotic and Vector-borne Viral Threats • Hanta virus • Nipah/Hendra • West Nile virus • SARS • Influenza • Chikungunya • Ebola • MERS • Zika • EV-D68 • SARS-CoV-2 Public health burden of re-emerging & emerging viruses Traditional Approaches • Licensed vaccines/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 Gene-based antigen delivery Isolation of human monoclonal HPV antibodies from single B cells Rotavirus 14 Rapid gene synthesis Varicella X Manufacturing Japanese 12 encephalitis 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 Yellow fever Cell Biology Rabies 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 • Antibody 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 Hendra virus, Cedar virus, PIV1–PIV3 Western equine encephalitis virus, Eastern equine encephalitis virus, Venezuelan equine Toga/alpha Rubella, Chikungunya encephalitis virus, Mayaro virus, Ross River virus, Barmah Forest virus, O’nyong’nyong virus, Semliki Forest virus, Getah virus, Sindbis virus Reo Rotavirus New rotaviruses, Banna virus, Nelson Bay orthoreoviruses Orthomyxo Influenza A, B Multiple subtypes of influenza A virus, Dhori virus, Thogoto virus, Bourbon 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 Monkeypox virus Hepadna Hepatitis B Herpes Varicella CMV, EBV, HSV-1, HSV-2, HHV-6, HHV-7, HHV-8 HCV, Zika virus, St. Louis encephalitis virus, West Nile virus, Powassan virus, Omsk hemorrhagic fever virus, Murray Valley encephalitis virus, Rocio encephalitis virus, Kyasanur forest virus, Yellow Fever, TBE, JEV, Flavi Alkhurma virus, Russian spring and summer encephalitis virus, Central European tick-borne Dengue encephalitis virus, Wesselsbron virus, Bussuquara virus, Cacipacore virus, Ilheus virus, Iguape virus, Usutu 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, Bhanja virus, Bunyavirales Dobrava-Belgrade virus, Erve virus, Puumala virus, Seoul virus, Tahyna virus, severe fever with Hanta, Rift Valley Order thrombocytopenia syndrome virus, La Crosse encephalitis virus, Cache Valley virus, Jamestown Canyon virus, snowshoe hare virus, Heartland virus, Oropouche virus, Andes Astro Astrovirus 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, Rift Valley fever, 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 picornaviruses 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 Clinical Trial 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 Paramyxoviridae 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 and Origins Coronavirus MERS-CoV 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
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