4/15/21 COVID 19 Vaccines 101: Outline – Hour 1 Vaccine Development and Regulatory Landscape n Part 1 – COVID-19 Vaccine Development Landscape (10:00 – April 17, 2021 11:00 AM) • Human Immune System Basics • Overview and Typology of Vaccines Vicky Pebsworth, PhD, RN • COVID-19 Vaccines Director of Research and Patient Safety • Vaccine Components National Vaccine Information Center Outline – Hour 2 n Part 2- COVID-19 Vaccine Regulatory Landscape (11:00 – 12:00 AM) • Policymaking - Federal Agencies and Advisory Committees, State Legislatures and Departments of Health • Research, Approval and Licensure Part 1. COVID-19 Vaccine Development Landscape Processes • Post-marketing Surveillance HUMAN IMMUNE SYSTEM • Current and Emerging COVID-19 BASICS Vaccine Issues Immune System Basics Innate Immune System n Innate (non-specific) immune system n Three main parts • Primary line of defense • Barrier part • Rapid response n Skin, mucosal and epithelial lining of the n Adaptive (specific, acquired) immune respiratory and gastrointestinal system system • Cells • Secondary line of defense n Mast cells, macrophages, granulocytes, • Slow response (the first exposure) dendritic cells • Specific, recognizes and targets specific • Lymphocytes (not specific to an antigens antigen) • Has memory to attack known antigens n Natural killer(NK) cells, gamma delta cells 1 4/15/21 Adaptive Immune System n Two separate, overlapping arms • Humoral (anti-body mediated) immunity n B lymphocytes/B cells • Antibodies (Ab) n Binding antibody (BAb) n Neutralizing (NAb) • Cellular (cell-mediated) immunity n T lymphocytes / T cells • Helper T cells/ CD4+ (Th1 and Th2) • Killer (cytotoxic) T cells/ CD8+ Infection and Immunity Part 1. COVID-19 Vaccine Development Landscape OVERVIEW AND TYPOLOGY OF VACCINES NIH Vaccine Classification Vaccine Overview Antigen Categories n Goals of vaccination 1. Whole Pathogen Vaccines n Categories by antigen type 2. Subunit Vaccines n Non-antigen vaccine components 3. Nucleic Acid Vaccines 2 4/15/21 Whole Pathogen Vaccines Subunit Vaccines 1. Live, attenuated 1. Component n Acellular pertussis n Measles, mumps, rubella, varicella 2. Polysaccharide (chickenpox), influenza (nasal spray), polio n Haemophilus influenzae type B (oral), smallpox, yellow fever, zoster 3. Conjugate (shingles) n Pneumococcal, meningococcal, Hib 2. Inactivated 4. Toxoid n Hepatitis A (Havrix), influenza, polio n Tetanus, diphtheria (injectable), rabies, whole cell pertussis 5. Recombinant protein n Hepatitis B, influenza 6. Virus-like particles n Human papillomavirus Nucleic Acid Vaccines Nucleic Acid Vaccines n Nucleic acid • DNA • RNA • Recombinant viral vector n Replicating n Non-replicating Nature 580, 576-577, 2020 Viral Vector and Protein Whole Pathogen Vaccines Vaccines 3 4/15/21 Milken Institute Part 1. COVID-19 Vaccine Development Landscape COVID-19 VACCINES New York Times World Health Organization Global Vaccines in Clinical US Operation Warp Speed Trials Type Developer Name Phase Total n 272 (total) = 184 (pre-clinical) + 88 (clinical trials) Whole 0 • Whole Pathogen – 16% Subunit Protein Novavax NVX-CoV2373 3 2 n Live – 2% Protein Sanofi/GSK VAT00002 3 n Inactivated – 14% Nucleic RNA Moderna/NIH mRNA-1273/1283 4 5 • Subunit – 37% n Protein subunit – 32% RNA BioNTech/Pfizer BNT162b2/ 4 n Virus-like particle – 5% Comirnaty • Nucleic Acid – 48% DNA Inovio INO-4800 2/3 n Viral vector – 23% Vector, NR Oxford/AstraZeneca AZD 1222/ 4 Covishield n RNA – 14% Vector, NR Janssen/J&J Ad26.COV2.5 4 n DNA – 11% Vector, R Merck/IAVI PC 4 4/15/21 COVID-19 Vaccine Types Vaccine Approaches n Whole Pathogen Vaccines • Live/attenuated • Inactivated n Subunit Vaccines • Recombinant viral protein • Virus like particles n Nucleic Acid Vaccines • RNA • DNA • Recombinant viral vector (replicating, non- replicating) US Funded COVID-19 Vaccines Pfizer/BioNTech n EUA n RNA: 3 LNP-mRNA (BNT162b) • Moderna n Emergency Use 12/11/20 • BioNTech/Pfizer n US, Canada, UK, Argentina, Mexico, • Janssen/J&J Saudi Arabia, Bahrain, European n Non-EUA/Phase 3 or 2/3 Commission • AstraZeneca/Oxford n Pediatric trials, 12-15, 11 to 6 mos. • Novavax • Sanofi Pasteur Moderna/NIAID Janssen/Johnson & Johnson n RNA: LNP-encapsulated mRNA n Non-Replicating Viral (mRNA-1273) Vector:Ad26.COV2-2 n Emergency Use 12/18/20 n Emergency Use 2/27/21 (US only) n US, Canada, Israel, Switzerland, EU, n Single dose UK n Trials expanded to 12-17 y/o n Pediatric trials, 12-18, <12 n Modified vaccine – mRNA 1283 – trial 3/15/21 5 4/15/21 Univ of Oxford/AstraZeneca Novavax/Emergent Biosolutions n Non-Replicating Viral Vector: AZD n Subunit:Recombinant Adjuvanted 1222 (ChAdOx1) Glycoprotein: NVX-CoV2373 n Not authorized in US n Phase 3 n Used in UK, Argentina, Brazil, n Potential for EUA May 2021 Dominican Republic, El Salvador, India, Mexico, Morocco, Pakistan Sanofi Pasteur/GSK n Subunit: Recombinant Protein, Baculovirus n Phase 2 n Potential for EUA late fall 2021 Part 1. COVID-19 Vaccine Development Landscape VACCINE COMPONENTS Vaccine Excipients Preservatives Non-antigen Components n Preservatives n Benzethonium chloride n Adjuvants n EDTA n Inactivating chemicals n Formaldehyde n Cell and growth culture materials, nutrients n Phenol n Antimicrobials n Thimerosal n Stabilizers, buffers, protein purifiers n 2-Phenoxyethanol n Surfactants n Other 6 4/15/21 Adjuvants Inactivating Chemicals n Aluminum - Amorphous aluminum n Formaldehyde hydroxyphosphate sulfate, aluminum n Glutaraldehyde hydroxide, aluminum phosphate, potassium aluminum sulfate (alum) n Beta-propiolactone n AS04 - Monophosphoryl lipid A (MPL) + aluminum salt n AS01 - MPL + QS-21 (soap bark) n MF59 – squalene n CpG 1018 – synthetic DNA Cell and Growth Cultures Medium Nutrients n Cell cultures and manufacturing n Medium nutrients residue • Amino acids, casein and extract (cow), • Aborted fetal cell strain – MRC-5, WI-38, calcium chloride, carbohydrates, • Animal - Vero cells – African green dextrose, dimethyl-beta-cyclodexrin, monkey kidney cells DMEM, ferric nitrate, galactose, glutamate, histidine, hydrocortisone, L- n Residual mediums cystine, L-histadine, L-tyrosine, • Albumin (egg), chick embryo lactalbumin hydrolysate, magnesium • DNA – human, porcine, insect, sulfate, peptone (soy),salts, sodium pyruvate, vitamins, yeast Antimicrobials Stabilizers n Antibiotics n Stabilizers • Amphotericin B, Chlortetracycline, • 2-phenoxyethanol, albumin (human, Gentamicin sulfate, Kanamycin, bovine, bovine serum, calf serum, calf Neomycin, Neomycin sulfate, Polymyxin, serum protein, fetal bovine serum), Polymyxin B, Polymyxin B sulfate, bovine extract, bovine casamino acid, Streptomycin gelatin (hydrolyzed and porcine hydrolyzed), lactose, monosodium n Phenol glutamate, monosodium l-glutamate, n Thimerosal potassium glutamate, sodium borate, sodium metabisulphite, succinate buffer, sucrose, sorbitol 7 4/15/21 Buffers Protein Purifiers n Calcium carbonate n Ammonium sulfate n Phosphates – monobasic potassium, n Chick fibroblasts monobasic sodium, diabasic sodium, n CTAB potassium dihydrogen, unspecified n Hexadecyltrimethylammonium n Potassium chloride bromide, n Sodium bicarbonate n Protamine sulfate n Sodium Borate n Sodium taurodeoxycholate n Vitamins Surfactants Other excipients n Polysorbate 20 n Latex n Gelatin n Polysorbate 80 n Xanthum (thickening agent) n Nonylphenol ethoxylate n Mineral salts (tone adjuster) n Octoxynol-10 (Tritan X-100) n Ascorbic acid (antioxidant) n Magnesium stearate (lubricant) n Octylphenol ethoxylate n Unspecified function – barium, citric n Sodium deoxycholate acid monohydrate, sodium citrate dihydrate, sorbitan trioleate, sodium hydroxide Aborted Fetal Cell Strains Aborted Fetal Cell Strains Non-COVID-19 Vaccines COVID-19 Vaccines n Human DNA and cell protein n HEK293 cells – kidney cells, female • MRC-5 – lung fibroblast, 14 week old male fetus • WI-38 – lung fibroblast, 12 week old female • Viral Vector n Vaccines n University of Oxford/AstraZeneca (UK/USA) • Hepatitis A (Hepatitis A and B formulas) • mRNA • Chickenpox (varicella) n ? • Rubella (included in MMR and MMRV) • Zoster n PER.C6 – retinal cells, 18 w fetus • Adenovirus • Viral Vector • Rabies n Janssen/ J&J (USA) 8 4/15/21 COVID-19 Vaccine Ingredients n Polyethylene glycol (PEG2000) n Matrix M – saponin (Chilean soapbark) n HEK293 cells n PER.C6 cells Part 2. COVID-19 Vaccine Regulatory Landscape n sf9 insect cells POLICYMAKING – FEDERAL AGENCIES AND ADVISORY COMMITTEES, STATE LEGISLATURES AND DEPARTMENTS OF HEALTH Federal Vaccine Advisory Vaccine Policymaking Committees n HHS – National Vaccine Program n Federal recommendations • NVAC (National Vaccine Advisory Committee) n FDA – Center for Biologics Evaluation and n State laws Research • Vaccine mandates/exemptions • VRBPAC (Vaccines and Related Biologic Products Advisory Committee) n Three exemption types n CDC – Immunization Services Division • NVIC Advocacy Portal • ACIP (Advisory Committee on Immunization (nvicadvocacy.org) Practices) n HRSA – • ACCV (Advisory Commission on Childhood Vaccines) Research and Approval Process n Preclinical – animals, immune response, 6 mo. n Phase I – small, dosing, safety, immune, 6 mo. n Phase II – larger, immune, safety, 1 yr. n Phase III – largest, placebo-controlled, effectiveness, safety, 3+ yrs. Part 2. COVID-19 Vaccine Regulatory Landscape n Approval/Licensure review, VRBPAC, ACIP RESEARCH, APPROVAL AND • Licensure vs EUA n Phase IV – post-marketing surveillance, LICENSURE PROCESSES safety 9 4/15/21 WHO / Cochrane Collaboration Ongoing COVID-19 Trials Published