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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

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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

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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

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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

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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

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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

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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

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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)

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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

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WHO / Cochrane Collaboration Ongoing COVID-19 Trials

Published COVID-19 Trials Global COVID-19 Vaccine Trials

US and Partners Trials Trial Registrations by Week Global / US

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Research Phase Vaccine Type

Global U. S. Global U.S.

Type of Subjects Type of Trial and Subject Age

Global U.S.

WHO Efficacy Endpoints

1. Symptomatic cases (PCR /NAAT confirmed) 2. Infection (compared to placebo group) 3. Hospital admissions (severe and non- severe) 4. Emergency room visits 5. Disease (severe and non-severe) Part 2. COVID-19 Vaccine Regulatory Landscape 6. Deaths 7. Seroconversion rates POST-MARKETING 8. Antibody quantification SURVEILLANCE 9. Booster dose – immunogenicity and safety

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Vaccine Adverse Events Reporting Federal Surveillance System System

Wisconsin Hospitalized Searching VAERS Example

Wisconsin Hospitalized Results Example

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Safety and Effectiveness VAERS Record Example Concerns

Effectiveness Safety n Choice of efficacy/effectiveness measures? n General concerns n What level of protection is acceptable? n Measurement during clinical trials and n How long do antibodies need to last? afterwards? n Effect of natural vs vaccine immunity? n Signal detection? n Breakthrough infections in fully vaccinated? n Evidence for subject types excluded n Vaccination of those with natural immunity? from clinical trials? n Evidence for subject types excluded from n Nucleic acid vaccine concerns? clinical trials? n Vaccine-enhanced disease? n Immune escape concerns?

FDA Surveillance Safety Signal Detection

n The inability to detect potential harms is remarkable. • Phase 3 trials of 30,000 will not be able to detect serious adverse events at rates < 1/10,000. • Vaccinate entire US population, SAE at 1/10,000 = 33,000 injured persons • 1976 swine flu vaccine – Guillian Barre Syndrome rate was 1/100,000

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Vaccine Enhanced Disease Vaccine Enhanced Disease n Vaccine-mediated disease enhancement n Type 2 - Vaccine-associated is characterized by a vaccine that enhanced respiratory disease results in increased disease severity if (VAERD) the subject is later infected by the natural virus. • Antibody immune enhancement n Complement activation, inflammatory n Type 1 - Antibody-dependent enhancement (ADE) cytokines n Need high quality neutralizing antibodies n Binding Ab > Neutralizing Ab • Th2-biased immune response n Fc receptor on cell binds Ab attached to n Allergic inflammation, Th2 cytokines virus and helps virus to enter cell n Need to ensure that Th1 response > Th2 response

Vaccine Enhanced Disease n Prior Experience • Measles vaccine • Respiratory Syncytial Virus vaccine, human n 1968, infected after vaccination, 16/20 (80%) hospitalized, 2/20 (10%) death • SARS-CoV1 vaccine, animal n 9 studies – mouse, ferret, non-human primate Part 2. COVID-19 Vaccine Regulatory Landscape • Dengue vaccine, human CURRENT AND EMERGING n 2018, infected after vaccination, no Ab, more likely to be hospitalized (RR>1.75) and have severe dengue (RR>2.62) COVID-19 VACCINE CONCERNS

Variants Variants of Concern

n Affects transmission, infectivity, severity of disease, potential to evade natural and vaccine associated antibodies n Escape Mutation E484K • B.1.1.7, UK variant • P.1, Brazil • B.1.351, South African variant n Moderna - modified vaccine trial underway n Pfizer/BioNTech – third dose

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Concerns Concerns, cont. n Duration and quality of natural v vaccine n Informed consent challenges due to clinical immunity trial subject exclusions and ability to n Loss of clinical trial control groups consent n Changes to RT-PCR testing standards and n Access to relevant information under EUA vs effect on monitoring effectiveness full licensure n Emergence of variants n Compensation for injuries and liability under Countermeasures Injury Compensation n Vaccine cross-reactivity Program (CICP) vs NVICP n Modification of vaccine antigens n State and employer mandates n Need for booster shots, annually? n Immunity passports for travel and indoor n Introduction of new aborted fetal cell lines venues

Concerns, cont. Conclusions n Will vaccine-resistant variants become a problem so vaccines have to be redesigned? n Will additional doses of the existing vaccines work against the variants? n What role will under-vaccinated people play? n Will immunosuppressed patients become sources of resistant variants?

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