Vaccine Development (Lecture + SGS) PDF

Vaccine Development (Lecture + SGS) Rod Russell - Phase 2  Objectives Describe how vaccination works to induce long-term 6477 immunity Describe the advantages and disadvantages of 6478 different vaccine types Compare and contrast the application...

Vaccine Development (Lecture + SGS) Rod Russell - Phase 2  Objectives Describe how vaccination works to induce long-term 6477 immunity Describe the advantages and disadvantages of 6478 different vaccine types Compare and contrast the application and roles for 7100 active immunization, passive immunization, therapeutic vaccines and prophylactic vaccines  The Plan Vaccine Development Lecture (30min) Vaccine Development Exercise (20min) Discussion (30-60min)  The Promise of Vaccines Specific activation of those aspects of immunity associated with protection from infection or protection from disease Immunity against pathogens without infection or without associated sickness Greater safety for all associated with “herd immunity”  Success Stories of Immunology - Vaccines against smallpox and chicken cholera - Global eradication of smallpox as of 1980 being its greatest triumph… - Polio may be the next to be extinguished - Hepatitis B virus vaccine greatly reduced the incidence of Cancer… - COVID-19 vaccines! Why its hard to make useful vaccines… Example: Influenza virus – At any one time, a single virus type is responsible for most cases of influenza – Population develops protective immunity, mostly by Ab responses against viral HA, but also NA – The Flu virus has two strategies of antigenic variation: Antigenic Drift Antigenic Shift  Antigenic Variation Human Flu Animal Flu Every 2-3 years Infrequent, but with pandemic Ab or T cell potential epitopes  Question What kind of antigenic variation is used by SARS-CoV-2? A) Gene-swapping B) Antigenic shift C) Molecular mimicry D) Antigenic drift E) Alternate splicing Types of Vaccines Used Live Attenuated Whole Inactivated Virus-Like Particles Subunit vaccines Live Recombinant Conjugated DNA mRNA?!?!?!?  Remember your Immunology ?!? Killed virus vaccines, recombinant or Live attenuated and live recombinant purified proteins only stimulate class II vaccines provide intracellular infection, presentation to stimulate antibody resulting in class I presentation as well production as class II to stimulate antibody AND cytotoxic T cell immunity 11  So what’s an RNA vaccine ?!?!?!? Pfizer and Moderna “mRNA in a nanoparticle” 12  Live Attenuated Vaccines Virus (oral polio, measles, varicella zoster, flu-mist) or Bacteria (Bacille Calmette-Guérin, oral typhoid) Disadvantage: potential for recovery of virulence by – genetic reversion to wild type or – inappropriate distribution to immunologically challenged populations such as: Inherited immunodeficiency Acquired immunodeficiency from poor nutrition, infection, or conditions arising from therapy Aged individuals  Live Attenuated Vaccines Advantages: – Effective and long lasting (oral polio, smallpox) – Actual infection, replication and spread, i.e. multiple arms of the immune system and memory. – Adjuvants unnecessary, reduces short term side effects – Possibility of alternative routes of administration Flu-mist (intranasal mucosal immunity) Oral polio (sugar cube mucosal immunity) – Only live vaccines effectively deliver antigens to the MHC class I processing and presentation pathway. – Activation of CD8+ T cells allows differentiation into cytotoxic T lymphocytes, generation of potent immune effector mechanism long term-memory Weakening of Viruses to Generate Live- Attenuated Vaccines  Live Recombinant Vaccines Idea: When antibody responses just aren’t enough, place immunogenic parts of the target virus into a different live but harmless virus backbone – Example: canarypox vaccines Advantage: Safer than live attenuated because there’s no chance for reversion AND it stimulates CD8+ killer T cells Disadvantages: – The “immunogenic parts” must be immunogenic enough to prevent infection of the target virus. – How do you test it? – Will it be safe for immunocompromised individuals?  Whole Inactivated Vaccines - Viruses (injected influenza, hepatitis A, injected polio) - Bacteria (older versions of pertussis and typhoid) - Advantages: inclusion of many antigenic determinants increases the likelihood of broad immunogenicity in population - Disadvantages: - potential for small amounts of exotoxin or endotoxin side effects - require adjuvant - require repeated administration - alternative routes of administration possible, but all or most currently delivered by intramuscular injection limits activation of mucosal immunity  Virus-Like Particles Human Papilloma Virus (HPV) Recombinant HPV L1 capsid protein expressed in yeast self assembles into particles - No nucleic acid, so no infection, but assembly into VLP creates authentic antigenic structures and antigen processing similar to genuine viral infection - Requires adjuvant, multiple inoculations and boosting, but humoral immunity greater than that arising through natural infection and clearance  Subunit Vaccines Representative component of pathogen that is important target of immune response. eg. Hepatitis B virus surface antigen Prepared by chemical synthesis, purification or recombinant gene expression. Need for immunogenicity at broad population level precludes simple peptides. Requires adjuvant, series of injections and boosting. Safe, but relatively weak. Toxoids are chemically inactivated subunit vaccines.  So what’s an RNA vaccine ?!?!?!? Pfizer/BioNT Moderna “mRNA in a nanoparticle”…??? Nanoparticles Hossen, JAR, 2019  Nanoparticles as Therapies (28 currently in the clinic) Doxil – Anti-cancer drug (doxorubicin encapsulated in a liposome) – Used to treat Kaposi’s Sarcoma, breat cancer, ovarian cancer, other solid tumors – Less side effects than the drug itself Abrazane – Nanoparticle formulation of Paclitaxel – Albumin-bound instead of lipid-based – Used to treat metastatic breast cancer, non-small cell lung cancer, pancreatic cancer, ovarian cancer  COVID-19 Vaccine Pipeline PIII CT Vaccine Type Doses Storage Impact of Variants Efficacy Pfizer-BioNTech mRNA LNP 2 -80 95% Beta 60% Moderna mRNA LNP 2 -20 95% Beta 6X drop in NtAb AstraZeneca/Oxfor Beta Nt'ion substantially Chimp Adeno5 2 -20 62% d less 66% (85 J & J (Janssen) Human Adeno26 1 4 Gamma 66% ; Beta 57% severe) Novavax (Perhaps Protein SU 2 4 89% Beta 50% next in CA) https://www.cdc.gov/flu/vaccines -work/effectiveness-studies.htm 23  The Bivalent Vaccines Moderna Pfizer-BioNTech Original Wuhan sequence Original Wuhan sequence Omicron BA.1 sequence Omicron BA.4/BA.5 sequence Waiting to see how effective these will be Will likely need to be updated again soon Keeping some of the original sequence actually helps in case an older variant re-emerges  The Immune Response Antibody Levels Waning of immunity is normal and expected 25 Source: Kuby  The Two Phases of the Immune Response After double (or triple/boosted) vaccination: 1. Antibodies in the blood can prevent actual infection if they are high enough. - Probably for 2-3 months post-vaccination 2. Memory B and T cells eliminate the virus after it has established infection. - For years post-vaccination 26  The “Vaccinated Elderly/frail Vulnerable” We still need to watch this group closely If cases rise in this group they could be in trouble Immunocompromised due to genetics People battling or recovering from cancer Anyone on treatment for autoimmunity, for example, could have a dampened immune response to the vaccine and/or the virus Recent data showed that only 40% of Canadians over 60 have had COVID.  Are Vaccines Failing? DEFINITELY NOT. Do they prevent SARS-CoV-2 infection? The vaccines are not great at preventing actual virus infection. Do they prevent severe disease? They are excellent at preventing severe disease. 28  Are Vaccines Failing? DEFINITELY NOT. Canada Omicron ~5X https://gisanddata.maps.arcgis.com/apps/dashboards/bda7594740fd40299423467b48e9ecf6 Can we talk about herd immunity yet? - Depends on your end goal… - Will now include significant contribution from both vaccines and natural infection 30  Burning Questions about COVID-19 Vaccines (Feb/2021) – Will they work in the real world? – Can you mix and match them? – Can we delay the second dose? – Will they work against the various variants? – Will there be immune escape? – Will we need a different one(s) each year? Exercise: Design a COVID-19 Vaccine Groups A - Live Attenuated Groups B - Live Recombinant Groups C - Whole Inactivated Groups D - Virus-Like Particles Groups E - Subunit Vaccines Groups F - mRNA Vaccine 1. How would you design and produce it? 2. How would you test it? 3. What kind of an immune response would it elicit? 4. What safety concerns would you have about it?