MICR439 Vaccination 2024 PDF

How Science Works How Google Works Flat Earth Society  What does efficacy mean?  As seen during COVID, the general public (and researchers), view efficacy of a vaccine as meaning that the vaccine will eliminate infection (Sterilizing immunity).  This is not realistic, nor is it the case...

How Science Works How Google Works Flat Earth Society  What does efficacy mean?  As seen during COVID, the general public (and researchers), view efficacy of a vaccine as meaning that the vaccine will eliminate infection (Sterilizing immunity).  This is not realistic, nor is it the case for most of the fully licensed FDA or USDA vaccines.  The FDA and USDA measures a statistical effect of the vaccine, which can include reduction in symptoms, reduction in loss of some production metric, reduction in death, transmission, or viral load, etc.  The goal is usually population immunity to control disease.  Just to be clear…. https://ourworldindata.org/grapher/united-states-rates-of-covid-19-deaths-by-vaccination-status  Prophylactic Vaccines  Protect against disease not infection  One of the best defenses against disease are vaccines  Safe  Adverse reactions vs Disease Preventing Disease Adverse Reaction Vaccination IMMUNE RESPONSES TO INVADING MICROBES  Humoral Immune System B Pl  Cellular Immune System  neutrophils, macrophages  killer cells, natural killer cells  helper T cells  cytotoxic T cells CTL Immune Responses In Vaccinates Copyright © 2014 Elsevier Inc. All rights reserved.  Vaccines- Active vs Passive  Active- person or animal generates their own immune response and produces Ab, T-cell response and memory  E.g. Moderna, Pfizer, J&J Covid Vaccines  Passive- administer preformed mAb or polyclonal antibodies  E.g. Regeneron Cellular Immunity is responsible for Memory  Emerging and re-emerging infectious diseases  Emerging = something new, not previously observed (e.g., HIV)  Re-emerging = something old, coming back again (e.g., TB in the U.S.)  May be the result of globalization and interactions between people and wildlife  Emerging and re-emerging infectious diseases  Some noteworthy new infectious diseases have appeared recently  Ebola (1976)  Legionnaires’ disease (1976)  Severe acute respiratory syndrome (SARS, 2002)  West Nile virus (1999 in U.S.)  Pandemic Influenza (2009)  Middle East respiratory syndrome (MERS, 2012)  Ebola 2014  Zika virus 2015  COVID-19 2019 !  Emerging and re-emerging infectious diseases  Diseases may re-emerge for various reasons  Combinations of diseases (HIV and TB)  Improper antibiotic use (MDR TB, MRSA)  Laxity in vaccination program adherence  Diphtheria reemergence in the former Soviet Union  Whooping cough outbreaks in the United States  Measles outbreaks in the United States Vaccine Design  Efficacy  Most vaccines effective in 80-95% of those immunized.  Vaccines need to contain protective epitopes from protective antigens. Best antigens  Particulate and 20-200 nm- enter lymphatic system and be taken up by APC and interact with B cells  Repetitive in nature  Contain PAMPS- TLR can activate immune system Why There is not a malaria vaccine? Too many targets Copyright © 2014 Elsevier Inc. All rights reserved.  Herd Immunity  A situation in which a sufficient proportion of a population is immune to an infectious disease (through vaccination and/or prior illness) to make its spread from person to person unlikely. Even individuals not vaccinated (such as newborns and those with chronic illnesses) are offered some protection because the disease has little opportunity to spread within the community. Also known as community immunity."  Synonyms: Community Immunity; Coverage  Cocooning- herd immunity within a household  http://www.vaccinestoday.eu/vaccines/what-is-herd- immunity/ Herd Immunity Basic reproduction number R0 = 3 Herd Immunity Thresholds for Selected Vaccine-Preventable Diseases Immunization Levels Disease Ro Herd 1999 Current Immunity 19-35 Pre-School Months Diphtheria 6-7 85%* 83%* 83% Measles 12-18 83-94% 92% 91.5% Mumps 4-7 75-86% 92% 91.5% Polio 5-7 80-86% 90% 92.7% Rubella 6-7 83-85% 92% 91.5% Smallpox 5-7 80-85% __ __ COVID-19 1-6 70%+ __ __ *4 doses † Modified from Epid Rev 1993;15: 265-302, Am J Prev Med 2001; 20 (4S): 88- 153, MMWR 2000; 49 (SS-9); 27-38; https://www.cdc.gov/nchs/fastats/immunize.htm  Safety and Efficacy  Pre-clinical and clinical trials regulated by Food and Drug Administration for Humans  Phase I- small numbers- immunogenicity, dose-response range, optimal route of administration, adverse events  Phase II & III- each larger study to assess efficacy with a challenge- passes approved for use  Phase IV monitor vaccine in the field after licensing-efficacy and side effects  Center for Disease Control-Vaccine Adverse Events Reporting System (VAERS)  Collects sound scientific data on adverse events  Source for accurate information on vaccine safety  Veterinary vaccines are regulated by Center for Veterinary Biologics (CVB) USDA-APHIS  Much easier to get licensed  Also has adverse events collection system  Vaccines – Types and Approaches  ALL vaccines must target the appropriate part of the agent to limit/halt/obliterate infection How does the Immune System Work? Antibody-Based Cellular Immunity Immunity  Antibody Protection Vaccine Targets Y Y Y Y  Types of Vaccines Live Killed Subunit 1 Dose Safe Safe Strong Cellular Response Easy to Make Science-Based Reversion 2 Doses 2 Doses Danger in Some Diversionary Need to know Target Responses  Safety and Efficacy  Pre-clinical and clinical trials regulated by Food and Drug Administration for Humans  Phase I- small numbers- immunogenicity, dose-response range, optimal route of administration, adverse events  Phase II & III- each larger study to assess efficacy with a challenge- passes approved for use  Phase IV monitor vaccine in the field after licensing-efficacy and side effects  Center for Disease Control-Vaccine Adverse Events Reporting System (VAERS)  Collects sound scientific data on adverse events  Source for accurate information on vaccine safety  Veterinary vaccines are regulated by Center for Veterinary Biologics (CVB) USDA-APHIS  Much easier to get licensed  Also has adverse events collection system TRADITIONAL VACCINES Live Heterologous Live – TB, Smallpox Modified/Attenuated Live Killed Grow/Kill Subunit DNA/RNA  MODIFIED-LIVE VACCINES Mutagenize and Attenuate passage in cell culture mutation and/or deletion- recombinant DNA technology Mutation-chemical treatment temperature sensitive- grow at lower temperatures MODIFIED-LIVE VACCINES Advantages Disadvantages u rapid u reversion to virulence u 1 dose usual give u immunosuppressive booster u abortion, tetratogenic-birth u long-lasting defects u no adjuvant u contamination with adventitial agents u less $ u not thermostable- need cold u Interferon, IgA, T storage and distribution- cold cells chain u Intranasal NONE of the current COVID vaccine approaches are Modified Live (NOTE – we will discuss LIVE VECTORED SUBUNITs in a bit….)  INACTIVATED (KILLED) VACCINES Inactivate physical treatment chemical treatment Includes any approach that delivers a dead, non-replicating target INACTIVATED VACCINES Advantages Disadvantages u Safe u $$$$ u long-lasting u less immunogenic 2+ doses initially u IgA, T cells l l revaccination u stable l adjuvants genetically l u hypersensitivity l heat  Other Inactivated – TOXOID VACCINE  Exotoxins that have been chemically altered (usually by formalin)  Loss toxicity  Still immunogenic  SUBUNIT VACCINES  Protein Subunit vaccines  purified from wild-type organism  Leukocell FeLV  cloned and expressed in vitro in bacteria or yeast, or in plants  RM Canine Lyme (GenetiVac FeLV)  Polysaccharide and Conjugate vaccines  B cell T-independent epitopes  Combination of carrier protein plus polysaccharide-conjugate vaccine  H. influenzae  Pneumococcus Virtually ALL of the existing COVID vaccines use a variety of this approach to deliver the Spike protein to the immune system. RECOMBINANT VIRUS VACCINES G G G G G G G G G G G G G G Rabies virus Vaccinia virus Recombinant G vaccinia virus… “Infect” an animal to immunize it!  DNA vaccines – A Variation of the Subunit Approach  Recombinant Vector Vaccines  Naked DNA/mRNA Vaccines  DNA VACCINE PLASMIDS Eukaryotic Promoter +/- Intron AntibioticR Gene for Gene Antigen of (kan, amp) Interest  WHY DNA VACCINATION?  Inexpensive to produce in large quantities  Thermostable (lyophilizable)  Marker vaccines allowing for concurrent surveillance control methods  Multivalency DNA VACCINE SAFETY ISSUES  Integration into the host cell genome tumor induction?  Induction of autoantibodies?  Induction of tolerance? mRNA based vaccines use a similar approach, however do not share the same level of concern over integration. However, RNA based vaccines are extremely unstable and must be stored at very low (-80F) temperatures  Adjuvant  Agent added to a vaccine to induce an enhanced immune responses to vaccine antigens  Used for over 80 years  Technology continually evolving  Advances in immunology  Advances in chemistry  Recombinant proteins and peptides can be poorly immunogenic Different Adjuvants – Different Strategies Carriers which stabilize vaccine antigens and allow them to be present for extended Delivery periods of time. Exert direct stimulatory effects on immune cells and initiate the immune response Immune through activation of innate immunity potentiator DANGER SIGNAL  The “Perfect” Adjuvant  “Perfect” adjuvant achieves both strategies  Delivery - Enhance the amount of antigen reaching the cells that are responsible for the induction of the immune response  Immune potentiator - Directly activates these cells.  Goal = Activate only the elements of the immune response required for protection, and avoid triggering a generalized activation of the immune response.  In other words “Effective and Safe”  Alums  Primarily aluminum adjuvants  Used extensively in veterinary vaccine products  Most commonly used adjuvant in human vaccines  Strong inducer of Th2 responses  Examples  Aluminum hydroxide  Aluminum potassium sulfate (often called “Alum”) - Used in many toxoid formulations (Clostridial vaccines)  Lipid/Oil Emulsions  Detergent-stabilized emulsions of oil and water  Precise mode of action is still not clearly understood  Depot  Induction of MHC responses  Primarily used in veterinary vaccine formulations  Gaining acceptance in Human vaccine formulations (MF59)  3 basic forms – multiple formulations  Oil in Water (O/W)  Water in Oil (W/O) (Freund’s)  Water in Oil in Water (W-O-W)  Oil Based Adjuvants Used in Veterinary Vaccines  Water in Oil Emulsions (W/O) – antigen-containing water droplets within external continuous oil phase  Oil in Water Emulsions (O/W) – emulsified oil droplets within continuous antigen-containing aqueous phase  Water-in-Oil-in-Water Emulsions (W/O/W) – antigen- containing water droplets entrapped inside of larger oil droplets, which in turn dispersed in continuous antigen containing water phase W/O/W ADJUVANT SYSTEM Water-in-Oil-in-Water (WOW) Adjuvant = Oil phase = Antigen = Surfactant 2 = Aqueous phase = Surfactant 1  PRR and Other Ligands Microbial PAMP’s – induce Th1 response LPS – interacts with APC, releases pro-inflammatory Derivatives cytokines CpG – Bacterial DNA Mucosal Heat labile E. coli enterotoxin (LT) Cholera toxin (CT) Plant derivative – Primary function is induction of cytokines Saponins Potentiates Th1 response (IL2, IFN-γ, IgG2a) Can be toxic in certain species (humans, mice) Commonly used in veterinary vaccine formulations  Delivery Vehicles  Membrane bound phospholipid vesicles (liposomes) with antigen trapped in lumen or incorporated in membrane  Targets increased antigen uptake by APC  ISCOMS (Immune Stimulating Complexes)  Liposomes containing saponin  Virosomes  Liposomes prepared from viral membranes  Virus-like Particles  30-90 nm self-assembled virus proteins with a nucleic acid or lipid genome  Vaccine Side Effects  Typically side effects- redness or pain at an injection site, sneezing or nasal congestion after intranasal administration, fatigue or headaches  Vaccine Adverse Events Reporting System (VAERS)-monitor adverse reactions-  Examples- Urban Legends  DTaP –sudden infant death syndrome (SIDS) – children vaccinated less likely to die SIDS  HBV-multiple sclerosis- no risk  Inactivated poliovirus vaccine (IPV)- contaminated with SV40, monkey virus- cancer- no increase  Polio vaccine and HIV- no evidence that HIV contaminated  Lyme Disease vaccine- caused arthritis- result of chronic Lyme Disease  MMR- the worst- connection with autism- completely made up  Future Vaccines  Prophylactic vaccines  Lots of targets- HIV, Ebola, hepatitis C virus, malaria  Therapeutic vaccines  Cancer  Dendritic Cell culture  Autoimmune and Allergy  Domestic animals- castration  Summary  Whole Organism  Modified live  Inactivated  Subunit  Recombinant Live  DNA  Adjuvant  Vaccine Usage  Vaccine Side effects outway disease  Next Lecture  Types of Vaccines  Mechanism of Action of Vaccines