Everything you really wanted to know but were afraid to ask!

Transcription

1 Manitoba 10 th Annual Travel Health Conference Winnipeg, April 26-27, 2012 Everything you really wanted to know but were afraid to ask! Barbara Law, Chief, Vaccine Safety Immunization and Respiratory Infections Division, Public Health Agency of Canada

2 Disclosure of Potential for Conflict of Interest Barbara Law, MD Vaccinology 101: Everything you wanted to know but were afraid to ask. FINANCIAL DISCLOSURE: Grants/Research Support none Speakers Bureau / Honoraria none Consulting Fees none Other Government (PHAC) employee

3 Vaccinology 101 Vacca = cow Vaccinus = of cows Ology = study of Vaccinology the study of cows Vaccinology = the science of vaccine development

4 Immunology 101 What s in a vaccine and why? Objectives Participants able to explain, in a way that is relevant to their practice setting, how the immune system works and differentiate between all types of immunizing agents and their components.

5 Historical Context 429 BC: Observation made during the plague of Athens, by the historian Thucydides: It was with those who had recovered from the disease that the sick and the dying found most compassion. These knew what it was from experience, and had now no fear for themselves; for the same man was never attacked twice never at least fatally.

6 Historical Context 429 BC: Observation made during the plague of Athens, by the historian Thucydides: 1st understanding that disease causing organisms have two distinct effects Sickness Immunity

7 Us Immunology 101 versus THEM!

8 Us Immunology 101 versus THEM! Innate Immunity Adaptive Battlestar Humana Immunity

9 Us Immunology 101 versus THEM! Innate Barriers Immunity Cells Molecules Battlestar Humana Behaviours

10 Innate Immunity Barriers SKIN: covers 2 square meters weighs 5 kilograms key physical barrier TEARS: contain lysozyme, a protein that breaks down bacterial cell walls NASAL TURBINATES: create 160 square cm of sticky wet mucous in the nasal cavity MUCOSA: Lungs,Gut,Bladder Respiratory ciliary escalator Stomach acid secretion Battlestar Humana Bladder emptying

11 Us Innate Macrophage (eg alveolar) Immunity Cells Battlestar Humana Polymorphonuclear Phagocyte

12 Us Innate Immunity Molecules CYTOKINES F chemical messengers F regulate immune responses F diverse cell targets Ø several molecules with same task Ø one molecule can multitask Membrane Attack Complex cytokines Battlestar Humana COMPLEMENT F proteins that work together in regulated sequential fashion F 3 paths to trigger leading to same endpoint (1 innate / 2 adaptive)

13 Us Behaviours safe sex Innate Immunity blood-body fluid precautions handwashing masking sterile procedure isolation / quarantine Battlestar Humana tradition Avoid pork

14 Us versus Behaviours Barriers Cells+Molecules THEM Innate Immunity non specific unchanging short term Battlestar Humana

15 Us versus THEM Behaviours Barriers Cells+Molecules Innate Immunity non specific unchanging short term Cells+Molecules Unique, tailored communications Adaptive Immunity specific gets stronger long lasting Battlestar Humana

16 Battlestar Humana Adaptive Immunity: Key Components Primary lymphoid organs Adaptive Immunity specific gets stronger long lasting

17 Battlestar Humana Adaptive Immunity: Key Components Primary lymphoid organs Cell differentiation +maturation Secondary lymphoid organs Activation, proliferation Adaptive Immunity specific gets stronger long lasting

18 Battlestar Humana Adaptive Immunity specific gets stronger long lasting Process Overview 1. Recognize and capture foreign invaders 2. Process+display invader s unique bits 3. Find matching immune cells 4. Train and expand army 5. Seek and contain enemy 6. Remember

19 Battlestar Humana 1. Recognize & capture foreign invaders F Border patrol team Ø Tissue macrophages Ø Dendritic cells Ø B lymphocytes = Antigen presenting cells (APC s) Jigsaw Puzzle process Ø receptors on APC recognize foreign invaders via PAMP Ø binding facilitates ingestion of the pathogen into the cell Ø once inside the cell the pathogen is broken down into unique component parts

20 Battlestar Humana 2a. Process & display invader s unique bits Virus (intracellular pathogen) Bacteria (extracellular pathogen)

21 Battlestar Humana 2a. Process & display invader s unique bits 2b. Deliver to nearest lymph node, maturing en route

22 Battlestar Humana 3. Find matching immune cells 25 billion naïve T4 lymphocytes flow through lymph node daily Each with pre-programmed specificity Ø unique types

23 Battlestar Humana 3. Find matching immune cells F 25 billion naïve T4 lymphocytes flow through lymph node daily F Each with pre-programmed specificity Ø unique types another Jigsaw Puzzle process

24 Battlestar Humana 4. Train & expand army Dendritic cells activate T cells via unique cellular and chemical interactions = immunological synapse T8 CD8 cells Ø cell mediated immunity B cells Ø antibody production T4 CD4 cells Ø direct immune response Ø TH1: cell-mediated Ø TH2: humoral

25 Battlestar Humana 4. Train & expand army Th1 CD4 + activated T8 cells = Cytotoxic T cells Th2 CD4 + activated B cells = Plasma cells Plasma cell can produce> 2000 antibodies per second for 4-5 days

26 Battlestar Humana 5. Seek & contain enemy Antibodies in blood, body fluids, mucosa may F block entry into cells F opsonize for phagocytosis F fix complement at the pathogen surface F direct dumb cells to destroy pathogen cells F interfere with intracellular viral assembly F block virus budding CTLs are like a whole cell antibody, binding to unique pathogen antigens on the surface of an infected cell in order to kill it

27 Battlestar Humana 6. Remember: anamnestic response 1 o Immune Response Slower IgM first IgG later Anamnestic(1 o ) response Faster IgG first & foremost Larger High affinity.ie antibodies are stickier

28 Battlestar Humana 6. Remember: anamnestic response Caveat: not all antigens induce immune memory T-cell independent antigens Able to trigger B cells to make antibody without T cells present POLYSACCHARIDES Eg: pneumococcal and meningococcal plain polysaccharide vaccines T-cell dependent antigens Needs T helper cells for B cell antibody production PROTEINS Eg: DTaP, IPV, HBV, HPV, HAV, influenza

29 Battlestar Humana Vaccine are designed to induce adaptive immunity before exposure to pathogens. When exposed to a pathogen, pre-existing antibody, or the ability to make an accelerated anamnestic response, prevents morbidity and mortality Innate Immunity Cells Molecules Adaptive Immunity specific gets stronger long lasting Process Overview 1. Recognize and capture foreign invaders 2. Process+display invader s unique bits 3. Find matching immune cells 4. Train and expand army 5. Seek and contain enemy 6. Remember

30 Correct Myth-information MYTH: Vaccine immunity is unnatural It is better to have the lifelong immunity that follows natural disease! FACTS Natural immunity Good BUT.too late to prevent disease morbidity and mortality Vaccine immunity offers protection at a much lower risk of complications than natural disease Measles Disease Vaccine Pneumonia Encephalitis 5-10% 1/1000 0% 1/ Mumps Disease Vaccine Meningitis 1/10 1/ Vaccines train the immune system to recognize foreign invaders before they cause damage

31 Correct Myth-information MYTH: Vaccines weaken the immune system; too many at once could overload it altogether! FACT: Human immune system capacity to respond to different antigens is enormous. Infants can respond to 10,000 unique antigens at once. ~33 antigens / immunization visit for: Ø DTaP Ø Polio Ø H. influenzae b Ø Pneumococcal conjugate Ø HBV ~ 10 epitopes / vaccine antigen Epitopes engage <0.01% capacity = 330 epitopes, each engaging 1 B cell Concept of using up capacity is invalid! System constantly replenishes itself and is built to deal with multiple antigens at the same time B cell capacity Epitopes Offit et al; Pediatrics 2002; 109:124-9

32 Vaccine Schedule: a balancing act! Younger versus Older risk +/or consequences of disease greatest Bacterial meningitis Pertussis Rotavirus Infants respond well to PROTEINS but not to POLYSACCHARIDES fewer doses for protective immunity meningococcal conjugate: 1 dose at 1 year instead of 3 if given to infants less concern re interference of maternal antibody measles POLYSACCHARIDE-PROTEIN conjugate vaccines improved on nature! Infants with Hib or pneumococcal meningitis didn t gain lasting immunity because of the inability to respond reliably to polysaccharide antigens until age 2 years Conjugating the polysaccharide to a protein fooled infant immune system into reacting as if it was a protein antigen

33 Vaccine Schedule: a balancing act! HBV: target infants or school-age? HBV infection acquired in infancy more likely to result in chronic infection and lead to liver cancer risk of exposure much higher once sexually active if vaccine given a decade or more before period of maximum risk, will immunity last? Immunization goals also enter into the equation Elimination: repeat immunizations to ensure immunity achieved measles, polio Prevent mortality and severe complications: 1 dose VZV Reduce community outbreaks: 2 doses VZV

34 Canadian Immunization Competencies Objectives 1. The Immune System and Vaccines Compare / contrast innate & adaptive immunity Differentiate primary vs memory immune response why some vaccines induce memory response & others don t Respond to concern that too many vaccines overload the immune system. Discuss pros & cons of immunity gained through immunization vs wild-type infection Differentiate passive & active immunity Name some host- & vaccine-related factors that affect the immune response to vaccines Explain how the immunization schedule accommodates factors that affect the immune response to vaccines

35 Canadian Immunization Competencies Objectives 1. The Immune System and Vaccines Differentiate between passive and active immunity passive immunity: provide pre-formed antibodies to an individual Ø Maternal antibody to infants across placenta Ø Immune globulin infusion / injection (eg TIG, VZIG, RIG) Ø Monoclonal antibodies Name some host- and vaccine-related factors that affect the immune response to vaccines Host: Extremes of age Congenital/acquired immunodeficiency (disease or drug-induced) Genetic differences in innate immunity Vaccine.

36 Immunology 101 What s s in a vaccine and why?

37 Vaccine Types & Composition Vaccine types by antigen content Ø advantages Ø disadvantages Ø impact on recommended schedules Other vaccine components Ø Preservatives Ø Adjuvants Ø Stabilizers Ø Manufacturing residuals

38 Vaccine Immunogen Classification BCG Vaccinia Virulent Organism Attenuated Organism Measles Mumps Rubella Oral polio Varicella H.Zoster Rotavirus Flumist Yellow Fever Typhoid(oral) IPV Influenza Hepatitis A Rabies Cholera JEV Killed Whole Organism Sub-unit Vaccine Toxoids Tetanus,Diphtheria Polysaccharides Pneumococcus Meningococcus Typhoid(injectable) Protein Conjugate H.influenzae b Pneumococcus Meningococcus Purified proteins acellular pertussis HBV, HPV,

39 single dose (often) broad immunity unpredictable unsafe in immunocompromised BCG Vaccinia Virulent Organism broad immunity has to replicate to work may revert to virulence Attenuated Organism MMR Oral polio Varicella H.Zoster Rotavirus Flumist Yellow Fever Typhoid(oral) IPV Influenza Hepatitis A Rabies Cholera JEV Toxoids Polysaccharidess Protein Conjugate Purified Proteins can use virulent bugs not too expensive weak responses need multiple doses Killed Whole Organism Sub-unit Vaccine combinations possible fewer side effects multiple doses narrow response

40 Vaccine Types & Composition Vaccine types by antigen content Ø advantages Ø disadvantages Ø impact on recommended schedules Other vaccine components Ø Preservatives Ø Adjuvants Ø Stabilizers Ø Manufacturing residuals

41 Preservatives Purpose: to prevent bacterial/fungal contamination of multi-dose vials Preservative Thimerosal Phenoxyethanol Phenol Vaccines Multidose: Fluviral, Vaxigrip, Menomune, Recombivax Trace: Twinrix, Engerix B, Infanrix-hexa Adacel, Avaxim, Boostrix, Engerix, Havrix, IPV, Infanrixhexa, Menomune, Pediacel, Quadracel, Twinrix, ViVaxim Pneumovax, Pneumo 23, Typherix, Typhim VI Thimerosal: concern re thimerosal-neurodevelopmental disorders link F Concern based on theoretical possibilities not proven toxicity F False assumption that ethyl mercury behaves like methyl mercury In fact ethyl mercury has a short half life and doesn t accumulate F Multiple studies, variety of designs, several countries, all trend in same direction: rejection of any link (IOM published conclusion) F Special masters court ruled against a link F NACI 2007: There is no reason for vaccine providers or other health car eprofessionals who may counsel individuals regarding immunization to raise any concerns about exposure to thimerosal

42 Adjuvants Prime purpose: enhance immune response to antigen(s) Class Mechanism Types Vaccines Delivery Systems F target antigen(s) to APCs F depot effect FActivate innate immunity Alum Emulsions (water & oil) DTaP, HB, HAV, prevnar, NeisVacC, Gardasil Arepanrix (ASO3) Fluad (MF59)

43 Adjuvants Prime purpose: enhance immune response to antigen(s) Class Mechanism Types Vaccines Delivery Systems F target antigen(s) to APCs F depot effect FActivate innate immunity Alum Emulsions (water & oil) DTaP, HB, HAV, prevnar, NeisVacC, Gardasil Arepanrix (ASO3) Fluad (MF59) Immunostimulators F activate innate immunity (mimic pathogen molecules that bind to APC receptors) MPL (monophosphoryl lipid A) Cervarix (also contains alum) Aluminum: Used in vaccines since the 1930 s F 3 rd most abundant element in environment (after oxygen and silicon) F Regulators have set maximum allowable dose for vaccines as 0.85mg F only proven adverse event is local inflammation at the vaccination site

44 Stabilizers Prime purpose: maintain potency through adverse conditions (freeze-drying/heat) & prevent loss through adherence to glass vial Additive Vaccines Gelatin MMR-II, Varivax-III JE-Vax, Vaxigrip, Fluviral Human serum albumin MMR-II, Priorix Varivax-III, Varilrix Fetal bovine serum MMR-II, Varivax-III 1993; 17 yr old Californian girl developed anaphylaxis after MMR confirmed to be due to gelatin. Studies in Japan show 20X higher risk of anaphylaxis for high molecular weight forms of gelatin Most vaccines with gelatin have lower molecular weight hydrolyzed gelatin

45 Manufacturing Residuals F Inactivating agents F Antibiotics F Egg proteins F Yeast proteins

46 Manufacturing Residuals Inactivating agents F Purpose: separate pathogen s immunogenicity from its virulence by eliminating the harmful effects of bacterial toxins or ablating the capacity of viruses to replicate F Examples: Ø Formaldehyde influenza, polio, diptheria / tetanus toxoids Ø β-propiolactone rabies. Ø Glutaraldehyde acellular pertussis. Formaldehyde: theoretical concern of DNA damage at high concentration; but neither high single doses (25 mg) nor chronic exposure ( mg/day) cause human cancer Vaccines with a trace of formaldehyde (< 0.1 mg/dose): (Quadracel,Act-Hib,Adacel,Td-adsorbed;Havrix,TwinRix,Vaqta,JE-Vax) Formaldehyde is an essential intermediate in the synthesis of thymidine, purines and amino acids humans normally have 2.5 μg/ml blood; total for 2 mos old infant=1.1 mg, which is > 10-fold more than in a dose of vaccine

47 Manufacturing Residuals Antibiotics F Purpose: prevent bacterial contamination during steps in manufacturing process Ø eg added to tissue culture for growing vaccine viral strains F Types used Ø Neomycin, streptomycin, polymyxin B, chlortetracycline Ø Amphotericin B Neomycin: F Trace amounts (0.025 mg/dose) found in: Ø MMR-II, Priorix, Varivax, Varilrix. F Up to 0.15 mg/dose found in Imovax. F Hypersensitivity theoretically possible, but anaphylaxis has not been clearly documented.

48 Manufacturing Residuals Cellular Residuals F Influenza, yellow fever viruses grown in eggs Ø Residual protein mostly ovalbumin ( μg/dose) Ø Egg allergies occur in 5% of atopic children and 0.5% of the population. F MMR propagated in chick embryo fibroblast cells in culture Ø Very small amounts of egg protein (~ 40 pg), 500-fold less than that in influenza F Yeast proteins (Saccharomyces cerevisiae or baker s yeast) Ø Engerix B (no > 5 mg/ml), Recombivax (no > 1 mg/ml) Ø immediate hypersensitivity occurs ~ once / 600,000 doses.

49 Canadian Immunization Competencies Objectives 4. Types of Immunizing Agents & Their Composition Classify each immunizing agent used in practice as live attenuated, inactivated, or subunit demonstrate ability to describe them to an audience with minimal or no science knowledge Compare their major advantages & disadvantages Identify key differences in the immune response to purified polysaccharide vs polysaccharide protein conjugate vaccines. Describe, in general terms, the purpose, action and potential concerns of components that may be present in a given product: adjuvant, preservative, additives, glass vial, stopper, and prefilled syringe. Name some vaccine-related factors that affect the immune response to vaccines Explain how the immunization schedule accommodates factors that affect the immune response to vaccines Locate & utilize current information resources on types and content of immunizing agents used in practice.

50 F Canadian Immunization Guide section 1 vaccine table

51 Innate Immunity non specific unchanging short term Us vs THEM Adaptive Immunity specific gets stronger long lasting Natural immunity, innate and adaptive, are good shields but vaccines tip the scales further in favor of us by priming the pump for a much more rapid response thus preventing a great deal of damage and destruction!

52

53

54 Vaccines and Antigen Content Changes Over Time Total Antigens HBV Hib+PC VZV MMR DT-Polio Pertussis Smallpox Offit et al; Pediatrics 2002; 109:124-9

55 Bovine-derived components F Reagents derived from cows: Ø Gelatin, glycerol, enzymes, amino acids, serum. F As a precaution, the US prohibited use of bovine-derived reagents from countries known to have cattle with BSE F BSE is unlikely to be transmitted because: Ø Prions are found in the CNS of cows but not in blood or other organs Ø no cases have been transmitted by blood/blood prod. Ø Epidemiologic evidence does not support vaccines as a cause of vcjd in England F Substitution of human recombinant albumin for animal-derived product

56 Canadian Immunization Competencies Objectives re Types of Immunizing Agents & Their Composition F Locate and utilize current information resources on the types and content of immunizing agents used in practice. F Canadian Immunization Guide section 1 vaccine table Ø Guide currently being updated with plans for a web-accessible evergreen version F Canadian Coalition for Immunization Awareness and Promotion Ø Specific page at the CCIAP site with Vaccine contents info and a link to vaccine manufacturer website Product Monographs for specific products F World Health Organization Ø Vaccine Safety Net a list of sites meeting WHO credibility & content good information practices criteria (includes CCIAP, CPS, PHAC, and many more)