1. VACCINE SAFETY

2. Vaccine-induced feline fibrosarcoma Current estimate is: 27,000 vaccine induced tumors expected per year ‘93 1-2 per 10,000 ‘97 3.6 per 10,000 ‘98 up to 5 per 10, 000

3. Pathogenesis of vaccine injection site fibrosarcomas Injection triggers inflammation and release of platelet-derived growth factor Activation of sis oncogene occurs Sarcoma develops at the site

4. Types of Adverse Responses Vaccine injection site fibrosarcomas Hypersensitivity Type 1 – Anaphylaxis Hypersensitivity Type 2- Cytotoxic Hypersensitivity Type 3 - Immune complex Hypersensitivity Type 4 - Granulomas Autoimmune disease Induction of disease/ increase in severity of disease/ reversion to virulence

5. Type I Hypersensitivity Systemic Anaphylaxis IgE mediated reaction requires previous sensitization sensitizing agent may be antigen, cross-reactive antigen, or other proteins present in vaccine factors to consider: adjuvant, genetics

6. Mechanism for type I reactions Histamine ECF-A Leukotrienes Smooth muscle contraction Vascular permeability Vasodilation Eosinophil Chemotaxis Mast Cell Ag Mechanism for systemic anaphylaxis

7. Induction of IgE by Vaccines Antigen itself virus e.g. Bovine Respiratory Syncytial Virus bacteria e.g. Hemophilus somnus Constituents of carrier gelatin Impurities in antigen preparation fetal bovine serum, ovalbumin

8. Examples of type I reactions to non-essential antigens IgE responses to gelatin as a stabilizer: measles-mumps- rubella vaccine, yellow fever vaccine, diptheria-tetanus- pertussis (DTP) vaccine, and DTaP (acellular pertussis) IgE responses to ovalbumin: yellow fever, influenza, measles, mumps

9. More Examples Horses vaccinated with egg-derived equine encephalitis vaccines Cattle vaccinated with baby hamster kidney derived foot and mouth disease vaccine Humans vaccinated with human diploid cell line rabies vaccine Cattle vaccinated with bovine respiratory syncytial virus vaccine

10. Type II Hypersensitivity IgG and/or IgM binding to cell-associated antigens Fixation of complement Cell lysis and/or phagocytosis

11. Mechanism of type II Reactions Host target cell Complement Lysis of target cell phagocytosis of target cell

12. Examples of type II reactions Immune-mediated hemolytic anemia has been associated with vaccination of dogs with combination vaccines Hemolytic anemia and thrombocytopenia have been associated with recombinant hepatitis B vaccine in humans

13. Type III Hypersensitivity Immune complex diseases IgG binds antigen fixes complement and attracts neutrophils Systemic form: arthritis, vasculitis, glomerulonephritis Local form: Arthus-type lesions in skin or lung

14. Mechanism of type III reactions Blood Vessel Vasculitis Kidney glomeruli Joints Skin

15. Examples of type III reactions Canine Adenovirus type 1 (hepatitis) vaccine-induced “Blue eye”anterior uveitis Local Arthus type skin reactions in all species within 24 hours of vaccine Serum sickness-like illness in humans after immunization with human diploid cell rabies vaccine (vasculitis, arthritis)

16. Type IV Hypersensitivity Delayed type reaction (DTH), occurs within 48 to 72 hours after antigen administration Mediated by sensitized T lymphocytes Indicates strong T helper 1 cell response Local response shows erythema, induration

17. Mechaniam of type IV response 48 - 72 hours later Macrophages & T lymphocytes Erythema induration

18. Examples of type IV reactions DTH reactions have been observed in humans after immunization with propionibacterium acnes autovaccine Children with non-anaphylactic reactions to gelatin-containing vaccine and increased lymphocyte stimulation to gelatin may have DTH reactivity

19. Examples of Vaccines Generated Autoimmunity Rabies vaccine-induced autoimmune encephalomyelitis Association is suggested: for hepatitis B vaccine with rheumatoid arthritis Auto Immune Hemolytic Anemia (AIHA) in infant girl after DPT and polio vaccination

20. Vaccine Mediated, Enhancement of Disease Respiratory syncytial virus formalin-inactivated vaccine caused severe RSV in vaccinated children Bovine RSV formalin-inactivated vaccine caused disease enhancement in BRSV vaccinated calves

21. Disease caused by vaccination Inadequate killing resulting in residual virulence e.g. formalin inactivated Salk polio virus in late 1950’s Immuno suppressed host, e.g. MLV in AIDS patient Intrauterine infection of fetus after immunization of mother with MLV, e.g. teratogenic effects with bluetongue virus

22. Summary Adverse effects of vaccines are rare Killed vaccines with adjuvant are more likely to have pathological sequel Systemic anaphylaxis may result from sensitization to components of the vaccine Immunomodulation is an important factor in disease development by vaccines

23. Importance of Vaccine Safety Decreased disease risks and increased attention on vaccine risks Public confidence in vaccine safety is critical higher standard of safety is expected of vaccines vaccinees generally healthy (vs. ill for drugs) vaccination universally recommended and mandated

24. Diphtheria 31,054 0 -100 Measles390,852 66 -99 Mumps 21,342 314 -99 Pertussis117,998 25,616 -78 Polio (wild) 4,953 0 -100 Rubella 9,941 11 -99 Cong. Rubella Synd. 19,177 1 -99 Tetanus 1,314 27 -98 Invasive Hib Disease 24,856 144 -99 Total566,706 26,179 -95 Vaccine Adverse Events 0 15,803 +++ Disease Pre-vaccine Era 2005 % change Comparison of Maximum and Current Reported Morbidity, Vaccine-Preventable Diseases and Vaccine Adverse Events, United States

25. Disease incidence Vaccine safety concerns

26. Prelicensure Vaccine Safety Studies Laboratory Animals Humans

27. Prelicensure Human Studies Phases I, II, III trials Common reactions are identified Vaccines are tested in thousands of persons before being licensed and allowed on the market

28. Postlicensure Surveillance Identify rare reactions Monitor increases in known reactions Identify risk factors for reactions Identify vaccine lots with unusual rates or types of events Identify signals

29. Postlicensure Vaccine Safety Activities Phase IV Trials ~10,000 participants better but still limited Large-Linked Databases Clinical Immunization Safety Assessment Network

30. Vaccine Adverse Event Reporting System (VAERS) National reporting system Jointly administered by CDC and FDA Passive (depends on healthcare providers and others to report) Receives ~15,000 reports per year

31. Vaccine Adverse Event Reporting System (VAERS) Detects new or rare events increases in rates of known side effects patient risk factors Additional studies required to confirm VAERS signals Not all reports of adverse events are causally related to vaccine

32. Adverse Event Classification Vaccine-induced Vaccine-potentiated Programmatic error Coincidental

33. Clinical Immunization Safety Assessment (CISA) Network Improve understanding of vaccine safety issues at individual level Evaluate persons who experience adverse health events Gain better understanding of events Develop protocols for healthcare providers

34. Vaccine Injury Compensation Program (VICP) Established by National Childhood Vaccine Injury Act (1986) “No fault” program Covers all routinely recommended childhood vaccines

35. The Provider’s Role Immunization providers can help to ensure the safety and efficacy of vaccines through proper: vaccine storage and administration timing and spacing of vaccine doses observation of contraindications and precautions

36. Invalid Contraindications to Vaccination Minor illness Mild/moderate local reaction or fever following a prior dose Antimicrobial therapy Disease exposure Pregnancy or immunosuppression Premature birth Breastfeeding Allergies to products not in vaccine Family history (unrelated to immunosuppression)

37. Benefit and Risk Communication Opportunities for questions should be provided before each vaccination Vaccine Information Statements (VISs) must be provided before each dose of vaccine public and private providers available in multiple languages