VACCINE SAFETY

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

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

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

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

Mechanism for type I reactions

HistamineECF-ALeukotrienes

Smooth muscle contractionVascular permeabilityVasodilationEosinophil Chemotaxis

Mast Cell

AgAg

Mechanism for systemic anaphylaxis

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

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

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

Type II Hypersensitivity

• IgG and/or IgM binding to cell-associated antigens

• Fixation of complement

• Cell lysis and/or phagocytosis

Mechanism of type II Reactions

Host target cell

Complement

Lysis of target cell

phagocytosis of target cell

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

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

Mechanism of type III reactions

Blood Vessel

Vasculitis

Kidney glomeruliJointsSkin

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)

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

Mechaniam of type IV response

48 - 72hourslater Macrophages & T lymphocytes

Erythemainduration

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

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

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

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

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

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

Diphtheria 31,054 0 -100Measles 390,852 66 -99Mumps 21,342 314 -99Pertussis 117,998 25,616 -78Polio (wild) 4,953 0 -100Rubella 9,941 11 -99Cong. Rubella Synd. 19,177 1 -99Tetanus 1,314 27 -98Invasive Hib Disease 24,856 144 -99

Total 566,706 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

Disease incidence Vaccine safety

concerns

Prelicensure Vaccine Safety Studies

• Laboratory

• Animals

• Humans

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

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

Postlicensure Vaccine Safety Activities

• Phase IV Trials • ~10,000 participants• better but still limited

• Large-Linked Databases

• Clinical Immunization Safety Assessment Network

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

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

Adverse Event Classification

• Vaccine-induced• Vaccine-potentiated• Programmatic error• Coincidental

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

Vaccine Injury Compensation Program (VICP)

• Established by National Childhood Vaccine Injury Act (1986)• “No fault” program• Covers all routinely recommended childhood

vaccines

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

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)

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