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
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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
Ag
Ag
Mast Cell
Histamine
ECF-A
Leukotrienes
Smooth muscle contraction
Vascular permeability
Vasodilation
Eosinophil Chemotaxis
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-mumpsrubella vaccine, yellow fever vaccine, diptheria-tetanuspertussis (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
Complement
Lysis of target cell
Host
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
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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
Kidney glomeruli
Joints
Skin
Vasculitis
Blood Vessel
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 - 72
hours
later
Erythema
induration
Macrophages & T lymphocytes
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
Comparison of Maximum and Current Reported Morbidity, Vaccine-Preventable Diseases
and
Vaccine Adverse Events, United States
Disease
Pre-vaccine Era
Diphtheria
31,054
Measles
390,852
Mumps
21,342
Pertussis
117,998
Polio (wild)
4,953
Rubella
9,941
Cong. Rubella Synd.
19,177
Tetanus
1,314
Invasive Hib Disease 24,856
Total
566,706
Vaccine Adverse Events
0
2005
% change
0
66
314
25,616
-100
-99
-99
-78
0
11
1
27
144
-100
-99
-99
-98
-99
26,179
-95
15,803
+++
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
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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
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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