When Vaccines Do Too Much

Issues involving cat vaccines. Questions, answers, theories, and evidence.
Why do vaccines cause cancer in cats but not dogs or humans?

When Vaccines Do Too Much

Postby malernee » Wed Apr 28, 2004 7:02 am

Vaccine Reactions Today & Tomorrow: When Vaccines Do Too Much
ACVIM 2003
George E. Moore, DVM, MS, DACVPM, DACVIM
West Lafayette, IN

INTRODUCTION

Vaccinations are among the most successful and cost-effective disease prevention interventions available to health care providers. The development of efficacious vaccines and successful implementation of vaccination programs constitute major reasons for the reduction of infectious diseases in companion animals in the United States. When high population coverage is achieved with an efficacious vaccine, the occurrence of cases of the disease that the vaccine prevents may be rare. In the rare occurrence of disease, however, morbidity associated with the vaccine itself or presumed to be associated with vaccination can cause more public concern than the prevented disease. This phenomenon has resulted in questions by veterinary practitioners and pet owners regarding "over-vaccinating" and the overall benefits of certain vaccination programs or schedules. A danger of dramatic reductions in vaccination coverage rates, however, is the precipitation of an epidemic of the disease that vaccination would prevent. Thus, the evaluation of benefit and risk is the central theme of discussions regarding companion animal vaccination.

GELL AND COOMBS HYPERSENSITIVITY REACTIONS (TYPE I-IV)

Adverse events associated with vaccines have historically included the Gell and Coombs classification of type I-IV hypersensitivity reactions (Goldsby et al, 2000). Type I hypersensitivity is an immunologic reaction that manifests itself by tissue reactions within minutes (or seconds) after exposure to the antigen/allergen. Upon exposure and binding of the antigen to two IgE molecules on the surface of the mast cell, inflammatory mediators of histamine, leukotrienes, prostaglandins, cytokines, proteases, and SRS-A are released, causing increased vascular permeability, smooth muscle contraction and the influx of inflammatory cells. Immediate hypersensitivity, anaphylaxis, and allergy such as allergic inhalant dermatitis are manifestations of type I reactions.

In type II hypersensitivity reactions, cell surface antigens elicit an antibody response with antibodies binding to the cell. The cell is usually either lysed or complement components attract phagocytic cells which damage tissues from the release of protolytic enzymes. Cytotoxic reactions are commonly seen in hematologic diseases as immune-mediated hemolytic anemia and transfusion reactions. Type II hypersensitivity reactions can also occur secondary to drugs and infectious agents. Examples of reactions in which the antibody binds to a cell receptor, activating or blocking the activation of the cell, are anti-receptor antibodies in myasthenia gravis and Grave's disease.

Type III immune complex-mediated hypersensitivity occurs when a cell or tissue is being destroyed not because an antibody is being made against that cell or tissue, but rather because the immune complexes either become "stuck" to the cell or deposited in that tissue. Once complexes are lodged or deposited in tissues, complement activation leads to neutrophil infiltration, release of neutrophil enzymes, and tissue damage. As in type II reactions, IgG and IgM are involved. Antigen-antibody complexes may be large and insoluble, removed from circulation by the mononuclear phagocytic system, or small and soluble becoming trapped beneath endothelial cells along the basement membrane. Localized type III reactions include staphylococcal hypersensitivity in pustular dermatitis, blue-eye from canine type 1 adenovirus, and arthus reactions. Generalized type III reactions include systemic lupus erythematosus and rheumatoid arthritis.

Delayed or cell-mediated type IV hypersensitivity results from the interaction of sensitized T lymphocytes (Th1) and a specific antigen. Lymphokine synthesis results in generation of cytotoxic T lymphocytes and the infiltration of macrophages in approximately 24-48 hours. Contact dermatitis is a type IV hypersensitivity in which T lymphocytes respond to antigens as synthetic fibers and plastics. Granulomatous inflammation can also be related to type IV hypersensitivity.

VACCINE SITE-ASSOCIATED SARCOMAS

In the last decade, reported adverse reactions to vaccinations in companion animals include vaccine site-associated sarcomas in cats (Kass et al, 1993; Hendrick et al, 1994). Recently reported rates of reactions were 0.32 vaccine site-associated sarcomas per 10,000 vaccine doses and 11.8 postvaccinal inflammation reactions per 10,000 parental vaccine doses in cats (Gobar and Kass, 2002). If inflammatory reactions are a necessary prelude to sarcoma, then these rates suggest that 1 in 35-40 reportable inflammatory reactions will transition to sarcoma. Immunologists currently do not agree on whether vaccine-site associate sarcomas should be classified as type IV hypersensitivity reactions, as oncogenesis has not historically been part of this classification's definition. Risk factors for development of these sarcomas include administration of vaccines containing aluminum adjuvants.

OTHER VACCINE-ASSOCIATED REACTIONS REPORTED IN VETERINARY MEDICINE

The use of vaccines to stimulate immunity against infectious diseases has in recent years also led to investigations of suspected associations between vaccine use and immunologic diseases. A retrospective study by Duval and Giger (1996) first reported an association between vaccination in the preceding 30 days and an increased risk for immune-mediated hemolytic anemia (IMHA) in dogs, but a subsequent retrospective study found no association (Carr et al. 2002). In the Duval and Giger study, a statistically significant (p<0.001) temporal relationship between the onset of IMHA and vaccination within the month preceding IMHA diagnosis suggested the vaccination caused IMHA or accelerated preexisting IMHA in this group of 58 adult dogs, compared to 70 control dogs. Carr et al compared time from vaccination to onset of IMHA in 52 case dogs with time from vaccination to presentation in 33 control dogs and found no significant difference (p=0.79).

Concerns related to anecdotal reports of autoimmune and immune-mediated diseases associated with vaccinations led investigators at Purdue University to examine if vaccination of dogs at a young age caused alterations in the immune system, including production of autoantibodies (HogenEsch et al., 1999). In their study, a group of vaccinated dogs and group of unvaccinated dogs were followed for 14 weeks after the first vaccination. Each group consisted of 5 Beagle dogs. The dogs in the vaccinated group were injected subcutaneously with a commercially available multivalent vaccine, Vanguard-5 CV/L (Pfizer, Groton, CT) at 8, 10, 12, 16, and 20 weeks of age according to the instructions of the manufacturer. They were injected subcutaneously with an inactivated rabies vaccine, Imrab-3 (Rhone-Merieux, GA) at 16 weeks of age. The unvaccinated group of dogs received subcutaneous injections of sterile saline at the same time points. Measurements of reactivity of serum IgG antibodies with homologous and heterologous antigens were made at 22 weeks of age when the study ended. At 22 weeks of age, there was a significant increase of IgG antibodies reactive with 10 of 17 antigens in vaccinated versus unvaccinated dogs. There were no tissue lesions identified at necropsy. The investigators concluded that vaccination of dogs using a routine protocol and commonly used vaccines induces autoantibodies. The autoantibody response appeared to be antigen-driven, probably directed against bovine antigens that contaminate vaccines as a result of cell culture process and/or as stabilizers. The pathogenic significance of these autoantibodies remained undetermined.

The same group of investigators performed a follow-on study to determine if routine vaccination induced antibodies against bovine thyroglobulin and autoantibodies against canine thyroglobulin (Scott-Moncrieff et al, 2002). Beagle dogs were again used, and antibodies were measured at 8, 16, and 26 weeks of age, and immediately prior to and 2 weeks after each yearly vaccination. The study concluded after 4.5 years. Results suggested that the multivalent and rabies vaccines both induced antibodies reactive with bovine thyroglobulin, but that only the rabies vaccine induced antibodies reactive with canine thyroglobulin. No dog developed evidence of thyroid dysfunction by 4.5 years of age, and the clinical importance of the research findings was undetermined.

VACCINE-ASSOCIATED REACTIONS REPORTED IN HUMANS

It is not surprising that concerns have arisen as to whether immunizations can lead to the development of autoimmune disease or phenomena in people. One well known incident occurred in 1976 when recent recipients of the 'swine influenza' vaccine were found to have an eight-fold increased risk of developing Guillain-Barré syndrome compared to non-vaccinates (Schonberger et al, 1979). Before and since that event, the medical literature has been filled with many case reports of a wide range of autoimmune illnesses temporally associated with vaccinations, but case reports are a weak means of establishing associations or cause. In the human medicine field's search for more rigorous evidence, Shoenfeld and Aron-Maor (2000) acknowledged that the first, and to their knowledge the only, controlled experimental animal model to test the causal relation between vaccines and autoimmune findings was performed by HogenEsch et al.

In the evaluation of antigenic exposure related to a vaccine, it is important to define exposure to include the ingredients contained in the final administered vaccine. In addition to the antigens of the vaccine-preventable disease, antigens may include adjuvants (e.g., aluminum), stabilizers (e.g., gelatin), bacteriostatic agents (e.g., thimerosal), as well as various residues from cell culture or other manufacturing processes. The etiologic basis for idiopathic thrombocytopenic purpura (ITP) after measles-mumps-rubella (MMR) vaccine was found to be associated with egg protein from the cell culture (Beeler J et al, 1996; Miller et al, 2001), but the reported frequency has ranged from 1 in 22,300 to 1 in 40,000 vaccinated children.

Other diseases of immune (or possible immune) origin that have been temporally associated with vaccinations in people include myelitis, vasculitis, arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, and autism (Shoenfeld and Aron-Maor, 2000). Of this latter disease, data is conflicting on whether a causal association exists between the measles (or MMR) vaccine and autism in children.

In people, measles vaccination has also been suggested as a risk factor for inflammatory bowel disease (Ekbom et al, 1994; Thompson et al, 1995) but the study methods have been criticized (Patriarca and Beeler, 1995, Farrington and Miller, 1995) and the results not reproduced (Morris et al, 2000).

CONCLUSIONS

Knowing that the purpose of immunization is to stimulate the immune system, it should be no surprise that licensed products are "successful" in that stimulation. Further research will be necessary to define the full parameters and sequelae of that stimulation, as well as defining which specific antigens are responsible for desired and undesired antibody production.

If vaccine-associated immune-mediated diseases only occur at rates of 1 case (or less) per 30,000 vaccinates and if the immune-mediated disease is known to occur naturally, then proof of cause by statistical association in small retrospective and prospective studies will be difficult. Nevertheless immune-mediated disease, unrelated or possibly related to vaccination, is expected to occur within the companion animal population, keeping this question of relationship before us and our clientele.

The recent AVMA Council on Biologic and Therapeutic Agents' report on cat and dog vaccines, published in the Nov. 15, 2002, issue of JAVMA, acknowledged that current adverse event reporting systems need substantial improvement in the capture, analysis, and dissemination of information. An improved system of surveillance is necessary to further characterize adverse events temporally related to vaccinations.

REFERENCES

1. Beeler J, Varricchio F, Wise R (1996), "Thrombocytopenia after immunization with measles vaccines: review of the vaccine adverse events reporting system (1990 to 1994)", Pediatr Infect Dis J, vol 15, pp. 88-90.

2. Carr AP, Panciera DL, Kidd L (2002), "Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: a retrospective study of 72 dogs", J Vet Intern Med, vol 16, pp. 504-509.

3. Duval D, Giger U (1996), "Vaccine-associated immune-mediated hemolytic anemia in the dog", J Vet Intern Med, vol 10, pp. 290-295.

4. Ekbom A, Adami HO, Helmick CG, Jonzon A, Zack MM (1990), "Perinatal risk factors for inflammatory bowel disease: a case-control study", Am J Epidemiol, vol 132, pp. 1111-1119.

5. Farrington P, Miller E (1995), "Measles vaccination as a risk factor for inflammatory bowel disease", Lancet, vol 345, p. 1362.

6. Gobar GM, Kass PH (2002), "World Wide Web-based survey of vaccination practices, postvaccinal reactions, and vaccine site-associated sarcomas in cats", J Am Vet Med Assoc, vol.220, pp. 1477-1482.

7. Goldsby RA, Kindt TJ, Osborne BA (2000). Kuby Immunology. 4th ed. New York: WH Freeman and Company, pp. 395-421.

8. Hendrick MJ, Shofer FS, Goldschmidt MH, Haviland JC, Schelling SH, Engler SJ, Gliatto JM (1994), "Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991-1992)", J Am Vet Med Assoc vol 205, pp.1425-1429.

9. Hogenesch H, Axcona-Olivera J, Scott-Moncrieff C, Snyder PW, Glickman LT (1999), "Vaccine-induced autoimmunity in the dog", Adv Vet Med, vol. 41, pp.733-747.

10. Kass PH, Barnes WG Jr, Spangler WL, Chomel BB, Culbertson MR (1993), "Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats", J Am Vet Med Assoc, vol. 203, pp.396-405.

11. Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B (2001), "Idiopathic thrombocytopenic purpura and MMR vaccine", Arch Dis Child, vol. 84, pp.227-229.

12. Morris DL, Montgomery SM, Thompson NP, Ebrahim S, Pounder RE, Wakefield AJ (2000), "Measles vaccination and inflammatory bowel disease: a national British Cohort Study", Am J Gastroenterol, vol. 95, pp.3507-3512.

13. Patriarca PA, Beeler JA (1995), "Measles vaccination and inflammatory bowel disease", Lancet, vol. 345, pp.1062-1063.

14. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA, Zeigler DW (1979), "Guillain-Barré syndrome following vaccination in the national influenza immunization program, United States, 1976-1977", Am J Epidemiol, vol. 110, pp.105-123.

15. Scott-Moncrieff JC, Azcona-Olivera J, Glickman NW, Glickman LT, HogenEsch H (2002), "Evaluation of antithyroglobulin antibodies after routine vaccination in pet and research dogs", J Am Vet Med Assoc, vol. 221, pp.515-521.

16. Shoenfeld Y, Aron-Maor A (2000), "Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?", J Autoimmun, vol. 14, pp.1-10.

17. Thompson NP, Montgomery SM, Pounder RE, Wakefield AJ (1995), "Is measles vaccination a risk factor for inflammatory bowel disease?", Lancet, vol. 345, pp.1071-1074.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)
George E. Moore, DVM, MS, DACVPM, DACVIM
Pathobiology, CVM
Purdue University
1243 Vet. Pathology Bldg.
W. Lafayette, IN 47907-1243
malernee
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