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Vaccinosis
in Great Danes Submitted by: Background: There is
great concern among dog owners and veterinarians that some currently
used vaccines or vaccine practices (e.g., yearly vaccination)
adversely affect the health of dogs. Although few question the effectiveness of current vaccines
for preventing common infectious diseases such as parvovirus,
distemper, and rabies, the potential adverse effects of these vaccines
are just becoming apparent. More
and more owners are asking whether some vaccines used today could be
responsible for the increasing prevalence of autoimmune diseases such
as hypothyroidism, Addison's (hypoadrenocorticism), and hemolytic
anemia, especially when the vaccines are administered annually.
The situation has become so troublesome for some dog owners;
they have stopped vaccinating their dogs entirely.
The risk versus benefits of vaccinating however cannot be fully
evaluated without a clearer understanding of the frequency and types
of adverse events that result from vaccination.
The term vaccinosis describes the abnormal physiologic
changes or clinical diseases associated either directly or indirectly,
with the administration of a vaccine.
Such adverse events may be obvious when they occur soon after
vaccination, but are more difficult to identify when their onset is
delayed by months or even years following vaccination.
Yet, there has been little research conducted on the frequency
or severity of vaccine-related adverse reactions in dogs. Specific Objective: to
compare the health of fully vaccinated, partially vaccinated, and
unvaccinated, Great Dane dogs with respect to their immune status and
to identify specific vaccine types associated with a higher
concentration of auto-antibodies.
Of particular interest was the concentration of antibodies
produced against the dogs’ own thyroid gland, since an increased
level of thyroid auto-antibodies has been associated with a greater
probability of developing thyroid disease.
For example, in one study, approximately 20% of anti-thyroglobulin
positive dogs without overt signs of hypothyroidism developed thyroid
dysfunction within 1-year. Specific
Hypotheses Tested: Vaccinated
compared with unvaccinated Great Dane dogs have: 1)
A significantly higher serum concentration of antibodies
directed against their own tissues 2)
A significantly higher serum concentration of TSH and lower
concentrations of T3 and T4 hormones
3)
A significantly higher proportion of dogs with a history or
clinical signs of an autoimmune disease, particularly hypothyroidism Materials and Methods Great Danes for the
proposed study were recruited through personal contacts, the Purdue
University School of Veterinary Medicine website and the website of
the Great Dane Health Foundation of America. The intent was to enroll
100 dogs divided among the following groups: 1) Dogs with no history
of vaccination (never vaccinated), 2) Dogs with a history of
vaccination only in the first year of life (partially vaccinated), and
3) Dogs that were vaccinated regularly throughout their life (fully
vaccinated). The dogs
were required to be 2 years of age or older and of either sex or
neuter status to enter the study.
Each owner was asked to complete a 15-page questionnaire that
was developed specifically for this study.
It included questions about their dog's age, weight, sex and
neuter status, coat color, vaccine history, previous illnesses, diet
and nutritional supplements used, medications, flea and tick control,
housing, environment, etc. Each
owner was also asked to take his or her dog(s) to a veterinarian to
collect 10ml of blood, centrifuge the blood specimen, and send the
serum on ice by express mail to the laboratory of Dr. Harm HogenEsch
at Purdue University in W. Lafayette, IN.
The veterinarian was also asked to conduct a physical
examination and record any current conditions or diseases on a form
provided to them by Purdue.
The serum specimens were
assayed for the following: ♦
Total immunoglobulins IgA, IgG, and IgM ♦
Antibodies against bovine fibronectin, bovine thyroglobulin,
canine thyroglobulin, bovine DNA, murine laminin, and
porcine insulin ♦
Acute phase
protein serum amyloid ♦
Hormones including TSH, T3, and T4 ♦
Antibodies against canine distemper, parvovirus, and rabies, in
order to validate the vaccination status of the dog The test results and owner reported information were compared
between the three groups using Analysis of Variance and Covariance,
T-tests, and Chi-square tests. A
p-value of <0.05 was considered to be statistically significant.
All of the information collected from owners and veterinarians
are being kept strictly confidential.
Results: A total of 75 Great
Danes who met the eligibility requirements were enrolled in the study.
A majority of these 75 dogs were female (47 dogs), neutered (41 dogs),
and in average or optimum body condition (59 dogs).
The mean (standard deviation) age was 5.7 (2.3) years with a
minimum of 2.2 years and a maximum of 10.5 years; the median age was
5.0 years. Only 15 of the
dogs had never been vaccinated during their life Eighteen dogs had
never received a distemper vaccine, 19 dogs had never received a
parvovirus vaccine, and 23 had never been vaccinated against rabies.
It should be noted that totally unvaccinated dogs were much
harder to recruit into the study than vaccinated dogs, because many
owners of unvaccinated dogs did not have a regular veterinarian.
Therefore, they either could not or would not provide us with a
serum sample or a questionnaire completed by a veterinarian.
Very few dogs, whether vaccinated or not, had a history of
either an endocrine or autoimmune disorder. The disease most commonly
reported by owners (7 dogs) or their veterinarians (6 dogs) was
hypothyroidism.
The dogs in this study
were divided into three vaccine groups (never vaccinated, partially
vaccinated, and fully vaccinated) based on owner reports.
Therefore, it was important to document the validity of these
reports. This was done by
measuring the antibody titer against distemper, parvovirus, and
rabies, and comparing them with the owners’ answer to the question
“How frequently and when was your dog vaccinated against distemper,
parvovirus, and rabies?” A
very significant and strong correlation was found between the
owners’ responses regarding the pattern of administration of
distemper vaccine and the distemper antibody titer. A similarly strong
relationship was found for rabies. However, there was no clear-cut
relationship between the parvovirus vaccine history and antibody
titers to parvovirus. In fact, the parvovirus antibody titers of dogs
belonging to owners who said they never vaccinated or only
sporadically vaccinated their dog for parvovirus were not
significantly different from dogs belonging to owners who claimed they
had never vaccinated their dog against parvovirus. The findings with
regard to rabies and distemper antibody titers support the validity of
the owners’ answers on the questionnaire.
It is not surprising however, that many dogs unvaccinated for
parvovirus based on owners’ reports had antibody titers as high or
higher against parvovirus than dogs that were reported to have been
vaccinated against parvovirus either regularly or sporadically.
Parvovirus is commonly shed in dog feces (either the vaccine or
natural strain) and contaminates the environment of parks, homes,
kennels, etc. Once in the
environment it is highly resistant to a wide range of climatic
conditions and is readily transmitted from dog to dog, by fecal oral
contact. In contrast,
distemper and rabies virus are not stable in the environment and
transmission from dog to dog requires closer contact between
individuals. Therefore,
we believe the vaccine groups (never vaccinated, partially vaccinated,
and fully vaccinated) to which dogs were assigned in this study were
valid. The dogs vaccinated at
least once in their lifetime did not differ significantly from those
that were never vaccinated with respect to their gender, body
condition, age, weight, and height.
However, the unvaccinated dogs were significantly less likely
to have been neutered. Also, there were significant differences between the vaccine
groups related to whether the dog had a regular veterinarian and if it
had received routine medication for heartworm or flea/tick prevention.
In general, dogs in the never vaccinated group were less likely to
have received routine preventive medical care or had been surgically
neutered, compared with dogs in the vaccinated group.
However, dogs reported by owners as never being vaccinated were
not more likely to have a history of non-infectious conditions
including cancer, allergies, endocrine abnormalities, autoimmunity,
urinary tract problems, neurological disease, musculoskeletal disease,
or genetic problems. There were 7 adverse reactions reported by Great Dane
owners. Three reactions
were to vaccinations while four were to drugs or anesthesia.
None of these adverse reactions had deleterious long-term
consequences.
Specific Hypotheses Tested:
Hypothesis 1:
Vaccinated compared with unvaccinated Great Dane dogs have a
significantly higher serum concentration of antibodies directed
against their own tissues, particularly the thyroid gland Thyroiditis or inflammation of the thyroid gland is thought
to be a precursor of clinical hypothyroidism in dogs.
Approximately 40% of dogs with thyroiditis have an increased
concentration of antibodies in their blood directed against thyroid
tissue. It is not known
what triggers production of these thyroid autoantibodies.
Environmental factors such as estrogenic-like chemicals that
disrupt hormone function and viruses have been suggested as causing
the dog’s immune system to produce antibodies that destroy its own
tissues. Recently,
evidence from experiments in Beagles and epidemiological studies of
owned dogs indicate that commonly used vaccines may act to trigger
autoimmune responses, particularly against the thyroid gland.
For this reason we evaluated whether dogs receiving regular
vaccinations for distemper, parvovirus, and rabies, had higher levels
of auto-antibodies in their blood than dogs never vaccinated or
partially vaccinated. Furthermore,
we looked for a positive relationship between the number of vaccines a
dog had received and the auto-antibody titer.
While our primary interest was in auto-antibodies directed
against the thyroid gland, we also measured those directed against
connective tissue components (fibronectin), laminin, DNA, and insulin,
since such antibodies have been associated with health disorders in
people and dogs. As in previous studies,
the strongest positive relationship was shown between previous
vaccination for rabies and an antibody response to bovine fibronectin
and bovine thyroglobulin. A
strong positive association was also observed between vaccination for
distemper or parvovirus and bovine thyroglobulin.
In contrast, there was only a weak positive relationship
between previous vaccination for parvovirus and antibody to canine
thyroglobulin. It thus appears that vaccinated dogs in this study were
producing antibodies that reacted to bovine contaminants plus adjuvant
in the canine vaccines. This
reaction was evidenced by higher concentrations of antibodies against
bovine thyroglobulin, but these antibodies only weakly cross-reacted
with canine thyroglobulin. Similarly,
the increasing antibody titers to bovine laminin in dogs with regular
rabies vaccination, was likely caused by contaminants in the rabies
vaccine combined with the presence of adjuvant. These findings
alone do not tell us whether the serum auto-antibodies might be
responsible for clinical autoimmunity in dogs. They do however
warrant further investigation o determine if they play a causal role
in thyroid disease. The concentration of
anti-bovine thyroglobulin antibodies in the serum was significantly
correlated with the concentration of anti-canine thyroglobulin
antibodies Each unit increase in anti-bovine thyroglobulin antibodies
was associated with a 0.07 increase in anti-canine thyroglobulin
antibodies. This
relationship is not surprising, since we previously hypothesized that
dogs respond to impurities of bovine origin in canine vaccines by
producing anti-bovine thyroglobulin antibodies that then cross-react
with canine-thyroglobulin.
In contrast to the
findings for specific auto-antibodies, no relationship was found
between the vaccine history of dogs and the concentration of
immunoglobulins IgG, IgM, IgA, or serum level of amyloid protein (SAA).
(Figures 11A-14C) Hypothesis
2: Vaccinated compared with
unvaccinated Great Dane dogs have a significantly higher serum
concentration of TSH and lower concentrations of T3 and T4 hormones Dogs diagnosed with
clinical hypothyroidism typically have lower serum concentrations of
T3 and/or T4 hormones and an increased concentration of serum TSH
hormone. The serum T3 and
serum T4 concentrations were consistently lower for Great Danes in
this study that were previously vaccinated compared with those never
vaccinated, but these differences were not statistically significant.
However, the vaccinated dogs in this study also had
consistently lower serum concentrations of TSH compared with dogs that
were never vaccinated. In addition, no significant correlation was
found between the concentration of TSH in serum and either the T3 or
T4 concentration. These
findings when taken together, suggest the differences observed in
thyroid hormone levels between dogs in the three vaccine groups, were
more likely associated with non-thyroidal causes rather than any
abnormality in their thyroid function.
It is also possible that vaccination results in substances in
blood that interfere with the laboratory assay for T3, T4, and TSH.
These findings warrant additional studies. Hypothesis
3: Vaccinated
compared with unvaccinated Great Dane dogs have a significantly higher
risk of autoimmune diseases, particularly hypothyroidism We were unable to test
this hypothesis because only one owner of a dog in the unvaccinated
group reported having a regular veterinarian or even using a
veterinarian when their dog was ill.
Since the diagnosis of an autoimmune disease requires specific
tests that must be requested and or preformed by a veterinary
laboratory, it was impossible to know if dogs in the unvaccinated
group ever experienced an autoimmune disease. We did not anticipate
this when the study was designed.
We assumed that all Great Dane owners interested in
participating in this health-related study would either use veterinary
services regularly or would take their dog to a veterinarian when it
was sick. Because
many of the owners of dogs in the never vaccinated group had not
established a veterinary-client relationship, it was difficult to even
obtain blood samples for these dogs. Conclusions
As in two previous
studies we conducted, we confirmed that vaccinated dogs when compared
with non-vaccinated dogs have a higher concentration of antibodies in
their serum directed against bovine proteins such as thyroglobulin and
fibronectin. These
antibodies are probably produced in response to contaminants from
fetal calf serum commonly used to make canine vaccines.
These anti-bovine antibodies probably then cross-react with a
dog’s own thyroglobulin and fibronectin, resulting in detectable
concentrations of autoantibodies in their serum.
It would be difficult to design a study in pet dogs to prove
this process of cross-reaction between bovine and canine proteins
actually causes clinical signs of autoimmune disease in vaccinated
dogs. There were too many
differences between the vaccinated and unvaccinated Great Danes in the
present study to further explore the clinical consequences of
vaccine-related auto-antibodies produced against fibronectin or
thyroglobulin. The best way to
determine if repeated vaccination of Great Danes causes autoimmune
disease would be to prospectively follow a large number of regularly
vaccinated and non-vaccinated dogs from birth, performing annual
physical examinations and blood tests for autoimmunity.
In our experience however, it is unlikely owners of
unvaccinated Great Danes would actively participate in such a study.
Therefore, the long-term potential adverse consequence of
repeated vaccination is likely to remain unknown.
Until further studies are done, we recommend that all Great
Danes continue to be vaccinated using core vaccines as per guidelines
published by the American Animal Hospital Association.
You should discuss these guidelines with your veterinarian and
work together to determine how they can be individualized to fit your
dog’s life style. We would like to thank
all of the Great Dane owners for both their participation and interest
in this study. We enjoyed
communicating with many of you over the past few years and appreciate
your efforts. We plan to continue our research to make current canine
vaccines safer for all dog breeds.
We also thank the Great Dane Health Foundation and the Hayward
Genetic Foundation for their sponsorship of this study and for their
support of canine health research at the Purdue University School of
Veterinary Medicine. A more in-depth
summary of this study will be posted at www.vet.epi.edu/epi
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