It's about the adverse reactions regarding vaccination and causes of vaccine failure.

1. VACCINE FAILURE
&
POST VACCINAL REACTIONS
SUBMITTED BY- BANDITA PANIGRAHI
MVSC 1ST SEM

2. FAILURES IN
VACCINATIONS
There are many reasons why a
vaccine may fail to confer
protective immunity on ana
animal. Given is a simple
classification of the ways of
failure of vaccines.

3. Failure to Vaccinate
 Most cases of vaccine failure result from unsatisfactory or incomplete administration of the
vaccine or noncompliance with manufacturer's recommendations.
 A live vaccine may have died as a result of poor storage, the use of antibiotics in conjunction
with live bacterial vaccines, the use of chemicals to sterilize the syringe, or the excessive use of
alcohol swabs on the skin.
 Sometimes animals given vaccines by unconventional routes may not be protected. When
large flocks of poultry or mink are to be vaccinated, it is common to administer the vaccine
either as an aerosol or in drinking water. If the aerosol is not evenly distributed throughout a
building, or if some animals do not drink, they may receive insufficient vaccine.
 Inappropriate vaccination of young animals prior to loss of maternal immunity remains a
problem. Animals that subsequently develop disease may be interpreted as cases of vaccine
failure.

4. Failure to Respond
 Occasionally, a vaccine may actually be ineffective. The method of production may have
destroyed the protective epitopes, or there may simply be insufficient antigen in the
vaccine. Problems of this type are uncommon and can generally be avoided by using only
vaccines from reputable manufacturers.
 More commonly, an animal may simply fail to mount an immune response. Since
immunity is influenced by many genetic and environmental factors, the range of immune
responses in a large random population of animals follows a normal distribution. This
means that most animals respond to antigens by mounting an average immune
response, whereas a few will mount an excellent response, and a few will mount a poor
immune response.

5.  It is impossible to protect 100% of a large outbred population of animals by vaccination.
The size of this unreactive portion of the population will vary between vaccines, and its
significance will depend on the nature of the disease. Thus, for highly infectious diseases
against which herd immunity is poor and in which infection is rapidly and efficiently
transmitted, such as foot-and-mouth disease, the presence of even a few unprotected
animals can permit the spread of disease and disrupt control programs.
 In contrast, for diseases that are inefficiently spread, such as rabies, 70% protection may
be sufficient to effectively block disease transmission within a population.

6. Immuno-suppression or Underlying diseases
 Another type of vaccine failure occurs when the normal immune response is suppressed. For
example, heavily parasitized or malnourished animals may be immunosuppressed and should
not be vaccinated. Some virus infections induce profound immunosuppression. Animals with a
major illness or high fever should not normally be vaccinated unless for a compelling reason.
 Stress may reduce a normal immune response, probably because of increased steroid
production; examples of such stress include fatigue, malnutrition, and extremes of cold and
heat.
 Surgical neutering at or near the time of first vaccination does not impair the antibody
responses of kittens. Another most important cause of vaccine failure is passively derived
maternal immunity in young animals

7. A case study regarding vaccine
effectiveness-
 Analysis of an outbreak of influenza in race horses has shown some interesting and
important factors that appeared to determine vaccine effectiveness. Thus when the
effect of age was analyzed, it appears that 2-year-old horses were less susceptible than
other animals. Further analysis suggested that this increased resistance resulted from
recent vaccination of this age cohort despite other age groups possessing similar
antibody levels.
 There was evidence of gender differences in resistance (62% of females and 71% of
males were infected). There was also some evidence that vaccination at a young age (<6
months) in the presence of maternal antibody had detrimental long term effects on
protection when compared to foals first vaccinated between 6 and 18 months of age.

8. Correct Administration & Response
 Even animals given an adequate dose of an effective vaccine may fail to be
protected. If the vaccinated animal was incubating the disease before
inoculation, the vaccine may be given too late to affect the course of the
disease.
 Alternatively, the vaccine may contain the wrong strain of organisms or the
wrong (nonprotective) antigens.

9. ADVERSE CONSEQUENCES OF
VACCINATION

10.  Vaccine related toxicity is usually rare, mild, and transient, and hypothetical side effects must not dominate our
perceptions. Nevertheless, the use of vaccines is not free of risk. Residual virulence and toxicity, allergic responses,
disease in immunodeficient hosts, neurological complications, and harmful effects on the fetus are the most
significant risks associated with the use of vaccines.
 Veterinarians should use only licensed vaccines, and the manufacturer's recommendations should be carefully
followed. Since the advantages of vaccination are well documented and extensive, whereas the risk for adverse
effects is poorly documented and, in many cases, largely hypothetical.
 Traditionally, adverse events resulting from vaccine administration have been reported by veterinarians to
manufacturers or government agencies. The resulting figures have been impossible to analyze satisfactorily for two
major reasons. First, reporting is voluntary, so significant underreporting occurs. Many adverse events are regarded
as insignificant, or it may be inconvenient to report them. Second, very little data has been available on the number
of animals vaccinated. Although manufacturers know the number of doses of vaccine sold, they are unable to
measure the number of animals vaccinated.

11. A CASE STUDY-
 The use of a standardized reporting system within a very large population has permitted objective analysis
of the prevalence of adverse events occurring within 3 days of vaccine administration. Out of 1,226,159
dogs vaccinated, there were 4,678 adverse events recorded (38.2/10,000 dogs); 72.8% of these events
occurred on the same day the vaccine was administered, 31.7% were considered to be allergic reactions,
and 65.8% were considered “vaccine reactions” and were likely due to toxicity.
 Additional analysis indicated that the risk of adverse events was significantly greater for small than for
large dogs ; for neutered than for sexually intact dogs; and for dogs that received multiple vaccines. Each
additional vaccine dose administered increased the risk of an adverse event occurring by 27% in small
dogs (<10 kg) and by 12% in dogs heavier than 12 kg. High-risk breeds included Dachshunds, Pugs, Boston
Terriers, Miniature Pinschers, and Chihuahuas.
 Overall, the increased incidence of adverse events in small dogs and their relationship tomultiple dosing
suggests that veterinarians should look carefully at the practice of giving the same dose of vaccine to all
dogs irrespective of their size.

12.  Identification of an adverse event is based on the clinical judgment of the attending veterinarian
and is subject to bias. Standard case definitions of a vaccine-associated adverse event are not yet
available. On the other hand, the significance of such bias is reduced by the use of such a large
database.
 In a report from Japan, 359 dogs showed an adverse event out of 57,300 vaccinated (62.7/10,000
doses). Of these 351 dogs, 41 had anaphylaxis, 244 had dermatological signs, and 160 had
gastrointestinal signs. About half the anaphylaxis events occurred within 5 minutes of vaccination.
Additional analysis of these anaphylaxis cases reported 87% collapse, 77% cyanosis, and both in
71% of affected dogs. These are higher rates than reported elsewhere.
 This adverse event rate (62.7/10,000 vaccinated dogs) was higher than the USA (38.2/10,000).

13. Normal Toxicity
 Vaccines commonly elicit transient inflammatory reactions, and some degree of inflammation is
required for the efficient induction of protective immune responses. This may cause pain. Thus the
sting produced by some vaccines may present problems not only to the animal being vaccinated but
also, if the animal reacts violently, to the vaccinator.
 More commonly, swellings may develop at the reaction site. These may be firm or edematous and may
be warm to the touch. They appear about 1 day after vaccination and can last for about a week.
Without abscess development, these swellings leave little trace.
 Vaccines containing killed Gram negative organisms may be intrinsically toxic owing to the presence of
endotoxins that can cause cytokine release, leading to shock, fever, and leukopenia. Although such a
reaction is usually only a temporary inconvenience to male animals, it may be sufficient to provoke
abortion in pregnant females. Thus it is necessary to avoid vaccinating pregnant animals unless the risks
of not giving the vaccine are considered to be too great.
 Vaccination with either immune stimulating complex (ISCOM) vaccines or live recombinant vectored
vaccines against influenza and tetanus may induce an acute-phase response in horses.

14. Inappropriate Responses
 Vaccines may cause rare but serious allergic reactions. For example, allergic responses may
occur when an animal produces immunoglobulin E (IgE) in response not only to the
immunizing antigen but also to other antigens found in vaccines, such as egg antigens or
antigens from tissue culture cells.
 All forms of hypersensitivity are more commonly associated with multiple injections of
antigens and therefore tend to be associated with the use of killed vaccines.
 A type I hypersensitivity reaction is an immediate response to an antigen and occurs within a
few minutes or hours after exposure to an antigen.
 Type III hypersensitivity reactions are also potential hazards These may cause intense local
inflammation, or they may present as a generalized vascular disturbance such as purpura. A
type III reaction can occur in the eyes of dogs vaccinated against infectious canine hepatitis.

15.  Some rabies vaccines may induce a local complement-mediated vasculitis leading to ischemic dermatitis and
local alopecia. This type of reaction is most often seen in small dogs such as Dachshunds, Miniature Poodles,
Bichon Frises, and Terriers.
 Type IV hypersensitivity reactions may occur in response to vaccination, but a more common reaction is
granuloma formation at the site of inoculation. This may be a response to depot adjuvants containing alum or
oil. Vaccines containing a water-in-oil adjuvant produce larger and more persistent lesions at injection sites
than vaccines containing alum and aluminum hydroxide. These lesions can be granulomas or sterile abscesses.
If the skin is dirty at the injection site, these abscesses may become infected. For this reason, it is
inappropriate to administer vaccines intramuscularly to animals used for human consumption.
 Post vaccinal canine distemper virus encephalitis is a rare complication that may develop after administration
of a modified live canine distemper vaccine. The affected animal may show aggression, incoordination, and
seizures or other neurological signs. The pathogenesis may be due to residual virulence, increased
susceptibility, or triggering of a latent paramyxovirus by the vaccine.

16. Errors in Manufacture or Administration
 Some problems associated with vaccine use may be due to poor production or administration.
Thus some modified live vaccines may retain the ability to cause disease.
 Some modified live herpes vaccines or calicivirus vaccines given intranasally may spread to the
oropharynx and result in persistent infection. Indeed, such a virus vaccine may infect (and
protect) other animals in contact. Even if these vaccines do not cause overt disease, they may
reduce the rate of growth of farm animals with significant economic consequences.
 Some vaccines may trigger a mild immunosuppression. For example, some modified live
parvovirus vaccines may cause a transient decrease in lymphocyte responses to mitogens or
even a lymphopenia in some puppies. Some polyvalent canine viral vaccines can cause a
transient drop in absolute lymphocyte numbers and their responses to mitogens.

17.  Several vaccine combinations may result in transient immunosuppression between 5 and 11 days after
vaccination. For example, a combination of canine adenovirus type 1 or type 2 with canine distemper
virus suppresses lymphocyte responses to mitogens.
 This T cell suppression may be accompanied by simultaneous enhancement of B cell responses and
raised immunoglobulin levels. Rather than being a pure immunosuppressive effect, it may simply reflect
a transient change in the Th1/Th2 balance.
 Live bluetongue vaccine has been reported to cause malformations in the offspring of ewes vaccinated
while pregnant.
 The stress from vaccination may also be sufficient to reactivate latent infections; for example, activation
of Equine herpesvirus has been demonstrated following vaccination against African horse sickness.
Mucosal disease may develop in calves vaccinated against Bovine virus diarrhea.

18. Vaccine Associated Auto-immune
Diseases
 There is limited evidence that supports an association between vaccination and autoimmunity. A
retrospective analysis of the history of dogs presenting with immune-mediated hemolytic anemia (IMHA)
showed that 15 of 70 dogs with IMHA had been vaccinated within the previous month, compared with a
randomly selected control group in which none had been vaccinated.
 Dogs with IMHA that developed within a month of vaccination differed in some clinical features from dogs
with IMHA unassociated with prior vaccination. Epidemiological studies using very large databases tend to
confirm this effect, in that they show an approximately three-fold increase in diagnoses of auto-immune
thrombocytopenia, and a two-fold increase in diagnoses of IMHA in dogs in the 30 days following vaccination
compared with other time periods.
 The overall prevalence of these diseases, however, is low, and they can be diagnosed at times not
temporarily associated with vaccination. Vaccination may therefore serve as a trigger for these diseases in
some dogs, but other, undefined, stimuli must also exist.

19.  Vaccine-associated neonatal pancytopenia of calves is a lethal hemorrhagic disease results from
ingestion of maternal colostrum containing anti-BoLA antibodies.
 Contaminating thyroglobulin found in some vaccines (usually from the presence of fetal bovine
serum) may lead to the production of antithyroid antibodies in vaccinated dogs. Lymphocytic
thyroiditis has been found in 40% of Beagles on necropsy, but there was no association detected
between vaccination and the development of this thyroiditis.
 It is well recognized that Guillain-Barré syndrome, an autoimmune neurological disease of humans,
can be triggered by administration of some vaccines such as influenza vaccine. At least one case has
been reported in a dog following vaccination with a polyvalent distemper-hepatitis-parvovirus
vaccine.
 In some animals, the administration of potent, adjuvanted vaccines may stimulate the transient
production of autoantibodies to connective tissue components such as fibronectin and laminin.

20. Vaccine Induced Osteo-dystrophy
 Vaccination of some Weimaraner puppies may lead to the development of a severe hypertrophic osteodystrophy.
The disease appears within 10 days of administration of MLV canine distemper vaccine. Systemic signs include
anorexia, depression, fever, and gastrointestinal, nervous, and respiratory symptoms in addition to symmetrical
metaphyseal lesions with painful swollen metaphyses.
 Radiological examination shows radiolucent zones in themetaphyses, flared diaphyses, and formation of new
periosteal bone. Hind and fore limbs are equally affected. It is possible that the condition is triggered in genetically
susceptible animals by the vaccine.
 The disease responds well to corticosteroid therapy. In many cases, these dogs show a preexisting immune
dysfunction with low concentrations of one or more immunoglobulin classes, recurrent infections, and
inflammatory disease
 It has been suggested that Weimaraners are especially susceptible to this condition and that they therefore receive
only killed virus vaccines.

21. …contd
 A mild transient polyarthritis has been reported in some dogs following
vaccination. The dogs show a sudden onset of lameness with swollen and
painful joints within 2 weeks of vaccination. The dogs recover within 2 days. No
specific breed or vaccine has been associated with this problem.
 Vaccination against calicivirus has been associated with polyarthritis and a
postvaccination limping syndrome in cats.

22. Injection Site Associated Sarcoma
 When cats are vaccinated, any inflammation at the injection site usually resolves rapidly
and completely. In some cats, however, highly invasive sarcomas like fibrosarcomas,
malignant histiocytomas, and osteosarcomas & less common forms include
rhabdomyosarcomas, hemangio-sarcomas, chondrosarcomas, liposarcomas, and
lymphosarcomas develop at these sites many months or years after vaccination.
 These tumors were first noticed following the introduction of potent, inactivated,
adjuvanted vaccines such as those directed against rabies and feline leukemia. It has
been calculated that 1 to 3.6 sarcomas develop per 10,000 vaccinated cats in the US. The
risk increase with the number of doses of vaccine administered; a 50% increase following
one dose, a 127% increase following two doses, and a 175% increase following three or
four vaccines given simultaneously.

23.  It must be pointed out, therefore, that the chances of developing a sarcoma are considerably smaller
than the disease risks incurred by unvaccinated cats. In addition to rabies and FeLV vaccines, sarcomas
have also been associated with vaccines against feline panleukopenia, feline herpesvirus, and feline
calicivirus. Similar vaccination-related injection site sarcomas have been reported in ferrets, dogs, and a
horse.
 MECHANISM- Prolonged irritation will increase the activation state of the cells involved in inflammation
and tissue repair. The repair process involves stem cells that can differentiate to replace damaged ones.
These stem cells are long lived and so have plenty of opportunities to accumulate mutations. Signaling
pathways in stem cells promote cellular self-renewal.
 During chronic inflammation, macrophages secrete growth factors and angiogenic factors that enhance
cell growth. These factors upregulate NF-κB activity in affected tissues. Oxidants released from activated
macrophages may act as carcinogens, especially in rapidly dividing cells.

24.  NF-κB promotes both malignant transformation and metastases and may inhibit apoptosis of premalignant
cells. Fibroblasts proliferate at sites of chronic inflammation and wound healing. In some of these
fibroblasts, the cis oncogene may be activated, whereas in others, there are mutations in the gene coding
for the tumor suppressor factor p53.
 The cis oncogene codes for the platelet-derived growth factor (PDGF) receptor, and vaccine associated
sarcomas have been shown to express both PDGF and its receptor. Therefore, that lymphocytes within the
vaccine-associated sarcomas secrete PDGF, which then serves as a growth factor for the fibroblasts.
 The tumor suppressor gene p53 codes for a nuclear protein that regulates the cell cycle. Wild-type p53
increases in response to cell damage permits DNA repair before the cell divides. Damaged cells in which
p53 is absent or mutated can continue to divide, giving rise to abnormal and possibly malignant cells. As
many as 60% of injection site sarcomas may express mutated p53.

25.  To assess the risks of tumors developing at vaccination sites, it has been recommended that
vaccines be administered at standardized sites on cats. For example, current recommendations are
to inject rabies vaccine into the right pelvic limb and FeLV vaccine into the left pelvic limb (“rabies,
right; leukemia, left”).
 Vaccines should be administered as distally as possible to permit amputation if required. The site of
vaccine administration and the product used should be recorded for each vaccine to help in
assessing risk factors. Clients should be instructed to monitor injection sites for swellings or lumps
so that any developing tumors are detected and excised as early as possible.