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knowledge supports the statement that no vaccine is always safe, no
vaccine is always protective, and no vaccine is always indicated. However,
the information that this statement is based on is in a constant state
of flux; hence, the historical and current debate on appropriate vaccine
use.
While significant efforts have been expended and realized with respect
to vaccine efficacy and safety, their impact on product use (specifically
vaccine protocols) has largely been ignored until recently; this despite
early recommendations for less frequent revaccination. In 1978, “an
ideal vaccination program” was recommended where dogs and cats would
be vaccinated as puppies and kittens and then revaccinated at 1 year
of age and every third year thereafter.1 In 1998, the American Association
of Feline Practitioners (AAFP) debated and subsequently endorsed this
same recommendation for feline core vaccines; the AAFP recommendations
were updated in 2000. 2 Also in 1998, recommendations from a group of
canine vaccine experts were published.3 They recommended revaccination
with canine core vaccines no more than once every 3 years following
initial booster revaccination at 1 year of age. This proposed vaccination
program, and various iterations thereof, has been adopted to varying
degrees by a growing part of the profession, but misunderstandings,
misinformation, and the conservative nature of the profession have
slowed adoption of these protocols advocating decreased frequency of
revaccination.
In 2002, the American Veterinary Medical Association (AVMA) updated
their vaccine guidelines 4 after recognizing that traditional guidelines
were not compatible with the recommendations of a growing number of
veterinary practitioners and experts in the fields of vaccinology and
infectious diseases. Although many of these experts support triennial
vaccination against core diseases, there is a relative paucity of published
scientific documentation to indicate that every 3 years is any more
rational than every 2 years or any less rational than every 7 years.
For that reason, the AVMA and AAHA guidelines intentionally allow room
for individual veterinarians to apply them. Information (including discussions
on core/noncore vaccines, immunology, DOI, vaccine production and licensing,
adverse event reporting, and potential practice impact and opportunity)
is provided in this report for veterinarians to review and use as they
develop a vaccine program for their practices and their individual patients.
Many diseases we immunize against are ubiquitous. Many are serious
and some even life threatening. Some are of limited demographic concern
given the exposure risk for each patient. These factors have all been
considered in developing the AAHA Canine Vaccine Guidelines and Recommendations.
In the end, each veterinarian must do what he or she determines to be
in the best interest of the patient. Vaccination of individual animals
produces not only individual immunity but also population or herd immunity.
Since we have no readily available and reliable way to determine if
each patient has developed an adequate immune response, we encourage
the practice philosophy of vaccinating more patients while vaccinating
each patient no more than needed.
Task Force Recommendations Regarding the Selection and Use of Canine
Vaccine Antigens
Decisions on vaccine selection and use require a balance among disease
incidence and severity, vaccine efficacy (including DOI) and safety,
and the health, welfare, and lifestyle of the individual animal. When
taking all these variables into account, it becomes apparent that a
blanket or generic statement encompassing the use of all vaccine products
is impossible to make. However, based on the growing body of knowledge
in the areas of vaccinology and immunology, general vaccine guidelines
are appropriate and useful as a foundation upon which to make specific
recommendations for individual patients. The 2003 AAHA Canine Vaccine
Guidelines and Recommendations are discussed in the following sections
as well as presented in an easy-to-reference table format
[Table 1]
These guidelines are based on current knowledge with respect to disease
incidence and severity and vaccine efficacy.
Vaccine Selection: Core (Recommended), Noncore (Optional), and Not
Generally Recommended Canine Vaccines
Recommended or “core” vaccines are those that the committee
believes should be administered to all puppies (dogs <6 months of age)
or dogs with an unknown vaccination history. The diseases involved have
significant morbidity and mortality and are widely distributed. The
committee believes this group of vaccines comprises canine distemper
virus (CDV), CPV, canine adenovirus-2 (CAV-2), and rabies virus.
Optional or “noncore” vaccines are those that the committee
believes should be considered only in special circumstances because
their use is more dependent on the exposure risk of the individual animal.
Issues of geographic distribution and lifestyle should be considered
before administering these vaccines. In addition, the diseases involved
are generally self-limiting or respond readily to treatment. The committee
believes this group of vaccines comprises distemper-measles virus (D-MV),
canine parainfluenza virus (CPIV), Leptospira spp., Bordetella bronchi-septica,
and Borrelia burgdorferi.
Vaccines identified as “not generally recommended” are those
that the committee believes have little or no indication. The diseases
involved are either of little clinical significance or respond readily
to treatment. In addition, the
vaccines available against these diseases have not demonstrated clinical
efficacy in the prevention of disease and may produce adverse events
with limited benefit. The vaccines that the committee believes fall
into this category are Giardia spp., canine coronavirus (CCV), and canine
adenovirus- 1 (CAV-1).
Vaccine Frequency of Use
All commercially available vaccine products have attendant vaccine protocols
as defined by their manufacturers. These generally involve an initial
(often puppy) series, followed by recommendations for revaccination
(booster) at 1 year of age and annually (or less) thereafter. Regardless
of product chosen, the current controversy over vaccination protocols
centers on the traditional recommendation regarding revaccination schedules
for dogs >1 year of age. The currently recommended vaccination schedules
(with respect to frequency, not product choice) for dogs <1 year of
age have not been questioned. Based on a growing body of information
regarding immunology and product DOI in both animals and humans, the
need for annual revaccination has been placed in doubt. Duration of
immunity is the critical determining factor, but it defies simple definition,
principally, because it is derived from a complex interplay between
the host’s immune response (see The Immune System as it Applies to Vaccination
section) and the vaccine in question, and it is difficult to measure
in an individual animal without direct challenge. Current scientific
knowledge demonstrates that DOI varies among vaccines and is influenced
by vaccine type (e.g., modified live virus [MLV], killed, or recombinant),
route of administration, and antigen content and often extends for >1
year. This information is summarized in the following section on specific
vaccine recommendations.
Specific Vaccine Recommendations: Core Vaccines
Canine Distemper Virus (CDV): Infection with CDV causes significant
morbidity in unprotected animals and is associated with high rates of
mortality from respiratory, gastrointestinal, and neurological abnormalities;
there is minimal geographic difference in its distribution. Therefore,
all puppies should be vaccinated with a CDV vaccine, and boosters should
be administered throughout the dog’s life
[Table 1]
Dogs with unknown vaccine histories should be considered at risk and
vaccinated, and boosters should be administered throughout the dog’s
life
[Table 1]
Challenge of immunity studies have shown that the minimum
DOI for MLV-CDV vaccines derived from the Rockborn strain and the Onderstepoort
strain are 7 and 5 years, respectively, and for the canarypox-vectored
CDV vaccine, it is 1 year (not tested beyond 1 year). The minimum DOI
for these same vaccines, using antibody titers at levels that provide
sterilizing immunity, are 12 to 15 years for Rockborn and 9 years for
Onderstepoort
[Table 2]
. The canarypox-vectored CDV vaccine does not
provide sterilizing immunity in the majority of puppies receiving the
required two doses of this vaccine. The recombinant vaccine does provide
excellent immunity—infection occurs, but anamnestic (memory) humoral
and CMI responses develop and the challenged dog is protected from disease.
Therefore, following the initial vaccination series, revaccination
every 3 years is considered protective for MLV-CDV vaccines and, due
to the lack of information, revaccination every year for recombinant
CDV vaccines is considered protective.
Canine Parvovirus (CPV-2): Infection with CPV-2 causes high
morbidity and mortality in unprotected dogs primarily from gastrointestinal
disease; the organism has worldwide distribution. Therefore, all puppies
should be vaccinated with a CPV vaccine, and boosters should be administered
throughout the dog’s life
[Table 1]
. Dogs with unknown vaccine histories
should be considered at risk and vaccinated, and boosters should be
administered throughout the dog’s life
[Table 1]
Challenge studies have shown that the minimum DOI for MLV-CPV-2 vaccines
is 7 years. The minimum DOI for these same vaccines based on serological
data for sterilizing immunity is up to 10 years
[Table 2].
Therefore, following the initial vaccination series, revaccination
with an MLV-CPV-2 vaccine every 3 years is considered protective. However,
if a killed CPV-2 is being used, due to lack of DOI information, annual
revaccination is recommended unless it is used as a booster following
an initial series with an MLV-CPV-2 vaccine. In this scenario, revaccination
every 3 years is considered protective.
Canine Adenovirus-2 (CAV-2): Infection with CAV-2 causes a self-limiting
respiratory disease in some infected dogs but produces an immune response
that cross-protects against canine adenovirus-1 (CAV-1) infection, the
etiology of canine infectious hepatitis, which has worldwide distribution.
The CAV-1 vaccine has been associated with an unacceptable rate of serious
adverse events (e.g., interstitial nephritis, anterior uveitis) and
should not be administered; however, CAV-2 vaccines are safer. Therefore,
all puppies should be vaccinated with a CAV-2 vaccine, and boosters
should be administered throughout the dog’s life
[Table 1]
. Dogs with
unknown vaccine histories should be considered at risk and vaccinated,
and boosters should be administered throughout the dog’s life [Table
1].
The minimum DOI for CAV-1 and CAV-2 vaccines, based on challenge immunity
for CAV-1, is 7 years. The minimum DOI based on antibody titers is at
least 9 years
[Table 2].
Therefore, following the initial vaccination series, revaccination
every 3 years is considered protective.
Rabies Virus (RV): Infection with RV causes a fatal neurological
disease, and infected dogs are a potential source for human infection,
resulting in state and provincial laws mandating RV vaccination. Therefore,
all puppies should be vaccinated with an RV vaccine, and boosters should
be administered throughout the dog’s life
[Table 1]
. Booster revaccination
should be administered 12 months following
initial vaccine and then as required by local, state, or provincial
law. Dogs with unknown vaccine histories should be considered at risk
and vaccinated, an initial booster should be administered 12 months
later, and boosters should be administered throughout the dog's life
[Table 1].
The minimum DOI for killed rabies vaccine based on challenge studies
is 3 years; based on antibody titers, it is considered to be up to 7
years
[Table 2].
Specific Vaccine Recommendations: Optional Vaccines
Distemper-Measles Virus (D-MV) Combination Vaccine: When the
D-MV vaccine is given to a puppy between 6 and 12 weeks of age, the
measles component of the vaccine cross-protects against CDV and is not
inactivated by mater-nal antibodies directed at CDV. Protection occurs
within 72 hours of vaccination; however, the vaccine is not effective
<4 weeks of age. Puppies vaccinated with a D-MV vaccine should be vaccinated
at 3- to 4-week intervals using CDV vaccines until the immunization
series is completed [Table 1].
The D-MV vaccine is not indicated for
use in dogs >12 weeks of age, especially female dogs destined as breeding
stock, as it may result in the production of maternal antibodies to
MV that would be passed on to future puppies negating vaccine efficacy.
The D-MV vaccine may play a role in the prevention and control of CDV
in high-risk settings such as shelters.
Canine Parainfluenza Virus (CPV): Canine parainfluenza virus
is one cause of the "kennel cough" syndrome, an infection
in susceptible, unprotected dogs causing a mild, self-limiting upper
respiratory disease; the agent rarely causes life-threatening disease
in otherwise healthy dogs.
Parenteral CPIV vaccines do not block infection but only lessen clinical
disease, and vaccines produce only a short DOI. This vaccine antigen
is generally administered along with CDV, CPV-2, and CAV-2. Since these
three vaccines are recommended, the CPIV vaccine is considered optional
but recommended [Table 1].
The minimum DOI for CPIV is difficult to determine by challenge studies,
and serum antibody titers correlate poorly with protection, but the
duration of serum antibody without vaccination was up to 3 years
[Table 2]. Therefore, the value of
revaccinating dogs annually with CPIV cannot
be demonstrated; however, it is often combined with B. bronchiseptica
vaccines in dogs considered susceptible.
Leptospira spp.: Infection with Leptospira spp. can cause
clinical disease in some unprotected dogs. The organism can infect both
dogs and humans; therefore, infected dogs can serve as a source for
human infection (i.e., zoonosis) via contaminated urine. There are multiple
Leptospira serovars and minimal cross-protection is induced by
individual serovars, especially those defined to be the etiology of
recent leptospirosis outbreaks in specific geographic regions.a,5
Currently available vaccines do not contain all known serovars; therefore,
dogs considered to be at risk for infection can be vaccinated, but current
products do not provide assurance of protection
[Table 1].
Leptospira spp. products include two to four serovars; the efficacies
of these products are estimated to be between 50% to 75% and the DOI
<1 year for the majority of animals that do develop immunity
[Table 2]
. Immunity is an ill-defined term for Leptospira spp. products.
If immunity is defined as protection from infection or prevention of
bacterial shedding, then there is little or no enduring immunity. If
protection is defined as prevention of clinical signs of disease, then
duration of immunity could be >1 year. Thus, DOI for Leptospira spp.
becomes a problem of definition as to whether the goal of vaccination
is interruption of bacterial shedding and public health concerns, or
the prevention of clinical disease in the dog. It is generally agreed
that immunity, however defined, is serovar specific; thus, if only one
serovar is present in the vaccine, any protection, if provided at all,
is for that serovar (e.g., Leptospira canicola) and not the many
others that can infect the dog.
Bordetella bronchiseptica (B. bronchiseptica): Bordetella
bronchiseptica is another cause of the “kennel cough” syndrome.
Infection in some susceptible dogs generally causes a self-limiting,
upper respiratory disease and rarely causes life-threatening disease
in otherwise healthy animals. Clinical disease resolves quickly when
treated with appropriate antibiotics. Vaccination does not block infection
but appears to lessen clinical disease, and vaccines provide a short
DOI (<1 year) [Table 2]
. It is also unknown whether current vaccine
strains protect against all field strains. Animals considered to be
at risk may benefit from vaccination followed by boosters at intervals
in line with their risk of exposure
[Table 1].
Borrelia burgdorferi (B. burgdorferi): Infection with B.
burgdorferi can cause clinical disease syndromes in some susceptible
dogs; most dogs infected are subclinically infected. While the organism
infects both humans and dogs, it is not a direct zoonosis but a shared-vector
zoonosis. The distribution of the tick vector involved is geographically
limited and therefore the incidence of exposure is similarly geographically
limited. Dogs previously exposed to B. burgdorferi do not benefit
from vaccination and prevention of exposure to the tick vector is an
effective preventive approach. Animals considered to be at risk may
benefit from vaccination followed by boosters at intervals in line with
their risk of exposure [Table 1].
The minimum DOI for B. burgdorferi vaccines is 1 year
[Table 2].
Specific Vaccine Recommendations: Not Recommended Vaccines
Canine Coronavirus (CCV): Infection with CCV causes mild
gastrointestinal disease unless concurrent infection with CPV
occurs. The virus does not generally cause disease in dogs >6
weeks of age and is not indicated in adult dogs. In at least one
study, it was shown that vaccination with CPV protected puppies
against challenges with both viruses. The incidence of disease
and DOI is not known. Vaccination is not indicated in puppies
>6 weeks of age, and vaccination of adult dogs is not indicated
[Table 1]
. At present, there is no indication that this organism produces
a disease of clinical significance; therefore, administration of a CCV
vaccine is not recommended.
Similar to CPIV, CCV does not cause clinical disease in experimentally
challenged susceptible puppies, even those as young as 4 to 6 weeks
of age; thus, challenge studies cannot be done unless pups are given
immunosuppressive doses of corticosteroids. Serum antibody titers do
not correlate with protection from CCV infection. Thus, for a virus
that has not been shown to cause significant disease, and where serum
antibodies don’t correlate with resistance to infection,
DOI is impossible to determine [Table 2]
. Duration of immunity for CCV is a moot point
since a need for the vaccine has not been demonstrated. It has been
reported that DOI for CCV is the lifetime of the animal whether vaccinated
or not as a result of natural subclinical infection and agerelated
resistance. Revaccination with a CCV vaccine in the adult dog cannot
be justified, nor has it been shown to have value in preventing disease.
Giardia spp.: Infection with Giardia spp. can be subclinical
or can cause small bowel diarrhea. The incidence of disease is generally
<10% and approximately 90% of dogs respond to therapy; the disease is
usually not life-threatening. There are multiple strains of Giardia,
and it is unknown whether the vaccine is of value in more than one heterogeneous
isolate. The vaccine does not prevent infection but may reduce or eliminate
shedding of the organism and reduce clinical signs, which are rarely
seen except in very young puppies concurrently infected with certain
viruses and/or bacteria. The DOI is considered to be 1 year
[Table 2].
Vaccination against Giardia spp. is not generally recommended
[Table 1].
Canine Adenovirus-1 (CAV-1): Infection with CAV-1 can
cause acute and potentially fatal hepatic disease in unprotected
animals, and some dogs can experience chronic debilitating
disease. Although CAV-1 infection is rarely documented in dogs in
North America, the organism is still maintained in nature, and if
widespread vaccination were discontinued, it is likely that the
incidence of the disease would become common. Nevertheless,
since excellent cross immunity is provided against CAV-1 by
administering the CAV-2 vaccine and the use of CAV-2 results in
less frequent adverse events, vaccination using a CAV-1 vaccine
is not recommended
[Table 1].
Discussion and Supporting Literature
The genesis of these canine vaccine guidelines and recommendations
was to inform practitioners of the current vaccine controversy, clarify
any misunderstandings, and encourage practitioners to recognize that
immunization of patients is a medical procedure. In addition, the Task
Force members felt it was important to provide practitioners with relevant
supporting information. While it is beyond the scope of this report
to thoroughly discuss the extensive body of knowledge with respect to
vaccinology, certain key concepts and principles are fundamental to
the understanding and critical evaluation of these guidelines
and recommendations. What follows is a synopsis of some integral
concepts pertaining to immunology, DOI, serological testing,
vaccine production, adverse event reporting, legal implications
of biological use, and potential practice impact
and opportunities of adopting these guidelines. Some important vaccination
“do’s and don’ts” are summarized in Appendix 2.
The Immune System as it Applies to Vaccination
Understanding the immune system provides a basis for comprehending the
nature of vaccine immunity. The following summary of the salient principles
is further supported by suggested texts with more comprehensive discussions
and explanations.6-13
Two major types of immunity prevent or limit infectious diseases: nonspecific
(innate) immunity and specific (adaptive) immunity. In nature, it is
innate immunity (including skin, hair, tears, normal microbial flora,
and mucus and acidity of the gut) that prevents a majority of pathogens
from infecting and/or causing disease in animals. Innate immunity also
includes type-1 interferons (IFNs), some cytokines (e.g., interleukin-1
[IL-1], tumor necrosis factor [TNF]), complement components, neutrophils,
and natural killer (NK) cells. This first line of defense is already
active or immediately activated in response to inherent or elaborated
chemical substances of the infectious agent. Unfortunately, current
vaccines only occasionally have a significant beneficial effect on innate
immunity; however, immunomodulators (i.e., nonspecific immune stimulants),
some new experimental vaccines, and certain drugs are being designed
and targeted toward enhancing innate immunity as a nonspecific method
for disease prevention.
Adaptive immunity is characterized by specificity and memory and is
primarily or exclusively the type of immunity stimulated when an animal
receives a vaccine. This specific immune system is comprised of:
1. Humoral (antibody) immunity, where differentiated B lymphocytes
(plasma cells) produce the four immunoglobulin classes: IgG, IgM, IgA,
and IgE; phagocytic cells and effector molecules (e.g., complement)
also play an important role.
2. Cell-mediated immunity (CMI) is comprised of T lymphocytes
and their effector molecules, including T helper cells, T regulatory
cells, T cytotoxic cells, macrophages, and a number of products of the
cells called cytokines (e.g., IFN-ã , IL-2, IL-4, IL-12, TNF).
The Immune Response to Vaccination or Infection
When an animal is vaccinated or infected, the immune response includes
differentiation and expansion of clones of antigen-specific T and B
cells that serve as effector cells for immediate protection and memory
cells that provide long-term immunity. The effector cells themselves
are usually short lived, dying in days or weeks after stimulation. Memory
cells, on the other hand, survive for years, often for the life of an
animal for some vaccines and infections. Memory T and B cells and the
antibodies produced by long-lived memory effector B cells cooperate
to provide protection from challenge at a later time in life for the
vaccinated animals that come in contact with the pathogen. Available
information suggests that vaccinal protection from infection and/or
disease in the dog is regulated primarily by humoral immunity and secondarily
by cell-mediated immunity. This finding is particularly true when vaccination
is known to prevent reinfection (sterilizing immunity). This is the
ultimate form of immunity because disease cannot develop when infection
is blocked or infection is significantly limited. Sterilizing immunity
occurs after effective vaccination (protection) against certain pathogens
such as CDV, infectious canine hepatitis, and CPV.
However, when vaccination fails to protect against infection and instead
protects against the development of clinical disease (as is the case
for parenteral CPIV vaccination), systemic and local CMI together with
humoral immunity (including local IgA antibodies) all play a critical
role in preventing or reducing the severity of disease—not by preventing
infection but by limiting its effects or keeping the infection localized.
A CMI response is generally most effective against intracellular pathogens,
while antibodies are usually most effective against toxins or pathogens
in the extracellular areas. Whether a CMI or humoral response or both
are responsible for controlling or preventing the clinical disease depends
on the route of infection and the pathogenesis (the colonization and
replication) of the infectious agent. For instance, prevention of clinical
disease by many of the respiratory or gastrointestinal tract pathogens
requires generation of mucosal CMI and/or humoral immune responses,
with IgA being the most effective antibody class.
It is essential to note that the mechanism of protective immunity
in a vaccinated dog is very different from immunity in a naive dog
that strives to recover from a natural infection. Antibody is usually
present in a vaccinated dog and functions to limit or prevent infection.
It is never present at the time of infection in a naive animal. Furthermore,
CMI and humoral immunity due to memory cells is stimulated in minutes
to hours (i.e., anamnestic response) when a vaccinated animal is infected;
whereas it takes days or weeks (primary response) to be stimulated in
a nonvaccinated, immunologically naive dog.14,15
Types of Vaccines
Just as the natural immune response depends on the type of antigen and
the pathogenesis of the organism, these factors must also be considered
in order for a vaccine to induce an appropriate immune response. There
are several different types of commercially available canine vaccines.
The most common vaccines currently in use are infectious vaccines, including
MLV and live vectored vaccines. There are also noninfectious vaccines,
including killed whole cell vaccines, subunit killed vaccines, and
recombinant subunit vaccines. 3,7,11-13
Modified live virus vaccines, consisting of avirulent or attenuated
viruses that infect the host, are the most common canine viral vaccines.
Such vaccines are highly efficacious, inducing stronger local immune
responses than comparable killed products through the induction of serum
neutralizing antibodies, local antibodies, and systemic and local CMI
responses. The MLV vaccines create an immunity that is similar to immunity
after an animal recovers from natural infection. There are also modified
live bacterial vaccines consisting of avirulent or attenuated bacteria
(e.g., B. bronchiseptica) and, similar to MLV vaccines, the
modified live bacterial vaccines are often more effective than their
killed counterparts.
The canarypox viral vectored vaccine for canine distemper virus has
the ability to induce CMI and humoral immunity, but the humoral response
is not as rapid or robust as the antibody responses engendered by MLV-CDV
vaccines. When the canarypox viral vectored vaccine is used in puppies,
at least two doses are required for immunity; whereas one dose of the
MLV-CDV vaccine induces a strong, long-lasting immunity when passively
acquired CDV antibody is not present in the puppy (e.g., >12 weeks;
see Duration of Immunity section). Recent serological data showed that
a third dose of CDV recombinant canarypox viral vectored vaccine induces
an anamnestic antibody response equivalent to the response achieved
with a dose of MLV-CDV, suggesting immunity for the recombinant product
will last for >1 year and likely up to 3 years.b,16
Killed canine viral vaccines include vaccines for CPV-2, CCV, and rabies
virus. Killed vaccines generally require two doses (rabies is an exception),
because the response is slower and the immunity is predominantly but
not exclusively systemic antibody with CMI limited to T helper type-1
effector cells and little or no IgA antibody on mucosal surfaces. Similarly,
the killed bacterial products produce predominantly a systemic antibody
response. The killed and subunit products include two to four serovars
of Leptospira spp., killed B. burgdorferi (Lyme disease),
B. bronchiseptica, and a killed parasite vaccine for Giardia.
There is also an OspA Borrelia burgdorferi recombinant subunit
vaccine.
Immunological Factors Determining Vaccine Safety
Several characteristics of vaccines are integral to determining product
safety and efficacy, including the nature and dose of the antigen, the
use of adjuvants, and the number of vaccinal components in any given
product. Although increasing the number of components in a vaccine may
be more convenient for the practitioner or owner, the likelihood for
adverse effects may increase. Also, interference can occur among the
components. Care must be taken not to administer a product containing
too many vaccines simultaneously if adverse events are to be avoided
and optimal immune responses are sought.
It is often stated that MLV vaccines are the most efficacious but that
killed vaccines are the safest products; however, in light of advances
in vaccine technology, this statement should be carefully reexamined.11,13,14
Presumably, killed vaccines are safest because they cannot cause the
disease for which the vaccine was designed to prevent; however, killed
vaccines are much more likely to cause hypersensitivity reactions (e.g.,
immunemediated disease). If they fail to protect because of poor or
no CMI or local humoral immunity, or because it takes much longer to
provide protection (e.g., the requirement for two doses of killed CPV-2
for protection), then they clearly are not “safer.” Modified live virus
vaccines can and do cause disease because attenuation is a balance
between maintaining infectivity while eliminating its pathogenicity.
Individual response is dependent on the status of the recipient’s immune
system. Thus, an attenuated pathogen in a host which is severely immunosuppressed,
or genetically more susceptible, may result in the vaccine causing the
disease for which it was designed to prevent. For example, an MLV canine
distemper vaccine given to black-footed ferrets will induce clinical
disease and death.17 Furthermore, in a small percentage
(estimated 0.01%) of dogs, the MLV-CDV vaccine may cause postvaccinal
encephalitis.15,18
The Immune System and Frequency of Revaccination
When vaccinating an animal, the age of the animal, the animal’s immune
status, and interference by maternal antibodies in the development
of immunity must be considered. Research has demonstrated that the presence
of passively acquired maternal antibodies significantly interferes with
the immune response to many canine vaccines including CPV, CDV, CAV-2,
and rabies vaccines. Age of the animal is also an important consideration.
Puppies <4 months of age may be more susceptible to disease, and they
are the main target for core vaccines. Also, very young and possibly
very old animals may have a diminished response to vaccination due to
agerelated suppression of the immune system. Several
other illnesses (e.g., neoplasia, immunemediated disease, endocrine
diseases) and their treatments (e.g., chemotherapeutic medications,
immunosuppressive drugs) can influence the immune response to vaccines
and should be taken into account when vaccinating individual animals.11-13,18,19
When a healthy puppy’s immune system is initially activated by vaccines
through antigenic stimulation, a robust humoral and CMI response is
expected to develop with concomitant effector and memory cells. If
a pup fails to respond, primarily due to interference by passively acquired
maternal antibody, it is necessary to revaccinate at a later time to
ensure adequate immunity. Multiple vaccinations with MLV vaccines are
required at various ages only to ensure that one dose of the vaccine
reaches the puppy’s immune system without interference from passively
acquired antibody. Two or more doses of killed vaccines (except rabies)
and vectored vaccines are often required to induce an immune response,
and both doses should be given at a time when the passively acquired
antibody can no longer interfere. Thus, when puppies are first vaccinated
at >16 weeks of age (an age when passively acquired antibodies generally
don’t cause interference), one dose of an MLV vaccine, or two doses
of a killed vaccine, are adequate to stimulate an immune response. When
MLV vaccines are used to immunize a dog, memory cells develop and likely
persist for the life of the animal. Resident memory cells respond rapidly
providing an anamnestic immune response at the time of challenge (infection)
with the pathogen.
So why revaccinate animals with these products annually when the minimum
DOI (memory cells and antibody) is many years, if not a lifetime, for
some of the vaccines? Ironically, there is no scientific basis for
the recommendation to revaccinate dogs annually with many of the current
vaccines that provide years of immunity (e.g., CDV, CPV-2, rabies);
however, there are other vaccines that often provide <1 year of immunity
(e.g., B. bronchiseptica, Leptospira spp.).3,14,15
Vaccinating an animal multiple times at intervals <2 weeks is likely
to cause a hypersensitivity reaction in genetically predisposed animals,
and a less than robust protective immune response develops.15
The Critical Interplay Among Vaccine Efficacy, Safety, and Frequency
of Administration (CDV as an example)
Obviously, a killed CDV vaccine (none are available commercially) will
not cause disease, but the killed CDV vaccines produced prior to the
1960s failed to protect most dogs from disease, and when protection
was inferred, it was short lived. That is the main reason why killed
CDV vaccines are currently not produced. Another reason is the inability
of biologics producers to make an efficacious product for dogs although
effective killed CDV vaccines have been produced for use in zoo and
wildlife species.17,18 In contrast to both conventional
MLV and killed CDV vaccines, the canarypox viral vectored CDV vaccine
won’t cause disease (e.g., postvaccinal encephalitis), but, unlike killed
vaccines, it does provide immunity. The kinetics of the immune response
are much slower with the vectored CDV vaccine than with the MLV-CDV
vaccine, because for immunity to develop, a second dose of vectored
vaccine is required. Thus, in humane shelters or puppy rearing facilities
where exposure to CDV is common, MLV vaccines are essential if a vaccine
is expected to protect prior to infection with wild type (i.e., street
virus) CDV. In fact, the best product in an environment where CDV is
prevalent is a combined vaccine that contains both measles virus (MV)
and CDV. This type of vaccine is recommended because MV will provide
protection from disease with CDV at a much earlier age than CDV-only
vaccines, as the MV vaccine is not inhibited by passively acquired CDV
antibody.15,17
Duration of Immunity
Estimating Duration of Immunity and Frequency of Revaccination
It’s believed that the annual revaccination recommendation originated
in the late 1950s when MLV-CDV vaccines were first introduced. This
recommendation was based in part on the observation that approximately
one-third of the dogs vaccinated with a first generation CDV vaccine
as part of a limited experimental trial did not have antibody titers
considered protective 1 year after vaccination. Therefore, to ensure
the canine population had a protective antibody titer, James A. Baker
recommended that all dogs should be revaccinated annually as it was
not practical nor cost effective to test each animal for antibody.20
At that time, there were very few vaccines (notably CDV and CAV-1),
few people were vaccinating their dogs, and the practice of vaccination
for companion animals was not well established or accepted. In 1961,
Piercy wrote the following regarding annual administration of the canine
distemper vaccine:
“It is felt, therefore, that the usefulness of booster injections in
dogs already immune is still open to question and cannot be truly evaluated
until considerably more research has been done. The value of revaccinating
dogs whose antibodies have declined to a low level, however, is not
in doubt. Although a serum analysis (antibody titer) is the most scientific
way of judging the need for revaccination, in practice the owner would
presumably be obliged to pay a fee for the examination and a further
fee should revaccination be advised. The alternative, and less expensive
way to the owner, is simply to have the animal revaccinated if there
is a reason to doubt its immune status and it is likely to be exposed
to infection. The practitioner is favorably placed to advise what should
be done in light of such local circumstances as the incidence of canine
distemper in his district, the history of the animal concerned, the
risk involved in going to shows and kennels and other similar hazards.”21
Thus, the practice of annual revaccination was accepted as a “principal
of vaccination.” Forty years later, we are finally reviewing the recommendation
of annual revaccination. This critical review is based on scientific
information and the knowledge of vaccines and immunity which have accumulated
over that period.
As we analyze Piercy’s statements, it is obvious that a significant
amount of information has been developed to answer the questions posed
40 years ago, but the practice of vaccinating dogs has not changed.
1. Piercy stated: “The usefulness of booster injections in dogs already
immune is still open to question and cannot be truly evaluated until
considerable more research has been done.” This statement was made with
specific reference to the CDV vaccine. We now know that booster injections
are of no value in dogs already immune, and immunity from distemper
infection and vaccination lasts for a minimum of 7 years based on challenge
studies and up to 15 years (a lifetime) based on antibody titer
[Table 2].
2. Piercy comments: “The value of revaccinating dogs whose antibodies
have declined to a low level, however, is not in doubt.” Indeed, it
is in doubt! Dogs with a CDV antibody titer, no matter how low when
challenged, may become infected if antibody levels are below titers
which provide sterilizing immunity (i.e., resistance to infection),
but they will have protection from clinical disease mediated by an anamnestic
humoral and CMI response. However, if after vaccination “no antibody”
is detected in the dog’s serum, then there is “no doubt,” as suggested
by Piercy, that revaccination will be of value in boosting the animal’s
immune response.
3. Piercy was very perceptive when he stated, “a serum analysis is
the most scientific way of judging the need for revaccination.” This
is absolutely correct, and antibody titer is of great scientific value
in determining if the dog has sterilizing immunity. Piercy emphasized
the importance of antibodies since he didn’t know about CMI; however,
antibody is very important for protecting the vaccinated dog from CDV,
as well as several other canine viral infections.
4. The economics of the 1960s remains unchanged today. Piercy’s statement
that “it would be less expensive to vaccinate than to have the animal
bled and an antibody titer performed” remains, for the most part, relevant
to today’s practice economics. However, the ethical issue that our profession
struggles with today is whether economics justifies giving an animal
a drug (vaccines are biologic drugs) that is not necessarily required.
As a minimum, we should allow pet owners to make this choice rather
than make it for them.
5. Piercy’s advice on risk assessment analysis and making the decision
to vaccinate is an important medical issue and excellent advice that
should receive careful attention whenever vaccines are administered.
Which vaccines should be given? When and how often do they need to be
given? The answers will undoubtedly vary according to which geographic
region the dog resides, the lifestyle of the dog, the age and medical
history of the dog, as well as the needs and expectations of the owner.
Such questions must be asked if the animal is to receive the best medical
care.
There are very few published studies on the minimum DOI for canine
and feline vaccines and this is compounded by the fact that the criteria
for determining DOI cannot be easily agreed on. Some researchers suggest
that the only true way to determine DOI is by way of a prospective study
that would be comprised of two (one group vaccinated; one group nonvaccinated)
relatively large groups of dogs (representing common breeds) housed
within a pathogen-free environment; therefore, at the end of the study,
the nonvaccinated group would remain antibody-negative. Both groups
would then be challenged with virulent isolates of each of the pathogens
for which the vaccines were designed to provide protective immunity.
Few minimum DOI studies using this study design have been done, and
few, or none, will be done due to the high cost and difficulty of maintaining
control (i.e., negative) animals. More important, based on current knowledge
of immunity resulting from vaccination, studies of this type need not
be done.17,18,22-26
There is no indication that the immune system of canine patients functions
in any way different from the human immune system. In humans, the epidemiological
vigilance associated with vaccination is extremely well-developed and
far exceeds similar efforts in animals whether companion or agricultural.
This vigilance in humans indicates that immunity induced by vaccination
in humans is extremely long lasting and, in most cases, life-long. Current
information (as presented in the section on Task Force Recommendations
Regarding the Selection and Use of Canine Vaccine Antigens and Table
2) supports the contention that immunity to canine vaccines persists
for years.
The canine core viral vaccines have been demonstrated by challenge studies
to provide a minimum DOI of at least 3 years, and up to 7 years for
some vaccine antigens.3,14,15,27-29 When antibody
titers considered to provide sterilizing immunity are evaluated, this
minimum DOI is even longer
[Table 2].
3,14,15,18,30
Duration of immunity for bacterial vaccines is considerably different
than for viral vaccines. In contrast to viral immunity, bacterial immunity
from vaccination is generally limited to <1 year, and the efficacy
of most of the bacterial products is considerably less than for the
viral products and directed at minimizing clinical signs of the disease
in question. Protection from reinfection (sterilizing immunity) generally
does not occur with canine bacterial vaccines.
Antibody titers from bacterial vaccines generally do not correlate directly
with sterilizing immunity, and they would be significant only if there
was no antibody detected after vaccination.30
This would be a clear indication that the vaccine failed to stimulate
an immune response. Such vaccines should be given again or another product
should be used. Bacterial vaccines, especially killed whole organism
products like certain Leptospira spp. products or B. bronchiseptica
given systemically, are much more likely to cause adverse reactions
than subunit or live bacterial vaccines or MLV vaccines, especially
if given topically. Several killed bacterial products are used as immunomodulators/adjuvants.
Thus, their presence in a combination vaccine product may
enhance or suppress the immune response or may cause an undesired immune
response (e.g., IgE hypersensitivity or a class of antibody that is
not protective).3,14
Serological Tests to Monitor Immunity
Antibody titer tests are controversial, generally because many individuals
fail to understand their significance. Furthermore, there is substantial
confusion regarding the roles of humoral immunity and CMI in vaccinated
versus naive animals.31 When the protective mechanism
of immunity in a naive dog infected with CDV is considered, the mechanism
of recovery involves CMI and antibody, with CMI playing a primary
and critical role. When one considers protective immunity to CDV in
a vaccinated animal, antibody plays the primary role, because it prevents
infection (sterilizing immunity) or limits the infection, and CMI plays
a minor role.17,18,31 When naive animals are infected
with CPV-2, virus-neutralizing antibody promotes recovery and viral
elimination; CMI plays a limited role in this scenario.32
Conversely, in a vaccinated animal, antibody prevents infection. If
infection occurs, antibody increases rapidly and restricts infection
(often to lymphoid cells) so there is little or no viral infection of
gut epithelial cells and no fecal shed of the virus. These are only
two examples, but there are many more examples where antibody plays
the principle role in protective immunity in the vaccinated, but not
necessarily the naive, animal.14,15
How then should antibody titers be used in clinical practice to monitor
vaccine immunity? They can be helpful in the following ways:
• to determine if there has been an immune response following vaccination
• to determine the duration of immunity
• to ensure the vaccine is immunogenic
• to know precisely when to vaccinate the puppy
• to determine whether the animal is a “low or nonresponder” to certain
vaccines
The important issue regarding antibody titers is not their value but
the accuracy of the results reported from various laboratories. To have
any clinical value, any test used to determine an individual’s immunity
must be standardized against an accepted reference and demonstrate a
very high degree of specificity and sensitivity. It is reported in the
literature that titers of 20 for CDV and 80 for CPV are protective.
30,32 However, what is often not reported, or
little understood, is that the test for CDV must be the virus neutralization
(VN) test, and the test for CPV-2 should be the hemagglutination inhibition
(HI) test performed with pig or monkey erythrocytes or the VN test,
if those titer values are to be used. Those are the tests (VN and HI)
that correlate with immunity by challenge studies. None, or few, of
the commercial laboratories perform these tests, and the results of
enzyme-linked immunosorbent assay (ELISA) or fluorescent antibody (FA)
tests may not correlate with the titers from the VN and HI tests. Thus,
antibody titers are useful if you have a laboratory that performs the
correct test, or if a test like the VN and HI or another test that has
been standardized to correlate with protective immunity were available.
Veterinarians should be sure that the laboratories they use for serological
testing adhere to these principles.
Recently an “in-office test” was approved for detection of antibody
to CDV and CPV-2 in dogs.c The test is designed
so that a positive sample indicates that the antibody level in the
sample is above the titer that provides sterilizing immunity for these
respective viruses. A negative test result shows the titer to be below
the level providing sterilizing immunity but does not indicate the animal
would be susceptible to developing clinical disease if challenged by
exposure, because infection could lead to an anamnestic (secondary)
response, thus no clinical disease. The test is useful if the clinician
needs to have some assurance that a vaccinated animal has immunity to
CDV and/or CPV-2. These are the two most important viruses in the list
of core vaccines. It is not necessary to determine a titer for rabies
since revaccination once every 3 years after the first year is required
and the 3-year rabies vaccines have that period as a minimum DOI. The
CAV-1/CAV-2 titers need not be done, because exposure as well as vaccination
with CAV-2 ensures protection from CAV-1, the more important pathogen
of the two CAVs.
Although the committee does not feel it is necessary to determine titers
to these core viruses on an annual basis because of the long minimum
DOI for these products, titers can be used for your and/or your client’s
assurance that the animal has immunity. Experience with postvaccination
titers for CDV, CAV, and CPV shows that sterile immunity lasts for years;
thus, if the test is positive 1 year after vaccination, it is likely
to be positive >3 years after vaccination. The primary reason for
the test is to ensure that you have a positive test after completing
the puppy vaccination series. For example, if you have vaccinated at
6 to 8, 9 to 11, and 12 to 14 weeks of age and test the serum >2
weeks after the final vaccination at 14 to 16 weeks, the test should
be positive. If the test is negative, then you should revaccinate again
immediately. If the test is not positive shortly (>2 weeks) after
the final vaccination, it suggests that the animal was not immunized.
If you waited until 1 year of age, as we do now, the animal would potentially
be susceptible during the most critical time in its life, the time when
the animal needs to have vaccinal immunity. Experience with the test
demonstrates greater than 90% of the dogs tested after the puppy series
and up to 3 years after vaccination are positive, an indication they
have sterile immunity and don’t need to be revaccinated with core vaccines.33
Licensing of Vaccine Products
The licensing and production of veterinary biological products is regulated
by the U.S. Department of Agriculture (USDA) under federal legislation,
21 U.S.C. § 151, et. seq., commonly known as the Virus-Serum-Toxin
Act (VSTA) of 1913 (amended in 1985 and again in 1988).34
This legislation gives the Secretary of Agriculture the ability to
prohibit
the sale of any “worthless, contaminated, dangerous, or harmful virus,
serum, toxin, or analogous product intended for use in the treatment
of domestic animals.” The regulations created by the Secretary of Agriculture
under the VSTA are found in Title 9 of the Code of Federal Regulations
(9 CFR).34 These regulations define “biological
products” as all viruses, serums, toxins, or analogous products which
are intended for use in the treatment of animals and which act primarily
through the direct stimulation, supplementation, enhancement, or modulation
of the immune system or immune response. The Center for Veterinary
Biologics (CVB) is the regulatory agency within the USDA responsible
for overseeing veterinary biological products. Its mission is to ensure
that pure, safe, potent, and effective veterinary biologics are available
for the diagnosis, prevention, and treatment of animal diseases. The
CVB reviews license applications for production facilities and biological
products, establishes licensing and testing requirements and procedures,
reviews supporting data involved in the licensing process, works to
ensure that veterinary biological products are produced and maintained
in compliance with regulations, and conducts assays on veterinary biological
products.
The following is intended to provide a general overview of the considerations
used by the CVB for licensure of biological products. In order to provide
pure, safe, potent, and efficacious products, the CVB requires each
manufacturer to file an “Outline of Production” for each product, which
details how and where the product will be manufactured. Products can
only be manufactured in an approved facility that undergoes periodic
inspection. However, in the licensure of biological products, the exception
is the rule. This is due to the nature of biological products and evolving
technologies. The requirements set forth in the regulations can be
modified by agreement of the CVB and the manufacturer as specified in
the Outline of Production.
Overview
In order to market a veterinary biological product, a firm must obtain
a product license and an establishment license from the CVB. In order
to obtain an establishment license, firms must establish the appropriateness
of the facility for the product in question as well as the appropriateness
of the qualifications of the personnel involved in developing and producing
the product, and the facility must be inspected by the CVB. In order
to obtain a product license, firms must submit:
• An application that includes an Outline of Production, which is a
detailed analysis of the proposed production. Once approved, firms cannot
deviate from the Outline of Production without permission from the CVB.
• The labels and claims to be used with the product, which must be reviewed
against data submitted and approved by the CVB.
• Supporting data, including data from studies to support efficacy,
safety, and field studies. The CVB reviews and approves protocols prior
to the initiation of the studies to ensure quality of design and acceptability
of the data generated. Applicants must demonstrate to the satisfaction
of the CVB that the proposed product is pure, safe, potent, and efficacious.
• Three consecutive serials for testing by the CVB. A “serial” is an
identifiable, homogeneous quantity of completed commercial product.
Each serial must be produced according to the Outline of Production
from separate batches of medium, cells, production serum, and other
applicable production components. The purpose is to demonstrate commercial
consistency of production.
• Samples and the firm’s test results from each serial must be sent
to the CVB once the product and establishment are licensed. The serial
cannot be released for commercial sale until the firm is notified by
the CVB.
Purity
Purity is the quality of a biological product (in its final form) that
ensures the product is free of extraneous microorganisms and material
(organic or inorganic) which can adversely affect safety, potency, or
efficacy (9 CFR 1.101.5 (c)). Purity of biological products is determined
by test methods or procedures established by the Animal Plant Health
Inspection Agency (APHIS) or established in the approved Outline of
Production for the product. Purity is first determined (by the firm)
and confirmed (at the CVB) by testing of Bacterial Master Seeds, Viral
Master Seeds, and/or viral Master Cell Stocks created (in a licensed
biological production facility) and used to produce the product. Purity
evaluations of biological products continue throughout the production
process and conclude with final product testing. This testing ensures,
to a reasonable level of confidence, that all components of biological
products are correctly identified and free of contaminating agents (pathogenic
or not). The exact specifications of the testing performed depend to
a great extent on the nature of the antigen (or microorganism).
Safety
Safety is defined as freedom from properties causing undue local or
systemic reactions when used as recommended or suggested by the manufacturer
(9 CFR 1.101.5 (d)). As with purity, safety testing begins with evaluation
of the Master Seed and concludes with testing of each serial prior to
release. For Master Seed evaluation, an amount of Master Seed equivalent
to one dose is administered to each of 10 susceptible dogs, followed
by daily observation for 14 days. The Master Seed is found unsatisfactory
if unfavorable reactions occur in any of the dogs during the observation
period. This test is designed to detect major safety problems. Relatively
rare safety issues will be seen either during field safety tests that
involve larger numbers of animals or by postmarketing surveillance.
One of the requirements for product licensure is to test the final product
(at the titer and dose for commercially released product) using vaccine
from at least two prelicensing serials in a minimum of 600 animals,
of which at least one-third needs to be of minimum age. Many companies
use 1,000 or more animals. Safety
testing for serial release involves the administration of 10 dog doses
to each of two healthy dogs for 14 days.
Potency
Potency is the relative strength of a biological product as determined
by test methods or procedures established by the CVB, or in the approved
Outline of Production for a product (9 CFR 1.101.5 (f)). The purpose
of potency testing is to ensure that each serial of vaccine produced
is equal to, or more potent than, a reference serial (equal to or more
antigen than a reference) or the minimum antigenic content as specified
through licensure. The type of potency assay used can be both product
(antigen) and firm specific. Standard potency assay requirements for
some established canine antigens can be found in 9 CFR. As standard
assays are developed for emerging antigens, the procedures should become
available from the Center for Veterinary Biologics-Laboratory (CVB-L)
as a “supplemental assay method” (SAM).
Due to the heterogeneity of antigens required to protect the health
of canine patients, a multitude of potency assay formats exist. These
include laboratory animal based in vivo tests, target animal based in
vivo tests, and in vitro tests. Regardless of the format, all potency
assays must be approved by the CVB and be correlated to efficacy. Making
the reference vaccine a serial that was used to demonstrate efficacy
generally allows a firm to make this correlation. While this system
of potency testing ensures that each serial produced contains a minimum
amount of antigen, no upper limits to antigen content currently exist.
This should be given further consideration as excessive amounts of antigen
could result in both safety and efficacy concerns.
Efficacy
The efficacy of a biological product is the specific ability or capacity
of the product to effect the result for which it is offered when used
under the conditions recommended by the manufacturer (9 CFR 1.101.5
(g)). In other words, efficacy is generally thought of as the ability
of a product to stimulate the immune response required to provide protection
from challenge (i.e., protective immunity). In contrast, immunogenicity
is the ability of a product to elicit an immune response whether or
not the response is correlated to protection. As with potency, standard
efficacy requirements for some established canine antigens can be found
in 9 CFR, Part 113. Where they exist, these standard requirements for
efficacy determinations must be followed.
In general, two types of standard procedures exist for efficacy testing.
In the first case, a product can be approved based on a serological
response in which at least 75% of vaccinated animals develop an antibody
titer greater than a reference value. In the second case, efficacy
of a product can be established using a challenge model where 80% of
the vaccinated animals are protected while 80% of the nonvaccinated
control animals develop clinical disease or lesions. In many cases,
challenge typically occurs within a month of completing the vaccination
schedule and typically only a small number of animals are evaluated
due to animal welfare concerns.
While these standard procedures allow at least a limited comparison
of efficacy between vaccines, they do not exist for all canine antigens.
For antigens that fall outside standard procedures, the variety of
efficacy tests becomes much more complex and any ability to compare
vaccines is lost. For these antigens, each firm is given an opportunity
to develop their own efficacy data in support of licensure, usually
based upon standards developed from information published in the scientific
literature. All procedures for generating efficacy data must be approved
by the CVB. However, considerable variability could exist in how similar
products are evaluated for efficacy. In addition, there is currently
no method or requirement that would allow for the simultaneous evaluation
of products with similar antigenic components using a single efficacy
study.
Vaccine Adverse Event Reporting
Background
The National Childhood Vaccine Injury Act (NCVIA) of 1986 mandated the
reporting of certain adverse events following the vaccination of children
to help ensure the safety of vaccines distributed in the United States.
The Act led to the establishment of the Vaccine Adverse Event Reporting
System (VAERS) in November 1990 by the Department of Health and Human
Services. Today, VAERS provides a database management system for the
collection and analysis of data from reports of adverse events following
vaccination of humans. However, there is currently no federal or state
mandate for veterinarians to report adverse events associated with
animal vaccination. Practitioner reports of known or suspected vaccine
adverse events in animals may be voluntarily submitted to either the
vaccine manufacturer, the U.S. Department of Agriculture Center for
Veterinary Biologics, or the United States Pharmacopeia (USP) through
the Veterinary Practitioners’ Reporting Program (VPRP).
At the time of this writing, an amendment 35 to
the Virus-Serum- Toxin Act has been proposed by the U.S. Animal and
Plant Health Inspection Service to:
1. require veterinary biologics manufacturers (licensees and permittees)
to record and submit reports to the APHIS concerning adverse events
associated with the use of biological products they produce or distribute,
2. require veterinary biologics manufacturers to report to the APHIS
the number of doses of each licensed product they distribute, and
3. provide definitions for adverse event and adverse event
report.
NOTE: The definitions and information provided below on vaccine adverse
events and adverse event reporting are subject to change if this amendment
is approved.
Definition
For purposes of this discussion, a vaccine adverse event is defined
as any undesirable side effect or unintended effect (including lack
of desired result) associated with the administration of a licensed
biological product (vaccine).
For vaccines administered to animals, adverse events are those involving
the health of the treated animal and include the apparent failure to
protect against a disease. It is important to note that an adverse
event includes any injury, toxicity, or sensitivity reaction associated
with the use of a vaccine, whether or not the event can be directly
attributed to the vaccine. In other words, it is appropriate to
report any known or suspected event associated with vaccination. A vaccine
adverse event report may be defined as a source of communication
concerning the occurrence of one or more suspected adverse events, which
identifies the product(s), animal(s), and person making the report.
Purpose of Reporting
Reporting field observations of unexpected vaccine performance is the
most important means through which the manufacturer and the regulating
agency (and the American Veterinary Medical Association) can be made
aware of potential vaccine safety or efficacy problems that, if necessary,
warrant further investigation. If a particular adverse event is well
documented, reporting serves to provide a baseline against which future
reports can be compared. In addition, reported adverse events could
lead to the detection of previously unrecognized reactions, to the
detection of increases in known reactions, to the recognition of risk
factors associated with reactions, to the identification of vaccine
lots with unusual events or unexpected numbers of adverse events, and
to further clinical, epidemiological, or laboratory studies. Therefore,
veterinarians are encouraged to report any clinically significant adverse
event occurring during or after administration of any vaccine licensed
in the United States. Reporting a vaccine adverse event is not an indictment
against a particular vaccine. Reporting simply facilitates review of
temporally associated conditions and adds to the safety database of
the product.
Reporting a Vaccine Adverse Event
The AVMA Council on Biologic and Therapeutic Agents has reported that
the current adverse event reporting system needs significant improvement
in the capture, analysis, and reporting of adverse events.36 Veterinarians
are encouraged to participate in the vaccine adverse event reporting
process by reporting suspected and known adverse events to any of the
following three locations:
1. The vaccine manufacturer, usually through telephone communication
with technical services [Table 3];
2. the USDA-CVB by toll-free call (800-752-6255); or
3. the United States Pharmacopeia (USP) Veterinary Practitioners’
Reporting Program (VPRP) by toll-free call (800-487-7776; press #3),
by fax (301-816-8373), or online (www.usp.org/vprp).
Reports made to the USDA are forwarded directly to the vaccine manufacturer
without specific action. Although adverse event reports made to the
USP VPRP are collected and maintained in a database, individual vaccine
adverse event reports are not necessarily forwarded by USP to the vaccine
manufacturer. While still available, the future of the USP VPRP is currently
under review.
Event Criteria
Reporting a known or suspected vaccine adverse event should include
the:
1. Manufacturer’s name
2. Product brand name, lot/serial number, and expiration date
3. U.S. veterinary license number and product code
4. Signalment (age, species, breed, gender) of patient affected
5. A description of the clinical signs or diagnosis associated with
administration of the vaccine. Although specific reporting criteria
are not defined for clinical events, the type of reaction and length
of time between administration of the vaccine and onset of the adverse
event should be documented using the following guidelines:
a. Local (injection-site) reactions occur exclusively
at or around the site of inoculation. They may occur at the time of
injection, or several minutes, hours, or days later and may persist
from minutes (e.g., pruritus) to months (e.g., granuloma). Reports should
include the route of administration (i.e., subcutaneous, intramuscular,
or topical [oral, conjunctival, or nasal]). Examples of injection-site
(local) reactions following vaccination include pain, pruritus, swelling,
injection-site alopecia, abscess formation, granuloma formation, and
neoplasia. Infection and skin necrosis are rare but have been reported.
Vaccines licensed for administration by the topical (conjunctival/intranasal)
route have been associated with sneezing (persisting =3 days), nasal
and oral ulceration, ocular discharge, and cough (persisting >24 hours).
b. Systemic reactions are events that involve
the entire body or a defined location/region other than the injection
site. Like injection-site reactions, systemic reactions typically don’t
occur at the time of injection but can develop within minutes or hours
and may persist for hours or days. Examples of systemic reactions following
vaccination include angioedema, especially involving the face, muzzle,
and ears (most often reported in dogs); anaphylaxis and collapse; polyarthritis
(lameness); vomiting with or without diarrhea (most often reported
in cats); respiratory distress; fever; and lethargy. Severe events that
may be vaccine associated requiring long-term medical intervention and
patient follow-up include immunemediated hemolytic anemia, immunemediated
thrombocytopenia, icterus, renal failure, and glomerulo-nephritis.
c. Vaccine-associated death, although rare,
does occur. In dogs, anaphylactic shock is the most commonly reported
adverse event leading to death. There has been no trend to suggest an
association between anaphylaxis and a particular manufacturer’s vaccine.
Veterinarians are strongly encouraged to report any death suspected
or known to be associated with vaccination to the vaccine manufacturer
[Table 3].
Legal Implications of the Discretional
Use of Biologics As a general rule, the use of biological products by
small animal veterinary practitioners is left to their professional
judgment. The latitude afforded practitioners is broad, but there are
boundaries.
The analysis of the law governing use is complicated. The USDA-CVB regulates
the licensure and preparation of most veterinary biologics. The Virus-Serum-Toxin
Act empowers the CVB to stop the sale, barter, or exchange of “any worthless,
contaminated, dangerous, or harmful virus, serum, toxin, or analogous
product.” If veterinary use of a CVB-regulated product was viewed as
unsafe, the CVB could initiate an enforcement action; however, unless
a safety issue is implicated, the USDA has historically not considered
such enforcement to be a priority. In addition, some vaccines are licensed
with specific restrictions regarding their use, which will be noted
in their labeling.
The FDA’s Center for Veterinary Medicine (CVM) also regulates some products
that most practitioners would consider biologics. The jurisdictional
gray zone between the two agencies is confusing, constantly blurred,
and evolving. Products regulated by the CVM are covered by the Animal
Medicinal Drug Use Clarification Act, which established specific rules
for “extra-label” drug use.
Potential Liability
Potential liability for medical decision making is a fact of life for
any health-care provider, including veterinarians. This potential professional
liability encompasses all aspects of veterinary practice, including
the selection and use of vaccines and other biological products. Generalizations
about potential legal liability are as difficult to make as generalizations
about medical practice. The range of possible legal liability theories
used in litigation is broad and limited only by the creativity of the
plaintiff’s attorney. To further complicate matters, there are variations,
some subtle and some not, between states. However, most lawsuits against
practitioners are grounded in negligence theory, although other possibilities
include product liability, breach of express or implied contract, breach
of express or implied warranty, guaranty, battery, and breach of fiduciary
relationship. These principles apply to all aspects of professional
veterinary practice, not simply vaccine or biological issues. Discussed
below are some types of negligence suits that could arise out of use
of biological products.
Malpractice: Negligence actions involving veterinarians are
usually cast as traditional medical malpractice cases. The law of professional
medical negligence has evolved in the context of human medicine. Most
jurisdictions will apply the legal concepts developed in the litigation
of physician malpractice cases to veterinary malpractice cases. The
traditional elements of a medical malpractice lawsuit are the duty to
conform to a certain standard of care, a failure to conform to the
required standard, actual injury or damage, and a legally sufficient
causal connection between the conduct and the injury. The duty arises
out of the veterinary- client-patient relationship (VCPR) and is typically
stated as the duty to exercise reasonable care. That is, the duty to
exercise the same level of care and competence as a reasonably prudent
practitioner, with the same or similar training, under the same or similar
circumstances. This duty is often referred to as the “standard of care.”
In this context, standard of care is a legal term of art and does not
necessarily equate with professional practices or standards. Establishment
of the relevant standard of care and whether a practitioner deviated
from it, with few exceptions, must be established by competent expert
testimony.
In practice, many medical negligence cases become a “battle of experts.”
The plaintiff, using an expert witness, presents a standard of care
and the opinion that the practitioner failed to meet the standard,
and that such failure caused the plaintiff’s injury or damages. In turn,
the defendant practitioner offers differing expert testimony, establishing
a different standard of care, that the defendant veterinarian met the
standard, and that the defendant’s conduct did not legally cause the
plaintiff’s injury or damage. Faced with conflicting evidence, the jury
resolves the issue based on innumerable variables, including the qualifications
and presentation of the various experts and the defendant.
The scenarios that could give rise to a lawsuit are as varied as the
imagination allows. For example, a practitioner who chooses not to vaccinate
an animal could be potentially sued for negligence if the animal contracts
the disease the vaccination could have prevented. In such a case, the
plaintiff would be required to have expert testimony that the defendant’s
failure to vaccinate the animal was a departure from the standard of
care and the cause of the injury to the animal. On the other hand, a
practitioner who vaccinates an animal could potentially be sued for
negligence if the animal has a complication from the use of the vaccine.
In such a case, the plaintiff would be required to have expert testimony
that the defendant’s vaccination of the animal was a departure from
the standard of care and the cause of the injury to the animal. Whether
a plaintiff would prevail on such theories will depend on the facts
of the individual case, the qualifications of the defendant and the
experts, and the intangible items that always come into play in trials.
Informed Consent: The legal doctrine of informed consent arises
out of the obligation to obtain consent prior to providing care to
a patient. The essence of informed consent is that a practitioner informs
the client of the material risks of a proposed treatment or procedure
and potential alternatives, including the risk of no treatment, and
the client/patient, having been informed, either gives or withholds
consent. It is important to remember that the informed consent of the
patient/client is the goal, not simply the act of obtaining a signature
on a form. One of the best deterrents to an informed consent lawsuit
(or any other for that matter) is to communicate with, not talk at,
clients and document the discussions.
The laws governing this area developed as human medicine evolved from
a paternalistic profession to one that recognizes the importance of
a patient’s self determination. Informed consent cases are common in
human medicine and could also be brought against veterinarians. These
cases are often based on negligence principles, due to the manner in
which they developed in physician malpractice cases. In some jurisdictions,
they may be brought under other legal principals, such as battery. Most
informed consent cases arise out of a patient’s/client’s misunderstanding,
misperception, and from the practitioner’s perspective, sometimes unreasonable
expectations.
The complicating factor is a split of authority on the standard by which
a practitioner’s actions are judged in informed consent cases. There
are two primary standards utilized, with a fairly even split between
those states that use a practitioner-focused inquiry and those that
use a patient/client-focused inquiry. Thus, the standard by which a
veterinarian’s conduct will be evaluated depends upon the state in which
one practices. Under the practitioner-focused standard, the inquiry
is whether the defendant provided the information that a reasonable
practitioner would disclose under the circumstances. The level of the
required disclosure is established by expert testimony.
Under the patient/client-focused standard, the inquiry is whether the
practitioner provided sufficient information (in understandable terms)
to allow a “reasonable person” to make decisions about the course of
treatment. The real issue becomes, under the circumstances, what information
would a reasonable person need to make informed, rational decisions.
Regardless of which standard is employed, the other elements of a negligence
case, including the causal connection, would have to be established
in order for a plaintiff to prevail.
Whether the use of written consent forms deter informed consent cases
is often discussed. Documentation of informed consent discussions is
always helpful in the defense of an informed consent case. The documentation
often ranges from a note in the chart (with or without cosignature
by the client), to a generic consent form signed by the client, to a
very detailed document specific to the treatment or procedure contemplated.
The more general the language used, the less helpful, and, conversely,
the more specific the language the more helpful in the defense of a
case. It is important to note that in human medicine, most informed
consent lawsuits have signed consent forms in the chart. While they
are helpful tools, they do not preempt all lawsuits over consent issues.
In fact, there are times that consent documents could be harmful to
the defense of a case. Some consent forms for vaccination estimate the
odds of disease exposure or the chance of an adverse event occurring
following vaccination. The practitioner should have a medically or scientifically
defensible basis for making any such precise representations in a consent
document. If precise numbers cannot be justified, more general statements
are preferable. For example, a statement indicating that the true incidence
of a particular adverse reaction is not known, but is believed to be
low, or has been reported in the literature to be in the range of “X%–Y%”
would be appropriate. In addition, a statement that the exact chances
of exposure to a particular disease cannot be quantified but should
be less where the animal is not exposed to other animals would be more
defensible. Such statements may be harder to craft, but a practitioner
would not want to be in the unenviable position of explaining to a jury
that the representations made to a client prior to a treatment or procedure
were simply a “guesstimate,” leaving the practitioner to explain the
basis for the statements. There is obviously room for professional judgment,
but very specific numbers
based solely on experience or judgment will be harder to defend. One
of the best methods for crafting consent forms for use in a practice
is to talk with an attorney who has defended informed consent cases
in your state. They can provide invaluable assistance in understanding
the laws in your jurisdiction and crafting consent documents that best
meet your particular needs.
Vaccinations as a Component of Comprehensive, Individualized Care
For many years, the practice of veterinary medicine has benefited from
the annual administration of vaccines. By encouraging dog owners to
bring their pets in yearly for vaccinations, veterinarians have been
able to recognize and treat disease earlier than might otherwise have
been the case. The annual visit has also provided an opportunity to
inform clients of important aspects of canine health care; therefore,
vaccinations are a component but not the principle aspect of a comprehensive,
individualized wellness program for patients. This annual general examination
and client interaction is good veterinary medicine and good veterinary
business practice.
Unfortunately, many clients have come to believe that vaccination is
the most important reason for annual veterinary visits. Veterinarians
are justifiably concerned that a reduction in vaccination frequency
will cause clients to forego routine annual visits for their dogs and
that the quality of care they deliver will be diminished. To avoid this
consequence, it is vital that veterinarians stress the importance of
all aspects of a comprehensive, individualized health-care program.
Clients should be informed that dogs with serious disease often appear
healthy and that regularly scheduled health evaluations facilitate early
detection. Emphasis should be placed on a comprehensive physical examination
performed by the veterinarian as well as individualized patient care.
The importance of dental care, proper nutrition, appropriate diagnostic
testing, and the control of parasites and other zoonotic diseases should
also be addressed during each patient evaluation. Behavior concerns
should be discussed, as should the necessity for more frequent examination
of puppies and geriatric dogs.
Each patient’s vaccination needs should be assessed at least yearly
and, if appropriate, vaccination schedules should be modified on the
basis of changes in the dog’s age, health status, home and travel environment,
and lifestyle. An explanation of the types of vaccines currently available,
their potential benefits and risks, and their applicability to the particular
dog given its lifestyle and risk of exposure should be undertaken. The
regional incidence and risk factors for various infectious diseases
should also be discussed. With a focus on the welfare of the patient,
these discussions should take place even with clients who choose to
vaccinate their pets themselves or have them vaccinated by individuals
other than the primary care veterinarian. Ways to reduce the impact
of acquired disease (e.g., avoiding overcrowding, improving nutrition,
and restricting access to infected animals) should also be reviewed.
Vaccinations should be considered just one component of an individualized,
comprehensive preventive health-care plan based on the age, breed, health
status, environment (potential exposure to harmful agents), lifestyle
(contact with other animals), and travel habits of the dog.
Age
Obviously age has a significant effect on the preventive health-care
needs of any individual. Puppy programs have traditionally focused on
vaccinations, parasite control, and sterilization. Today, opportunity
exists to incorporate behavior counseling and zoonotic disease management
as well. With aging pets, tiered senior care programs are increasingly
popular. Nutritional, dental disease, and parasite control assessment
and counseling should take place throughout the life of the pet.
Breed
It’s common knowledge that certain breeds are predisposed to various
diseases. Early detection and management of breed-associated disease
can significantly improve the quality of a dog’s life.
Health Status
Dogs with chronic medical conditions, such as diabetes mellitus, hypothyroidism,
heart disease, renal failure, hyperadrenocorticism, hypoadrenocorticism,
glaucoma, and keratoconjunctivitis sicca, warrant periodically scheduled
medical examinations and testing designed to monitor the progression
of diseases and provide for therapeutic adjustments. Dogs receiving
certain medications also warrant therapeutic monitoring of blood levels
and/or organ systems. The development of recheck protocols for chronic
diseases and medications, which can be included in reminder systems,
can greatly improve client compliance and accordingly patient care.
Environment
The environment in which a pet resides can profoundly affect the health
status of that pet. Exposure to trauma (e.g., automobiles, animal fights,
high rise syndrome), weather (e.g., heat stroke, frostbite), water (e.g.,
drowning), toxins (e.g., antifreeze, human medications, poisonous
plants, household and industrial toxins), sunlight (e.g., solar dermatitis),
as well as internal and external parasites should be assessed during
annual health-care visits in order to define risk factors and appropriate
preventive measures.
Lifestyle
By determining the extent to which dogs come in contact with other animals
either in controlled or unobserved circumstances, veterinarians can
assess the need for noncore vaccinations. Dogs that visit kennels, grooming
salons, common areas, and wooded, tick-infested areas are at greater
risk from certain infectious diseases than dogs that do not frequent
these areas.
Travel Habits
Just as the human population has become much more mobile, so has the
canine population, resulting in potential exposure to infectious agents,
parasites, and environmental hazards not found in the home environment.
The determination of past and anticipated future travel of dogs during
each preventive care visit allows for greater individualization of
preventive care and diagnostic testing plans.
Medical Record Documentation
At the time of vaccine administration, the following information should
be recorded in the patient’s permanent medical record: date of vaccine
administration, identity (employee name, initials, or code) of the person
administering the vaccine, vaccine name, lot or serial number, manufacturer
and expiration date, and site and route of vaccine administration. The
use of peel-off vaccine labels and stamps that imprint the medical record
with the outline of a dog facilitate this type of record keeping. Adverse
events should be recorded in a manner that will alert all staff members
during future visits. Informed consent should be documented in the
medical record in order to demonstrate that relevant information was
provided to the client and that the client authorized the procedure.
At the very least, this notation should indicate that a discussion
of risks and benefits took place prior to vaccination.
Conclusion
The burgeoning knowledge in the fields of vaccinology and immunology,
together with the continued enhancements of vaccine efficacy and safety,
have placed the traditional approaches to vaccine use in doubt and engaged
our profession in a long overdue debate. What is clear is that the
complexity of the issues involved make it impossible for our profession
to make blanket statements with respect to vaccine selection and use—one
size simply does not fit all. This underscores the fact that vaccination
is a medical procedure and, as such, needs to be tailored to the individual
and administered under a valid VCPR on the basis of informed consent.
Not all vaccines are indicated in all animals and no vaccine should
be given without a thorough knowledge of the risks of acquiring the
disease, the potential for adverse reactions to vaccination, and the
health of the animal in question. Current knowledge clearly indicates
the need to refine vaccine selection and to re-establish vaccine protocols
when revaccinating animals >1 year of age that have undergone an initial
vaccine series. In the case of core vaccines (i.e., CDV, CPV, CAV-2,
and rabies virus), every 3 years is considered adequate to maintain
appropriate protection. Regardless of your eventual decision, we challenge
you to keep an open mind and critically evaluate and incorporate new
information as it becomes available.
a McDonough P, personal communication; Cornell University Diagnostic
Laboratory, Ithaca, NY
b Schultz RD, unpublished results; University of Wisconsin, Madison,
WI
c Titercheck; Synbiotics Corp., San Diego, CA
Acknowledgments
The members of the Task Force would like to recognize Drs. W. Jean Dodds,
Larry Glickman, Craig Greene, Dennis Macy, Niels Pedersen, Larry Swango,
and Alice Wolf for their pioneering work to raise both the knowledge
and awareness of vaccinology and issues pertaining to DOI within the
veterinary profession. The members of the Task Force would also like
to thank Dr. Walt Ingwersen for his editorial assistance.
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