vaccines and immunity

Question 1

active immunity and outcome

Answer 1

individual exposed to vaccine (ag)

outcome:
- not immediate
- long lasting
- memory cells generated (B and T cells via clonal expansion)

Question 2

passive immunity and outcome

Answer 2

individual receives protective molecules (antibodies) or cells (lymphocytes) produced by another individual
outcome:
- immediate protection
- temporary
- no memory cells generated

Question 3

passive immunity examples

Answer 3

colostrum
commercially: antibodies against toxins like tetanus, snake venom -> function as neutralizing antibodies

Question 4

vaccine definition

Answer 4

suspension of live or dead microorganisms
used to induce active immunity against communicable disease

Question 5

history of vaccines

Answer 5

• originated in China and Middle East in the early 1700’s
• initially called “variolation”, which was inoculation with the smallpox (variola virus). It
  involved collecting scabs and/or pus-fluid from a patient with smallpox and applying as
  superficial skin scratches on the arms of healthy patients. The desire effect was to
  induce a weakened form of the disease, denoted by pustular formation at the inoculation site. The plan being that the patient would survive the treatment and any further exposure

Question 6

variolation procedure

Answer 6

he source for inducing immune
protection was the actual variola virus that induced the disease. Dr. Edward Jenner’s, a British
physician, approach was different in that the source for inducing protection came from a
different virus (vaccinia, cowpox). It is important to note that he was not the first investigator
to actually experiment with vaccinia. There were other researchers in England and Germany.
Of particular note, there was a farmer in Dorset County, England named Benjamin Jesty, who
reportedly successfully innoculated his wife and two children with vaccinia during a smallpox
epidemic in that region in 1774. Based on some literary accounts, it is very likely that Dr. Jenner
was aware of Jesty’s success
- By the late 1770’s, Dr. Jenner was experimenting with the cowpox virus. At that time, it was
commonly recognized that milkmaids were generally protected against (immune) smallpox.
In 1796, Dr. Jenner hypothesized that the pus residing in the cowpox blisters of the milkmaids
was what protected them from smallpox and he thus, conducted a number trials.

Question 7

dr edward jenner: small pox and vaccination

Answer 7

• The most historically well-known case involved the collection of pus from pox blisters on the
  hand of a milkmaid, Sarah Nelmes, who was infected with cowpox from a cow named Blossom.
  Jenner then inoculated an 8 year-old boy named James Phipps on both arms. The boy
  developed a fever and clinical signs of a mild infection. He then challenged James with a variola
  fraction (inocula) via injection and he showed no signs of the disease. He challenged the boy
  again, but the boy was immune to smallpox. He coined the term vaccination (vaccus, latin for
  cow) and the inoculum he called vaccine.
• There were two likely factors
  that contributed to Dr. Jenner receiving the credit for the discovery. One, he was a physician,
  which infers that he was an individual of stature. The second reason, is that Jenner performed
  “repeated challenges” with the variola strain and was able to show protection, which is
  undoubtedly more important. In honor of Jenner’s work, Louis Pasteur, in 1891, re-defined
  vaccination as the “artificial induction of immunity against any infectious disease”. From that
  point on, the words vaccine and vaccination were immortalized in the field of medicine
• the primary reason for
  Jenner’s success for using the vaccinia-derived crude products, as a vaccine for preventing
  smallpox is that both viruses are in the same pox family (viridae). Immunologically, these
  viruses share a number of homologous antigenic epitopes, and fortunately for Dr. Jenner,
  a number of which are immunoprotective against smallpox

Question 8

immunoprotective antigen or epitope

Answer 8

• An immunoprotective antigen or epitope is that which is capable of inducing a host immune
  response that results in protection against the development of a specific disease .
• Essentially, it is the key component for developing a successful vaccine. What this implies and in fact is true, is that not all antigens/epitopes that comprise a pathogen are immunoprotective.
  However, it does not infer that the host’s immune system cannot process these epitopes and mount an immune response against them. It just means that the immune response against those particular epitopes is not sufficient to protect the host from infection and disease
• a pathogen is comprised of many macromolecular structures, which the
  host’s immune system sees as a collection of foreign antigens (i.e. epitopes) for it to respond
  against. Some of these structures or epitopes are what actually cause or are associated with the
  disease. These are known as virulence epitopes and are the primary targets of well-constructed
  vaccines

Question 9

immunoprotective epitope examples

Answer 9

• parvo virus- AAV1 and CPV epitopes
• rabies- rabies glycoprotein G epitopes
• distemper- CDV-F- T cell epitope, CDV-N- B cell epitope

Question 10

objective of developing a vaccine

Answer 10

involves selecting the
antigenic epitopes (virulent) that are linked to the infectivity and or virulence of a pathogen.
Further, recognizing that each host has a defined capacity to respond to a select number of
epitopes, it is the crucial that the vaccine be comprised of a sizeable number of these diverse
epitopes to ensure a strong protective immune across a population

Question 11

characteristics of an ideal vaccine

Answer 11

• The degree of immune response should be long–lasting (i.e. generates immune
  memory).
• It should be safe, it shouldn’t induce the disease.
• It should be cost effective and stable with proper storage.
• It needs to be relatively easy to administer.
• It should induce the optimal immune response (i.e. humoral (B-cell) and cell-mediated (T cell)).
• It should prevent or reduce the degree of illness against the targeted pathogen
• suitable for mass vaccinations
• immune response following vaccination is different from natural infection (distinction between immunized and infected individuals) multivalent and multideterminant

Question 12

major requirements for a vaccine to induce prolonged strong immunity

Answer 12

1. must stimulate APC (to process and provide co-stimulatory signals)
2. both T and B cells must be stimulated (generates large number of memory cells)
3. immune response must be directed against multiple epitopes
4. vaccinated antigens must persist for a long period to continually stimulate immune system

Question 13

types of vaccine strains

Answer 13

• live attenuated viral or bacterial strains
• killed whole organism
• toxoids
• surface protein molecules
• inactivated virus
• recombinant attenuated viral strain
• DNA vaccine

Question 14

types of vaccine composition

Answer 14

• live viruses/bacteria weakened (bordetella)
• entire organism (west nile)
• bacterial toxins in formalin (tetanus)
• baculovirus E2 protein (swine fever)
• chimera H5N3 inactivated virus in oil-base adjuvant (avian influenza)
• live vaccinia virus recombinant (rabies)
• spay/vac ZP(ZPC/ZP3)

Question 15

Modified-live or attenuated vaccines advantages vs disadvantages

Answer 15

advantages:
- better immunity
- the need for fewer inoculating doses
- lower cost to produce and
- lower incidence of adverse reactions to the vaccine
- INF-gamma inducers

disadvantages
1. residual virulence
2. contaminations
3. cannot vaccinate pregnant or immunocompromised individuals
4. preparation/storage/handling problems

Question 16

inactivated/killed vaccine advantages and disadvantages

Answer 16

advantages:
1. non-virulent
2. stable/storage is easy
3. less chances for contamination

disadvantages:
1. repeated inoculation
2. possible toxicity
3. increased risk of hypersensitivity
4. inexpensive

Question 17

what are the two outcomes that live viral vaccines upon infection continue to replicate within host cells

Answer 17

1.) viral replication prolongs the
time that the host’s immune system is exposed to all the antigenic epitopes expressed by the
virus. This greatly enhances B and T cell polyclonal activation as well as potentially providing an
internal booster response should the exposure be sustained for a long period of time.

2).Another important factor relates to MHC expression. For live-attenuated intracellular
pathogens (i.e. viruses), viral peptides that are produced in the cytoplasm are more efficiently
bound to MHC class I molecules. This in turn enhances CD8 T cell (Cytotoxic T cell) activation,
which are major players in targeting and destroying intracellular viral-infected cells. In addition,
polyclonal B cell activation ensures the production of antibodies that could bind to and
neutralize free virus

Question 18

why does live vaccines have the greatest chance of inducing a robust immune response to the whole vaccinated population?

Answer 18

they are designed to express the highest percentage of epitopes that are homologous to the virulent pathogen strain

Question 19

herd immunity

Answer 19

Some individuals (human, animals) possess B cells and T
cells that say recognize 95% of epitopes expressed by the rabies virus, where others can only
recognize 25% of the rabies viral epitopes. I think you can all appreciate that individuals capable
of recognizing only 25% of the rabies viral epitopes are more likely to not achieve protective
titers under the standard protocols compared to the other group.
Vaccines can only express a finite number of these epitopes based on their composition. Since
modified live vaccines tend to express more of the epitopes and in their native/natural form,
It would make sense that they would provide the better chance of protection for even those
individuals who have a lower percentage of B and T cells capable of recognizing the epitopes.
These individuals may actually need an additional vaccine to achieve a protective titer.
It goes back to the concept of “herd immunity”. Vaccination of the whole population also
serves to provide a biologic barrier for those individuals who might be at a higher risk.
Note, just because an animal (4-legged or 2-legged) is vaccinated with the appropriate vaccine
protocols does not ensure that they are “protected” against a targeted pathogen

Question 20

how the live attenuated vaccines are generated

Answer 20

Canine parvovirus is a good example. The well-known fact about viruses is their ability to adapt
to their changing environment. Typically, these viruses retain most of their genome and alter
only the genes that favor infection into insect cells. By culturing the canine parvovirus in
insect cells through numerous passages the vaccine researchers were able to select a strain
that genetically lost the ability to injure canine cells.
So, what the vaccine researchers were able to achieve, at an accelerated rate through
passaging the viral-infected insect cells, was an insect specific parvovirus that lost its
ability to infect its natural host (i.e. dog) and induce disease.
When dogs are vaccinated with this live-attenuated strain, a weakened infection ensues. So,
this means that these vaccines do yield a low level of virulence. Since the live-attenuated strain
still retains a large number of key antigenic epitopes the immune response and the antibodies,
B cells and T cells produced are cross protective against the natural, virulent parvo strain
and thus, protect the host.

Question 21

genetically modified live attenuated vaccines

Answer 21

These genetically engineered MLV are definitely the new generation of
vaccines. As I indicated at previously, not all viral genes and the proteins they produce induce
disease in the host. There are actually specific viral or bacterial genes coined “virulent genes”.
The new approach is to specifically target these viral or bacterial genes either for mutation or
silencing. The advantage of this approach is that these genetically-modified pathogens remain
highly “infective” and thus can induce a strong immune response, but they don’t cause disease.
Some examples of genetically modified live-attenuated vaccines are the tri-valent vaccine for
Herpes, Calici and parvovirus in dogs. Others include the Bordetella and distemper vaccines.

Question 22

risks associated with live–attenuated vaccines

Answer 22

Although these live-attenuated vaccines have a very low
“virulence” factor. It still needs to infect the cells to induce a robust immune response.
Individuals who have a weakened or deficient immune system are at risk of developing the
disease, which is sometimes fatal. So, we refrain from employing MLV in pregnant animals
or animals that are immune deficient or on immunosuppressive therapy. In rare situations, it is
possible for a live-attenuated virus to mutate while in the host’s cells and revert back to a
semi-pathogenic strain. Fortunately, this is not a common occurrence with MLV vaccines.
Other minor considerations, regarding the use of MLV is the requirement for proper storage
and handling and the potential for contamination, which is typically not a major concern for the
US medical profession

Question 23

Killed Vaccines

Answer 23

Going back to the early years of vaccine development, the scientists recognized that if they
could kill a pathogen, there would very little risk of disease development in the individual.
This procedure was initially achieved either by chemical treatment or with heat. An example is
one of the first rabies vaccines created by Louis Pasteur.
As the years passed, in addition to heat inactivation, radiation, novel chemicals and antibiotics
were employed. The desired goal from this approach was to generate a “dead” but
immunostimulatory microorganism.
What the scientists didn’t realize until later, was that the process (i.e. heat) used to kill the
microorganism also denatured some of the proteins. This may or may not have an effect on CD4
T cell recognition and activation, because T cells can only recognize and bind to processed (i.e.
chopped up) antigen. However, since the pathogen is dead, it can’t replicate in the host, thus
CD8 T cell activation would not likely be as robust.
Another major concern with killed vaccines is with their ability to effectively induce protective
humoral immunity. B cells bind to free antigen. Although they can recognize and bind killed
vaccine epitopes, if the proteins are too denatured, they may not be homologous to the native
pathogen. Thus, the antibodies generated are not able to recognize the epitopes of virulent
strain. Thus, there would be no or a lower level of humoral immunity protection.
Still, a number of killed vaccines that are marketed for use in veterinary species are available.
One example is the killed rabies vaccines used in dog, cats and horses. Since they are killed
vaccines, they can be combined with fixatives ± adjuvants. An apparent advantage of this type
of vaccine is that it is stable, easy to store with a potentially longer shelf life and minimal risk for
contamination. Still, there are disadvantages associated with killed vaccines, in addition to the
disproportionate immune response, there is a higher requirement for repeated boosters.
Further, some individuals can experience toxic effects or even allergic hypersensitivities to
the chemical components (i.e. adjuvants) of these vaccines

Question 24

Toxoid

Answer 24

Toxoids are a unique type of vaccine (Figure 8). They are essentially composed of specific
exotoxins produced by Gram+ and Gram- bacteria that are chemically denatured most
commonly with formalin. This is a similar process used with some killed vaccines. What is
different here is that target is the actual toxin and not the bacteria that produces it.
Interestingly enough, the formalin-denatured toxin retains sufficient immunogenic epitopes to
induce a robust immune response. There is a strong enough cross-over adaptive immune
response to induce host protection to the natural toxin. The most common toxoid used in
medicine is the tetanus toxoid, which neutralizes the tetanus toxin produced by the bacteria
Clostridium tetani

Question 25

Vaccine-conjugates

Answer 25

As vaccine scientists and immunologists continue to decipher the mechanisms involving
interactions between cells of the immune system, novel vaccines are being developed to
monopolize on this knowledge. Conjugate vaccines are a prime example of this new technology.
These vaccines are constructed or engineered in such a way that they contain components of
one microorganism that is linked to an immune-activating molecule. This has been proven to be
fairly successful against encapsulated bacterial pathogens.
A number of pathogenic bacteria are protected by a polysaccharide capsule surrounding the
cell wall. This makes it difficult for neutrophils and APC to phagocytose. Further, these type
pathogens can be recognized and bound by B cells, but due to a lack of APC activation, the T
cells are not activated. This results in an imbalance immune response, primarily B cells.
This is insufficient to induce opsonizing antibodies and no significant immunologic memory is
generated.
What the vaccine researchers have done is to conjugate (i.e. bind) a T cell-activating molecule,
(ie. tetanus toxoid) to the bacterial polysaccaharide microorganisms. The B cells bind to the
polysaccharide molecules and engulf the bound tetanus toxoid proteins, process it and present
these protein epitopes to T cells. The T cells become activated and in effect turn on and
coordinate both innate and adaptive immune system activation. This results in both B cell and T
cell clonal expansion, formation of opsonizing antibodies with the desired outcome
- immunologic memory. This is a pretty significant achievement in vaccination development. I
predict more vaccines will be developed off of this platform

Question 25

Vaccine-conjugates

Answer 25

As vaccine scientists and immunologists continue to decipher the mechanisms involving
interactions between cells of the immune system, novel vaccines are being developed to
monopolize on this knowledge. Conjugate vaccines are a prime example of this new technology.
These vaccines are constructed or engineered in such a way that they contain components of
one microorganism that is linked to an immune-activating molecule. This has been proven to be
fairly successful against encapsulated bacterial pathogens.
A number of pathogenic bacteria are protected by a polysaccharide capsule surrounding the
cell wall. This makes it difficult for neutrophils and APC to phagocytose. Further, these type
pathogens can be recognized and bound by B cells, but due to a lack of APC activation, the T
cells are not activated. This results in an imbalance immune response, primarily B cells.
This is insufficient to induce opsonizing antibodies and no significant immunologic memory is
generated.
What the vaccine researchers have done is to conjugate (i.e. bind) a T cell-activating molecule,
(ie. tetanus toxoid) to the bacterial polysaccaharide microorganisms. The B cells bind to the
polysaccharide molecules and engulf the bound tetanus toxoid proteins, process it and present
these protein epitopes to T cells. The T cells become activated and in effect turn on and
coordinate both innate and adaptive immune system activation. This results in both B cell and T
cell clonal expansion, formation of opsonizing antibodies with the desired outcome
- immunologic memory. This is a pretty significant achievement in vaccination development. I
predict more vaccines will be developed off of this platform

Question 26

Recombinant Vaccines

Answer 26

Another relatively new approach in vaccine development, is the insertion of select genes from
pathogens into innocuous (i.e. harmless) viruses. This technique is called recombinant vaccines
or vector vaccines. This method has been highly successful with the oral rabies vaccine used
with wildlife. It was developed in 1984 (Wistar labs), when scientists successfully cloned the
gene that coded for the rabies virus glycoprotein and inserted it into the genome of the
vaccinia virus. Note, the vaccinia virus alone is known to induce a strong immune response
across most species. So, during the infection phase the rabies glycoprotein when expressed by
the vaccinia virus during infection was also recognized by the host immune system. I don’t have
anything really negative to say about this type of vaccines except when they work they are
great. Cost may be a limiting factor too. Further, the newer generation of vaccines are showing
great process and may be even better that the vector vaccines.

Question 27

DNA Vaccines

Answer 27

Presently, the rationale behind DNA vaccines is to genetically incorporate naked protein-
encoding DNA targeting. This requires that the genome of the organism (microbial or even
animal) has been synthesized and you know which component of the DNA codes for your
targeted protein. Typically, the DNA vaccine is injected into the muscle. The desired immune
response is the formation of antibodies to the bound or secretory protein(s). The actual
mechanism for inducing the immune response is still not well defined. However, if the antibody
production occurs it is safe to predict that APC activation and processing, T cell and B cell
activation would be initiated. Currently, we don’t see many veterinary DNA vaccines
commercially available. I think they are little tricky to develop and likely also pretty expensive.

Question 28

adjuvant function

Answer 28

create a medium that promotes a strong and
sustained immune response for vaccine types (i.e. killed or subunit or conjugate vaccines etc),
that cannot do it alone. Adjuvants can be chemicals, microbial components (peptides
or particles) and mammalian proteins

Question 29

what are adjuvants?

Answer 29

• combined with vaccines to enhance the host’s immune response
• composed of select chemicals, microbial byproducts or mammalian proteins
• can serve as stabilizing agents for antigen formulations
• exact mechanism not known
• believed to aid in creating a “depot effect” but likely not attributed to all agents

Question 30

how adjuvants work

Answer 30

• non-specific immune stimulation effect
• antigen-carrier effect
• antigen-depot effect

Question 31

lipid particles

Answer 31

oil emulsions
- freund’s (complete or incomplete (CFA/ICFA)
- liposomes (virosomes for influenza)
- archaesomes
- immune-stimulating complexes (ISCOMS)

The nonspecific immune stimulation and antigen-carrier effects are a measure of the ability
of the adjuvant to directly stimulate the innate immune system. For example, antigens in lipid
oil-water emulsions (i.e. Freund’s adjuvant) are easily ingested by phagocytic cells.

Question 32

liposomes

Answer 32

Liposomes are lipid bilayer vesicles that crudely resemble cell membranes, which can store
antigen within in the lumen or on the membrane. They are effective in stimulating
humoral immunity. They have been used for many years as a drug delivery vehicle.
Archaeosomes are liposomes derived from lipids of the Archaea, a bacteria-like organism found
in mammalian hosts (i.e. Methanobrevibacter smithii, in the human GI tract. They are
strong Th1 and Th2 modulators. The safety of archaeosomes has yet to be defined

Question 33

Immune stimulating complexes (IS-COMS/ISCOMS)

Answer 33

The rationale for genesis of this type of lipid moiety vaccine involves the use of protein subunits
or peptides. Alone, these molecules are poorly immunogenic, so they need an adjuvant to
enhance their immunogenicity. The IS-COMs are essentially composed of lipid micelles that
surround the peptides. Upon entry, these IS-COMS function as a carrier for the subunit
(peptides) as well as strong stimulators of innate immunity, so they function as pretty effective
adjuvants. When the innate cells are activated, since the IS-COMS are a lipid moiety (cationic
charge), the IS-COMS fuse with the APC cell membrane (anionic -neg charge) and transfer the
intact peptides into the cytoplasm of the cell. This facilitates processing of the peptides with
both MHC class I and MHC class II molecules and thus, ensures a strong T cell response, as well
as B cell response. I think it is a very clever vaccine technology. The only caveat being that you
need to be sure the peptides in question are immunoprotective and I imagine it is costly to
produce

Question 34

mineral salts

Answer 34

• aluminum hydroxide (alum)
• aluminum phosphate
• calcium phosphate
  alum: fist approved for use in human and veterinary vaccines

The purpose behind the antigen-depot effect is to generate a prolonged, but sustained
release of the antigens at the site of injection and select mineral salts were once thought to
be effective in generating this depot effect. However, that belief is now being challenged.
Antigens can be bound or absorbed on to mineral salts (i.e. Alum, aluminum hydroxide
or aluminum sulfate). These mineral salts are believed to interact with lipid receptors
on dendritic cells. This in turn stimulates a Th2 T cell and antibody response. It is still one
of the most widely used of the commercial immunomodulating adjuvants. One important
advantage of this type of adjuvant is that it is still viewed as quite safe to use

Question 35

immunomodulatory agents

Answer 35

• saponins (Quil A, QS21 or ginseng root-derivatives)
• cytokines (IL-2, IL-12, GM-CSF)
• muramyl dipeptide and derivatives
• lipopolysaccharide (LPS)
• monophosphoryl lipid A (MPL-A)
• synthetic lipopeptides

One of the more common of these agents used in veterinary vaccines are
saponins, which are derived from chemical plant extracts. Quil A is commonly used in equine influenza virus, canine parvovirus and FeLV vaccines. QS21 has been used in FeLV and canine Lyme disease vaccines. They are known to be strong inducers of Th1 and Th2 and CTL
responses. They seem to be relatively safe the more purified the extract, but there have been
isolated reports of some toxicity, specifically in cats.

Question 36

particulate and mucosal adjuvant agents

Answer 36

particulate
- polyactide-co-glycolide (PLG) microparticles
- virus-like particles (VLP)- consist of one or more viral coat proteins that assemble into particles, poloxamer particles

mucosal
- cholera toxin (CT)
- heat-labile enterotoxin (LT)

Nanoparticles and microparticles are extremely small particles (~10-1000 nm) created from
biodegradable polymers such as polylactide-co-glycolide and cyanoacrylates co-polymers. Not
only are these polymers used as adjuvants they are used as drug carriers, in sutures and
prosthetics. Believed to be relatively safe, they can be manipulated to have a short-term or
long-term depot effect.
So, in theory, they could be employed in 1 vaccine as both a primary and booster stimulation.
This was reported in a rat model with a tetanus vaccine (Sing et al. 1997, Infection Immunity),
who showed that 1 microparticle mixed tetanus toxoid inoculation yielded immune titers
comparable to 3 inoculations with an alum-based tetanus toxoid. Note, they don’t appear to be
strong immunomodulators by themselves, but rather need to be paired with other
immunomodulators. Another perceived strength of these adjuvants is their ability to protect
antigens from low pH, bile salts and enzymatic activities making them quite attractive for use in
oral and intranasal vaccines provided they are manufactured properly and don’t attenuate the
antigens they are designed to protect. Still, it is a very exciting area of research and
development. Aspects of this vaccine technology appears to be employed in some of the new
COVID vaccines.

Bacterial toxins, in particular adenosine diphosphate-ribolysating toxins, have also been
evaluated for mucosal or transcutaneous application. Cholera toxin and E.Coli heat-labile
exotoxin work well as mucosal adjuvants inducing strong humoral and CTL responses. They are
typically mutated to diminish potential toxicity.
Clearly, the use of these adjuvants is necessary with specific vaccine types and likely will change
in formulations as we decipher in more depth the interactions between innate and adaptive
immune systems.
Note, these formulations continue to remain a highly guarded secret by the pharmaceutical
industry, which is unfortunate but, understandable

Question 37

modes of vaccine delivery

Answer 37

• subcutaneous (SC) or intramuscular (IM)- most common, rabies (all species)
• intranasal (IN)- canine (bordetella bronchioseptica, felines (feline rhino trachetitis and calciviirus), cattle (infectious bovine rhinotracheitis), birds (infectious bronchitis and newcastle disease)
• oral- human (sabin-polio), oral rabies vaccine (foxes, racoons)
• aerosolization, feed or water, full immersion (fish)- management of herds, flocks, or schools
• transdermal (needle-free)- feline (purevax, non-adjuvanted recombinant feline leukemia)

Question 38

Modes of Vaccine Delivery: Route of Administration

Answer 38

The most common routes are subcutaneous (SC or SQ) and
intramuscular (IM), followed by intranasal (IN) and oral. Transdermal vaccination, as a mode,
was developed as one way to minimize the induction of vaccine-induced sarcomas in cats
(Figure 6).
Other more specialized routes include intra-ocular, intraperitoneal, aerosolization, immersion
and in ovo (in poultry). The innate advantages, no pun intended, of IM and SQ injections is that
the inoculum tend to form small antigen deposits or depots which facilitate a slow, sustained
release of the vaccine particles. An additional rationale for using this site is that the
subcutaneous tissues and muscles are rich in dendritic cell, macrophages and mast cells.
Essentially, you are placing the vaccine at a site in the body where you can maximize innate
immune response. Mast cells are actually pretty powerful innate pro-inflammatory cells.
Depending on the type of pathogen and vaccine, the route of vaccine administration
can be very important.
For example, although IM and SQ injections are excellent for ensuring a strong immune
response, the type of immune response generated is more systemic. However, some
pathogens, (i.e. Bordetella bronchiseptica) infect at the level of the mucosa. Systemic
immune response may not be as effective at this infection site.
An IN Bordetella vaccine, on the other hand, is able to immediately activate mucosal immunity
in particular the mucosal B cells and stimulate the production of pathogen-specific IgA
antibodies. A negative aspect of this mode of delivery is that the immunity generated is short
term and frequent boosters are required. There have been some studies looking at combining
IN and SQ vaccines to try to generate a prolonged immunologic memory targeting the IgA
antibodies. At this time, I don’t think we are there yet.
A brief comment about the oral vaccines, similar to IN vaccines, they do a great job at
stimulating mucosal immunity. They are easy to administer and typically not associated
with any pain to the patient. An example which was previously mentioned is the oral rabies
vaccine (bait). In humans, the polio vaccine (Sabin) is a. good example.

Question 39

Frequency of vaccine administration

Answer 39

the most important stage of life for vaccinations is during the neonatal and
juvenile stage. Although the immune system of these young animals is functional, it is not
competent to handle a lethal pathogenic exposure. It speaks to the importance
of maternal passive immunity as well as ensuring maternal vaccinations are up-to-date.
Once maternal immunity wanes, then the recommended standard vaccination protocols are
provided by our professional societies (i.e. AMA, AVMA, AAHA, AAEP etc).

Question 40

AVMA core vaccines

Answer 40

those that protect from diseases:
- endemic to a region
- potential public health significance
- required by law
- virulent/highly infectious
- posing a risk of severe disease
- clearly demonstrate efficacy and safety
- exhibit high enough level of patient benefit and low enough level of risk to a majority of patients

Question 41

core vs non-core vaccines

Answer 41

Other than protecting
against disease, a core vaccine fulfills some of the other aspects on card above. This is
the same principle applied to human vaccines. Further, depending on what part of the country
or country in general, that you reside, some of the noncore veterinary vaccines may migrate
into a “core-like” category. I’ll give an example in just a few minutes.
Still, within the veterinary community, there seems to be a general agreement regarding which
vaccines are core or noncore and when these vaccines should be administered to the very
young patient (i.e. < 1year). This holds true with human vaccines as well, with human vaccine
protocols pretty much standardized. Beyond that first year-of-age with veterinary vaccines, the
opinions seem to vary based on what I perceive to be the age, level of training and duration in
practice of the clinician. Regardless, I firmly believe that each clinician should review each
veterinary patient’s health status, stage of life and activity/lifestyle and then customize a
specific vaccine program for that patient.
Currently, the only vaccine required by federal law is rabies largely based on its zoonotic
potential and lethality. The “core” vaccines are strongly recommended and the “noncore”
are suggested and maybe geographically more relevant depending on the pathogen in
question.
An example of a noncore vaccine would be the Borrelia burgdorfei or “Lymes disease,
which is a major health problem in the Northeast for humans, dogs and horses
making it viewed as a “core” by practitioners in the Northeast area of the US, but not here in
the deep south. Although, we have had reported cases in North Georgia

Question 42

antibody mediated negative feedback inhibition

Answer 42

B cells, in particular, is that they co-expressed Fc
receptors on their surface during antigen activation and if there were antibodies already bound
to the antigen with an exposed Fc portion and it bound to the Fc receptor of the B cell it
would become inactive. It functions as a natural negative feedback

Question 43

2013 article posted online regarding
canine vaccines

Answer 43

The author stated that the AAHA in 2011 had finally updated their vaccination
guidelines. They changed the core vaccine protocols to every 3-year with the exception of
rabies, which is 1 or 3 year depending on state regulations.
The article went on to say that immunity to distemper and parvo lasts for 5 years and
possibly longer ~ 7 years for adenovirus. Presently, I still don’t believe that there are enough
data out there to allow for a blanket statement across all canine breeds.
Frankly, we need a larger scale study to validate that claim.
The thing that surprised me the most was that the author also stated, that at the time of the
article was written, about 60% of veterinarians were still performing annual revaccinations.
Please note, his data were acquired through communication with the vaccine manufacturer
sales reps
What I envision as an academician and researcher is the need to develop a robust assay testing
platform to help address each immune status to the core and or noncore pathogens.
This has the potential to help validate or refute many of the beliefs as well as concerns about
vaccines

Question 44

reason for vaccine failure

Answer 44

Vaccines that are classified as “unsatisfactory” and fail are largely due vaccines that contain the
wrong strain of microbes (i.e. influenza), as with flu, the virus mutates so rapidly that it displays
novel epitopes not recognized by the host during infection. The other example of an
unsatisfactory vaccine is when the protein peptides used turn out not to be immunoprotective.
That is, the immunity generated by the host against these peptides does not present the
disease. Thankfully, these conditions are not that common in commercial US vaccines.
Still, vaccine failure can still occur with vaccines that are deemed as satisfactory. Vaccines can
fail if the dose used is inadequate or the route of administration is incorrect. Additionally, due
to improper storage or shelf-life, the vaccine viability or potency can be below the level of
effectiveness. These are compliance issues and correctable.
Finally, vaccine failure can occur if the vaccine is given too late and the animals are already
infected. Another vaccine failure outcome is when the animal fails to respond. This can be seen
with young animals where maternal passive immunity blocks or at the very least inhibits the
vaccine. The animals that are immune suppressed either via congenital defects or on animals
on immunosuppressive therapy can fail to respond. Another real reason for an animal’s failure
to respond to vaccine is that its immune system does not effectively recognize the vaccine
epitopes.

Question 45

low risk adverse effects following vaccination

Answer 45

transient fever, inflammation at site, pain, general malaise

Question 46

adverse vaccine reactions

Answer 46

1. residual virulence and toxicity
2. hypersensitivities- anaphylaxis-killed vaccines (tetanus toxoid vaccine preservatives- thimersol/mercury)
3. neoplasia- sarcomas in felines
4. disease in immunodeficient individuals (FIV or animals on immunosuppressive therapy)
5. possible harmful effects on fetus (thimersol containing vaccines, modified-live)

Question 47

adverse vaccine reactions

Answer 47

Residual virulence and toxicity have been reported and attributed to either errors in
manufacturing or administration like contamination.
Hypersensitivity reactions, in particular Type I or IgE-mediated can occur locally (arthrus
reaction) or systemically (anaphylaxis) with some killed vaccines containing Thimersol and the
tetanus toxoid.
Neoplasia in particular feline injection site sarcoma (FISS), although uncommon, has been
linked to the Rabies and FeLV vaccines.
Any animals or humans that are on immunosuppressive therapy or are known to be
immunodeficient, as a rule, should not be vaccinated with any type of modified live virus. If you
can wait, to be safe, I would recommend not vaccinating at all until the animal’s immunity can
be stabilized.
With regards to pregnant animals and human females, the general dogma is that no live
vaccines should be administered. More recently, that has shifted to killed vaccines as some
preservatives in these vaccines, like thimersol, can cross the placenta and harm the fetus. So, to
be safe, don’t vaccinate pregnant animals or humans.
Based on a 2005 study (Moore et al. 2005, JAVMA) using data from a standardized adverse
vaccine data reporting survey involving 1.2 million dogs, reported the incidence of adverse
reactions to be ~38/10,000 dogs (0.38%). Of these animals, > 70% of the adverse reactions
occurred on the day of vaccination with 32% of these being associated with a Type I
hypersensitivity (allergic reaction). The rest ~68% were considered to be associated with some
degree of vaccine toxicity. What was noteworthy in this study was that smaller dogs made up a
significant percentage of these cases compared to larger dogs. A similar study was conducted
with cats involving ~ 500k animals and the incidence of adverse reactions was about 52
cases/10,000 (0.52%)