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Animal Models in
Modern Vaccine Development
Animal Models
• The recognition that animals could be used as
potential models for human infectious diseases dates
back to Jenner, who in 1798 observed that milkmaids
were resistant to smallpox because they were
exposed to cattle infected with a related virus
• Pasteur investigated anthrax and rabies pathogenesis
in animal models
Animal Models
• Pasteur's studies with the rabies virus clearly
demonstrated the ability to transmit infectious
agents from one species to another
• Pasteur further enhanced the concept of vaccination
of dogs against rabies virus and finally tested his
theory of vaccination on Joseph Meister, who had
been bitten by a rabid dog
• As is now well-known, the experiment was a success
and Pasteur is recognized as the individual who
introduced the concept of inactivated vaccines
,which is still used today
Animal Models
• A more recent example of an animal viral disease being used
to develop a platform technology for use in licensing a human
vaccine are virus-like particles (VLPs) for immunization against
Papillomavirus
• The concept of using recombinant Papillomavirus VLPs was
first established for the control of disease caused by bovine,
canine and rabbit Papillomavirus, and eventually provided the
basis for subsequent licensure of a bivalent and quadravalent
HPV vaccine to control cervical cancer.
• The development of this vaccine confirms that studies in
animals remain relevant to the control of infectious diseases
in humans
Animal Models
• With availability of inbred, genetically-defined
strains, mice have become the species of
choice for most investigators
• Unfortunately, as these studies exploded in
number and with different pathogens, it
became clear that the mouse was not as
useful a model species as was anticipated
Why Mouse is a Model for Us Humans
• Humans and mice have a reasonable number of genes in
common– those involved in the development of major organs
and major sections of our physiology such as the nervous,
muscular, skeletal, cardiovascular, immune and endocrine
systems.
• In addition to having many structures and functions similar to
humans, mice are relatively short-lived and explosive
reproducers (potentially producing a new litter every nine
weeks).
• So studying these animals is one of the best ways to find out
how specific genes common to mammals function over
generations.
Use of Animal Models in Vaccine Production
• Animal models can be used in a variety of
ways to study
– Disease pathogenesis
– Host–pathogen interactions
– Mechanisms of protection following vaccination,
infection or treatment of disease
Use of Animal Models in Vaccine Production
Natural or surrogate animal models
• Natural animal models
• Natural disease models make use of a specific
pathogen and its natural host and have the
advantage of modeling the interaction
between host and pathogen, within the
appropriate biological context
Natural animal models
• This is important since it permits analysis of virulence
factors and their role in invasion, penetration and
toxicity, as well as the host's immune response to the
pathogen
• This also allows identification of specific molecules
that are often required by the pathogen for infection
or subsequent induction of disease and which often
represent targets for the host's immune response
Natural animal models
• Using these molecules as vaccine antigens has
proven to be a very successful strategy for
developing effective vaccines against both human
and animal diseases
Surrogate models
• Surrogate models refer to the use of species
that can only be infected with the pathogen of
interest under experimental conditions
• As a consequence, compromises such as
higher infection doses or artificial routes of
infection often have to be made
Surrogate models
• Most often, mice are the animal species of choice
• They offer the advantage of working in a consistent genetic
background, are easy to handle, and are very cost-effective
• Recent advances in creating constitutive or conditional gene
knockout mice have opened the door to understanding:
– Role of specific host genes in pathogen recognition
– Induction of acquired immunity
– Cellular interactions within various immune compartments
Surrogate models
• Prominent examples include the successful
knockout of:
– β-microglobulin
– Toll-like receptor
– Cytokine
– Chemokine genes
Surrogate models
• These gene deletions have created important animal
models such as B- and T-cell-deficient mice:
– Can help in vaccine development against many extra- and
intracellular pathogens.
• Transfer of normal or genetically modified cells from
one mouse to another is being used to characterize
the function of specific immune cells in the context
of infection and vaccine-induced immune responses
Surrogate models
• Animal models can also serve to analyze specific aspects of the
immune response, such as:
– The development of immune organs
– The role of specific immune compartments or individual cell
populations
– The trafficking of immune cells following infection or vaccination
– Various aspects of vaccine delivery including mucosal or topical
application
– Transmission amongst infected and non-infected animals
– Studying transfer of passive immunity via the placenta,
colostrum and milk
Surrogate models
• Animal models have been used to explore:
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Vaccine formulation and delivery
Route of administration
Targeting to specific receptors
Induction of mucosal versus systemic immunity
• Surgical models allow access to intestine, lymph
nodes or skin tissues for vaccine testing
• Large animal models provide the opportunity to
evaluate vaccine efficacy, for example West Nile virus
(WNV) or influenza infections in horses.
Surrogate models
• Since many disease models in mice utilize
artificial routes of challenge, in large animals
however, it is often possible to use the natural
route of challenge and therefore obtain more
relevant correlates of immune-mediated
protection
• In vaccinating such population, it has
frequently been observed that there are ‘low'
and ‘high' responders
Surrogate models
• This reflects a genetic component that determines
the magnitude of immune responses within
individual animals
• Inbred lines of pigs have been established that have
been defined as low and high responders following
vaccination
• The advent of genomics has made it possible to
begin defining the genetic basis of the immune
response to vaccination
Surrogate models
• Vaccine efficacy also varies dramatically when
immunizing the very young or the elderly
• Natural disease models including E. coli and rotavirus
infections in pigs and calves have been used to
establish the concept of maternal vaccination as an
effective strategy to:
– Reduce the risk of infection in the neonate
– Optimize the passive transfer of maternal immunity to the
newborn
– Determine the duration of protection following passive
transfer of maternal antibody
Limitations of Surrogate & Natural Animal
Models
• The dose of pathogen used for experimental
challenge frequently exceeds the dose known
to cause natural infection
• Differences in the infectious dose may be due
to passage in culture, and a consequently
hypoinfectious state or the attenuation of the
pathogen
Limitations of Surrogate & Natural Animal
Models
• The use of animal models for evaluating vaccines
remains critical prior to vaccine testing in humans
• Rarely is there an animal model that precisely
replicates human infections
• Natural routes of infection are often unavailable
owing to the lack of relevant receptors in model
species
• Consequently, the route of entry and disease
pathogenesis are different, which makes vaccine
testing less relevant in this model
Overcoming these Limitations of Surrogate &
Natural Animal Models
• Utilizing an animal model that expresses the required
receptors for a specific pathogen, or using natural
disease models with pathology comparable to the
human disease, can assist in overcoming these
difficulties
• For example pneumovirus (PVM) infection of mice,
which has a similar pathology to respiratory syncytial
virus (RSV), one of the most serious causes of
respiratory illness in infants
Overcoming these Limitations of Surrogate &
Natural Animal Models
• Likewise, bovine RSV (BRSV) is also an
appropriate model for RSV owing to the
genetic similarity of the viruses and similar
clinical disease
• Transgenic mice that carry receptors for
human pathogens may provide an alternative
model for evaluating host responses when
using the natural route of infection
Criteria for Appropriate Animal Models
• The quality of an animal model and its
appropriateness for vaccine development can
be defined by its ability to reproduce relevant
human physiology, which ultimately is the
target population for the vaccine
• Thus, good models share the same
physiological characteristics, or at least reflect
them as closely as possible
Criteria for Appropriate Animal Models
• The physiology of the skin is very similar between
humans and pigs, which renders the pig a good
model for studying intracutaneous or topical delivery
of the vaccine
• The development of the immune system, in
particular the maturation of the mucosa-associated
lymphoid tissues, is similar in humans, sheep, cattle
and pigs, which again makes these species good
models for studying mucosal delivery of vaccines
Criteria for Appropriate Animal Models
• In these species the mucosal immune system
develops well before birth, which stands in
clear contrast with mice, in which the mucosal
immune system only develops after birth
• Furthermore, the neonatal period in mice is
much shorter than in man, which makes the
use of mice for developing neonatal vaccines
highly problematic
Criteria for Appropriate Animal Models
• The ethical use of animals in human vaccine
research requires that we only choose animals
that match the human disease as closely as
possible
• Such a criteria will help to reduce the overall
number of animals used for biomedical
research
Criteria for Appropriate Animal Models
• DNA vaccines and recombinant viral vectors, have
been developed and demonstrated to provide
disease protection in horses
• The horse has been a very useful model for analyzing
several aspects of the immune response to
vaccination such as:
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Maternal immmunization
Passive transfer of immunity
Response to adjuvants such as bacterial DNA
Immunization of the neonate and the elderly
Criteria for Appropriate Animal Models
• Large animal models, such as the horse, could
provide geriatric populations for the screening of a
variety of possible adjuvants
• Very little is known, however, regarding the
functional or phenotypic changes in the immune
system of most domestic species and this
information will be critical to determine if these
animal models are appropriate surrogates for the
translation of vaccine technologies to clinical
application
Conclusion
• When choosing an appropriate animal model for human
disease, it is critical to ensure that the model simulates
as closely as possible the events occurring in humans
• First, it is more likely that higher similarity of pattern of
pathogenesis to human disease in an animal model will
correlate better to immune-mediated protection
resulting from that model
• Second, if the pathogen enters via the respiratory tract,
then the model should utilize aerosol challenge to expose
the pathogen to the defenses of the upper respiratory
tract
Conclusion
• Third, the pathogen dose should be similar to that
which would occur naturally, since it is always
possible to overcome an adaptive immune response
by excessive pathogen challenge or by using an
unnatural route of infection
• In choosing a model for respiratory infections, the
structure, function and development of the
respiratory tract in the animal model should
resemble that of humans