Salmonella in poultry_vaccination

Plan of Talk
 Aim of Salmonella vaccination
 Characteristics of an ideal Salmonella vaccine
 Types of salmonella vaccines
– Live attenuated
– Inactivated
– Subunit
 Immunoadjuvants

Aim of Salmonella Vaccination
The aim of vaccination as part of a complex control programs for
Salmonella infections in poultry is to:
1. Reduce or prevent the intestinal colonization resulting in
reduced fecal shedding and egg shell contamination.
2. Prevent systemic infection resulting in a diminished
localization in the reproductive tissues.

Ideal Salmonella Vaccine Strain
1. High degree of protection against systemic and intestinal
infection.
2. High protective potential against a variety of important
serovars (serogroups)
3. Adequate attenuation for poultry, other animal species,
humans and the environment.
4. Inactivated and live vaccines should not affect growth of the
animal.
5. Vaccine strains should not be resistant to antibiotics.

Cont. …
6. Vaccines should be easy to administer and need to have
markers enabling the differentiation from salmonella wild-
type strains.
7. Application of vaccines should not interfere with salmonella
detection methods.
8. Humoral antibody response after vaccination should be
distinguishably from a salmonella wild-type response to
allow the use of serological detection methods
9. Attenuated live salmonella vaccine strains should be able to
induce the colonisation inhibition effect between salmonella
organisms.

Cont. …
10. Salmonella vaccine strains should have preserved the ability
to invade the gut as prerequisite to induce the invasion
inhibition effect between salmonella organisms

Live Virus Attenuation
The aim of attenuation is to diminish the virulence of the
pathogen, but retaining its immunogenicity.

Live Attenuated Vaccines
Risk Factors
Several risks are associated with live vaccines, especially in
immunocompromised individuals:
1. Some of the structural components of the microorganism
used may contain immunosuppressive antigens.
2. Attenuated strains may still have some residual virulence
due to an incomplete inactivation.
3. Attenuated strains, after being released into the
environment, can recover their virulence in other hosts,
or can acquire genes from other microorganisms by
natural genetic transfer.

Cont. …
Under these points of view, despite their extended use, the
restrictions for the use of attenuated modified organisms in
vaccination are becoming more and more stringent.

Advantages Over Inactivated Ones
1. Easy administration.
2. Ability to carry heterologous antigens.
3. Capacity to induce cellular and humoral immune responses.

Empirical Attenuation
Methods
Attenuated Mutations
Metabolic functions
Virulence factors
Methods of Attenuation

Empirical Attenuation
Methods
Metabolic functions
Virulence factors

Empirical Attenuation Methods
The empirical attenuation methods developed by Pasteur and
Koch at the end of the twentieth century.
Many successful live viral and bacterial vaccines are produced by
repetitive in vitro passage in cell culture.

The knowledge we have nowadays about genomics allows us to
selectively knock out concrete virulence genes.

Cont. …
Salmonella has around 4,500 genes.
A change in any gene (mutation) can lead to an alteration in
protein.
This mutation may change the structure and function of the
bacterium.
Some mutation may have no effect.

Target Mutagenesis
Specific alteration by genetic manipulation of the genome;
Insertion, deletion or framshift changes alter the gene
structure or function.
Deletion and insertion frequently used experimentally and
in potential vaccines.

Deletion
 A gene or part of it is knocked out.
 The gene is no longer transcribed, no
RNA and no protein is synthesized.
A B C
A C

Insertion
 A foreign piece of DNA is inserted into
the targeted gene.
 This knocks out the gene function
although transcribed RNA no longer
encodes correct protein.
 Here gene B in an inserted.
 Insertions are less stable than
deletions, but easier to perform.
A C
A CB

Advantages of this strategy:
1. Some important antigenic determinants can be retained
by attenuated strains that are able to elicit both antibody
and cellular immunity.
2. Growing capacity of these attenuated vaccines provides
prolonged exposure of antigens to the immune system,
resulting in the production of long-lasting memory cells.

Attenuated Mutations/Metabolic Functions
The most widely studied metabolically attenuated strains include
mutants deficient in:
The biosynthesis of:
1. Aromatic amino acids (i.e. aroA, or aroC and aroD)
2. Purines (purA, purE)
Or in the production of:
1. Adenylate cyclase (cya)
2. Cyclic AMP receptor protein (crp).

Cont. …
In general, auxotrophy can interfere with bacterial replication
within the host whenever the required metabolites are:
1. Absent.
2. Present in amounts insufficient for bacterial growth in the
compartment where the bacteria reside.

Attenuated Mutations/Virulence Factor
 The two more extensively characterized virulence-attenuated
vaccine strains have mutations in the two-component
regulatory system phoP/phoQ or in Salmonella pathogenicity
island 2 (SPI2) loci.

Killed Whole Organisms
 To avoid the risk of live vaccines, the use of killed organisms
was introduced as safer vaccines.
 These vaccines are made from the entire organism but
inactivated (killed) by physical or chemical agents.

Cont. …
 However, protection induced by bacterins in poultry is
generally modest .
 The limitations of these kinds of vaccines are:
1. Their immunogenicity usually has to be enhanced by co-
administration with adjuvants.
2. Multiple doses are necessary for obtaining long-term
protective immunity; besides, as live vaccines, they may
contain immunosuppressive antigens.

Subunit Vaccines
Subunit vaccines contain immunodominant components of the
bacteria.
Subunit vaccines may be:
1. Crude or purified extracts of the pathogen.
2. Synthetic peptides.
3. Obtained by the use of recombinant DNA technology, pure
DNA or RNA.

Cont. …
The primary goal of this approach is:
1. To identify the individual antigens of the pathogen that
are involved in inducing protection.
2. Avoiding the immunosuppressive ones.

Cont. …
Combining genomics with our understanding of pathogenesis, it
is possible to identify specific proteins from most pathogens that
are critical in inducing the right protective immune responses.

Cont. …
The potential advantages are;
1. Vaccine safety.
2. The potential abilities to target the vaccines to the site
where immunity is required.
3. To differentiate vaccinated animals from the infected ones
through the right selection of the components.

Cont. …
 In spite of these data, low levels of resistance against
salmonellosis can be induced by administration of flagella,
porins or polysaccharide fractions.
 The potency of these vaccines is often poor when
administered without adjuvant and/or a delivery system.

Cont. …
 New generation adjuvants are designed to induce minimal
side effects, enhance the duration of the immune response,
and concurrently stimulate humoral and cellular immune
responses.

Ideal vaccine
properties
Attenuated Inactivated
Subunit
Classical
Adjuvant (Alum)
New adjuvants
(DDS)
I +++ + + +++
II +++ + + +++
III + ++ ++ +++
IV + + + +++
V + +++ + +++
Strong, protective and long
lasting immune response
Right sort of immune
responses.
Safe
Single dose of vaccine should confer
robust, long-lived immunity. Affordable

I
A good vaccine should stimulate a strong, protective and long
lasting immune response. Through the induction of strong, long-
lived immunological specific T and B cell memory cells.
Measurement of the specific subsets elicited by immunization
may guide vaccine development.

II
A good vaccine should induce the right sort of immune
responses.
The protective immune responses against extracellular
pathogens seem to be mediated by long-lived humoral immune
responses through the production of antibodies. However, in the
control of intracellular infection, cellular immune responses have
been shown to be crucial in mediating protection. Therefore, the
development of a successful vaccine against those diseases will
be facilitated by a thorough understanding of how cellular
immune responses are generated and maintained in vivo.

III
An ideal vaccine should be safe.
Despite the success of vaccination in eliminating disease and
death, the public acceptance of even minor side effects of
vaccination is very low. One major challenge faced in developing
new vaccines is to achieve strong immunogenicity without
increasing reactogenicity.

IV
A single dose of vaccine should confer robust, long-lived
immunity.
Only a few live vaccines have achieved this goal. In contrast to
the results with live vaccines, it has been difficult to promote
long lived immunity with a single dose of non-living antigen
vaccines. One goal of vaccine development is to rectify this using
new adjuvants and antigen delivery systems.

V
An ideal vaccine should be affordable by the population at which
they are aimed and should be formulated to resist high and low
temperatures to facilitate distribution. This is a main problem for
alive attenuated vaccines

Immunoadjuvants
Adjuvants
They are defined as a group of structurally heterogenous
compounds that enhance or modulate the immunogenicity of
the associated antigens.

Cont. …
 Despite the recognition of many
different types of adjuvant, however,
little is known about their mode of
action.
 Janeway called adjuvants “the
immunologists dirty little secret”,
because their mode of action is
poorly understood.

Cont. …
The events triggered by these immunomodulators appear to
come from one or the combination of several of the following
effects:

Immunoadjuvants Effects
Adjuvant Effect
Depot Effect
Effect On Antigen
Presenting Cells (APC)
Nonspecific
Immunostimulanting Effect
Particulated
Carrier Systems

Immunoadjuvants
Depot Effect
If antigen is present in
a solution, it is mostly
quickly removed by
neutrophils and
macrophages.
Subsequently,
antigens are unable to
prime naive T cells.
Following that, the
antigens disappear
and the immune
response is hardly
detectable.

Immunoadjuvants
Depot Effect
Adjuvants, such as:
1. Oil emulsions
2. Antigen absorbing aluminium salts
Retain antigen at the injection site,
Then, it is released in minute quantities over a prolonged period
of time.
These compounds mainly stimulate the production of antibodies
by the induction of Th2-lymphocytes.

Immunoadjuvants
Depot Effect
 In the case of use of alum, the mechanism of action seems to
be due to
 Formation of a depot of free alum that will induce the
recruitment and activation of immune cells to the site of
inoculation.

Immunoadjuvants
Effect On Antigen Presenting Cells (APC)
The adjuvant induced enhancement of an immune response may
be related to the improved delivery of antigens into the
draining lymph nodes.
This may be achieved by:
1. Facilitating the antigen uptake by APCs.
2. Increasing the influx of APCs into the injection site.

Immunoadjuvants
Effect On Antigen Presenting Cells (APC)
This results in:
1. Increase in the provision of antigen-loaded APCs, and in turn,
effective priming of specific T cells.
2. Promoting the activation state of APCs by upregulating
costimulatory signals or MHC expression.
3. This results in the corresponding cytokine release, enhancing
the speed, magnitude and duration of the specific immune
response.

Immunoadjuvants
Nonspecific Immunostimulating Effect
 Some agents can stimulate the non-specific component of the
immune system.
 Numerous microorganisms contain “alert signals”, the so
called “microbial or pathogen associated molecular patterns”
(MAMPs or PAMPs, respectively), which is not present in
mammalian cells.
 These structures activate immune cells through interaction
with specific receptors (toll like receptors, TLRs).

Immunoadjuvants
Nonspecific Immunostimulating Effect
Some examples are:
1. Lipopolisaccharide (LPS)
2. Monophosphoryl lipid A (MPL)
3. Flagellin
4. Lipoproteins
5. Muramil dipeptide (MDP)
6. Trehalose dimycolate (TDM),
7. Cpg DNA, among others.
Besides, the special chemical nature of some polymers used in
the formulation of vaccine delivery systems may also be
recognized as scavenger ligands for the APCs.

Immunoadjuvants Effects
Adjuvant Effect
Depot Effect
Effect On Antigen
Presenting Cells
(APC)
Nonspecific
Immunostimulanti
ng Effect
Particulated Carrier
Systems

Immunoadjuvants
Particulated Carrier Systems
 Particulated Carrier Systems have been proposed to improve
the mucosal bioavailability of antigens.
These carriers protect labile molecules from degradation in
the gastrointestinal tract.
 Nanoparticles are submicron-sized colloidal systems that may
protect antigen against chemical, enzymatic or immunological
degradation, and facilitates targeting and presentation of
antigens to inductive sites of mucosal immune system.

Salmonella in poultry_vaccination

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