1.vaccine delivery system

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Prepared by :-
DIVYESH BIPINCHANDRA
SHARMA
Vaccine delivery systemVaccine delivery system

CONTENT
 Introduction of vaccine
 How vaccine works ?
 Types of vaccine
 Single shot vaccine
 Uptake of Antigen
 Transdermal delivery of vaccine
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WHAT ARE VACCINES...?
A vaccine is a biological preparation that improves immunity to
a particular disease.
A vaccine typically contains an agent that resembles a disease-
causing microorganism, and is often made from weakened or
killed forms of the microbe, its toxins or one of its surface
proteins.
The agent stimulates the body's immune system to recognize
the agent as foreign, destroy it, and "remember" it, so that the
immune system can more easily recognize and destroy any of
these microorganisms that it later encounters.
Vaccines can be prophylactic ( to prevent or ameliorate the
effects of a future infection by any natural or wild pathogen), or
therapeutic ( vaccines against cancer).
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THE IMMUNE SYSTEM— THE BODY’S
DEFENSE AGAINST INFECTION
To understand how vaccines work, it is helpful to first look at
how the body fights illness.
When germs, such as bacteria or viruses, invade the body, they
attack and multiply.
This invasion is called an infection, and the infection is what
causes illness.
The immune system uses several tools to fight infection.
Blood contains red blood cells, for carrying oxygen to tissues
and organs, and white or immune cells, for fighting infection.
These white cells consist primarily of B-lymphocytes, T-
lymphocytes, and macrophages:
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1.Macrophages (big eaters):
Macrophages are white blood cells that swallow up and digest
germs, plus dead or dying cells. The macrophages leave behind
parts of the invading germs called antigens. The body identifies
antigens as dangerous and stimulates the body to attack them.
2. Antibodies :
Antibodies attack the antigens left behind by the macrophages.
Antibodies are produced by defensive white blood cells called B-
lymphocytes.
3. T-lymphocytes :
T-lymphocytes are another type of defensive white blood cell.
They attack cells in the body that have already been infected
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The first time the body encounters a
germ, it can take several days to
make and use all the germ-fighting
tools needed to get over the
infection.
After the infection, the immune
system remembers what it learned
about how to protect the body
against that disease.
The body keeps a few T-
lymphocytes, called memory cells
that go into action quickly if the
body encounters the same germ
again.
When the familiar antigens are
detected, B-lymphocytes produce
antibodies to attack them.
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HOW VACCINE WORK
Antigens
Sound
the
Alarm
The molecules on a microbe that identify as
foreign agent and stimulate the immune
system to attack it are called “antigens.” Every
microbe carries its own unique set of antigens,
which are central to creating vaccines.
Macrophages digest most parts of the
microbes but save the antigens and carry them
back to the lymph nodes ,where immune
system cells congregate.
In these nodes, macrophages sound the alarm
by “regurgitating” the antigens, displaying them
on their surfaces so other cells, such as
specialized defensive white blood cells called
lymphocytes, can recognize them.
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2. Lymphocytes Take Over
• There are two major kinds of lymphocytes, T cells and B cells, and
they do their own jobs in fighting off infection.
• T cells function either offensively or defensively.
• The offensive T cells don’t attack the microbe directly, but they use
chemical weapons to eliminate the human cells that have already
been infected. these, cytotoxic T cells also called killer T cells.
• The defensive T cells, also called helper T cells, defend the body
by secreting chemical signals that direct the activity of other
immune system cells.
• Helper T cells assist in activating killer T cells, and helper T cells
also stimulate and work closely with B cells (antibodies).
• The work done by T cells is called the cellular or cell-mediated
immune response.
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B cells make and
secrete extremely
important
molecular
weapons called
antibodies.
Antibodies usually
work by first
grabbing onto the
microbe’s antigen,
and then sticking
to and coating the
microbe.
Antibodies and
antigens fit
together like
pieces of a jigsaw
puzzle—if their
shapes are
compatible, they
bind to each other.
Each antibody can
usually fit with only
one antigen.
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3. Antibodies in Action
The antibodies circulate throughout the human body and attack the
microbes that have lurking in the blood or the spaces between cells.
When antibodies gather on the surface of a microbe, it becomes unable to
function.
Antibodies signal macrophages and other defensive cells to come eat the
microbe. Antibodies also work with other defensive molecules that
circulate in the blood, called complement proteins, to destroy microbes.
The work of B cells is called the humoral immune response, or simply the
antibody response. The goal of most vaccines is to stimulate this response.
In fact, many infectious microbes can be defeated by antibodies alone,
without any help from killer T cells.
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4. Clearing the Infection: Memory Cells and Natural Immunity
When T cells and antibodies begin to eliminate the microbe faster
than it can reproduce, the immune system finally has the upper hand.
Gradually, the virus or infection disappears from the body.
After the body eliminates the disease, some microbe-fighting with B
cells and T cells are converted into memory cells.
Memory B cells can quickly divide into plasma cells and make more
antibody if needed.
Memory T cells can divide and grow into a microbe-fighting army.
If re-exposure to the infectious microbe occurs, the immune system
will quickly recognize how to stop the infection.
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HOW VACCINES MIMIC INFECTION
Vaccines teach the immune system by mimicking a natural infection.
For example, the yellow fever vaccine, first widely used in 1938, contains a
weakened form of the virus that doesn’t cause disease or reproduce very well.
Human macrophages can’t tell that the vaccine viruses are weakened, so they
engulf the viruses as if they were dangerous.
In the lymph nodes, the macrophages present yellow fever antigen to T cells
and B cells.
A response from yellow-fever-specific T cells is activated.
B cells secrete yellow fever antibodies.
The weakened viruses in the vaccine are quickly eliminated. The mock
infection is cleared, and humans are left with a supply of memory T and B cells
for future protection against yellow fever.
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TYPES OF VACCINE
1.Live Attenuated Vaccines:
These vaccines are made up of living virus or bacteria that
have been weakened (attenuated) by scientists.
These vaccines are very effective, but in rare cases (such
as in people with compromised immune systems), can
cause infection.
Rotavirus, chickenpox, and measles, mumps and rubella
vaccines are live attenuated vaccines. The BCG vaccine is
also a live attenuated vaccine
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2.Inactivated Vaccines:
More stable than live vaccines, these vaccines contain disease microbes
that have been killed with chemicals.
Inactivated vaccines tend to stimulate a weaker immune response than live
vaccines, and may require booster shots to maintain immunity.
Hepatitis A, influenza and polio vaccines are inactivated vaccines
3. Toxoid vaccines:
These vaccines are used when a bacterial toxin is the main cause of illness.
Scientists have found that they can inactivate toxins by treating them with
formalin, a solution of formaldehyde and sterilized water. Such “detoxified”
toxins, called toxoids, are safe for use in vaccines.
Vaccines against diphtheria and tetanus are examples of toxoid vaccines.
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4. Conjugate Vaccines:
Some bacteria have special coatings that hide them from the immune system.
Conjugate vaccines link these coatings to an organism that an immature
immune system can recognize, so it can respond and produce immunity.
The vaccine that protects against Haemophilus influenzae type B (Hib)
is a conjugate vaccine.
5. Subunit Vaccines:
These vaccines are made with only the parts of the microbe that stimulate the
immune system.
Subunit vaccines can be made by taking apart the actual microbe, or they can
be made in the laboratory using genetic engineering techniques.
Since these vaccines contain only parts of the microbe rather than the whole
microbe, the chance of temporary reactions is even lower than with other
kinds of vaccines.
Hepatitis B virus is an example of subunit vaccine.
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GENERAL METHOD FOR VACCINE
PRODUCTION
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Selecting strain for vaccine production
Growing the microorganism
Isolation and purification of
microorganism
Inactivation of organism
Formulation of vaccine
Upper stream
process
Down
stream
process

SINGLE DOSE VACCINE
Single dose vaccines are given at a
single contact point for preventing 4
to 6 disease.
In order to increase the therapeutic
efficiency of such vaccines,
adjuvants are used .
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VACCINE ADJUVANTS
An adjuvant is an ingredient of a vaccine that helps create a
stronger immune response in the patient’s body. In other words,
adjuvants help vaccines work better.
Some vaccines made from weakened or dead germs contain
naturally occurring adjuvants and help the body produce a strong
protective immune response.
However, most vaccines developed today include just small
components of germs, such as their proteins, rather than the
entire virus or bacteria.
These vaccines often must be made with adjuvants to ensure the
body produces an immune response strong enough to protect the
patient from the germ he or she is being vaccinated against.
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TYPES OF ADJUVANTS
Gel types
eg : aluminum hydroxide and phosphate, calcium phosphate .
Oil emulsion and emulsifier based
Particulate based
eg : liposomes , biodegradable microspheres.
synthetic
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BIODEGRADABLE POLYMERS
Biodegradable polymers Defined as polymers comprised of monomers
linked to one another through functional groups and have unstable links in
the backbone.
Broken down into biologically acceptable molecules that are metabolized
and removed from the body via normal metabolic pathways
Types of biodegradable polymers:
Types of biodegradable polymers There are two types of biodegradable
polymers.
1.Natural biodegradable polymers
eg : Albumin, Collagen, Gelatin etc.,
2.Synthetic biodegradable polymers
eg : Aliphatic poly(esters), Polyanhydride , Polyphosphazene ,
poly aminoacid , Poly( orthoesters )etc.,
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BIODEGRADABLE POLYMERS
AS ADJUVANTS
Biodegradable polymers such as poly( lactide -co-glycolic acids) is most
commonly used for vaccine delivery.
This polymers is mainly required for
 controlled release of the drug from polymer matrix.
 Targeting to appropriate cell types to generate optimum response.
 Development of formulation that can be used as non-invasive.
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OBJECTIVES
To elicit a protective immune response for a long duration from a
single-contact immunization.
Potentiate the immune response to the vaccine without manifesting
any adverse effect.
Incorporate many vaccine in a single formulation.
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TRANSDERMAL DELIVERY OF
VACCINE
Transdermal delivery of vaccine is simple, painless and economical
approach to vaccination.
Transdermal delivery of vaccine is a novel immunization strategy by which
antigen and adjuvants are applied topically to intact skin to induce potent
antibody and cell mediated response.
Proteineous antigen alone or in combination with conventional bioactive
carriers could not penetrate through the intact skin.
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ADVANTAGES
Prevent unnecessary invasion to body.
Prevents or bypasses the problem related to degradation of peptidal
vaccine as in case of oral route.
It drains the antigens or carrier associated antigens to the
lymphatic system and hence to the lymph nodes.
It prevents unnecessary toxicity encountered in case of immunization by
other routes.
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SKIN AS A TARGET SITE FOR
DELIVERY
Various routes within the skin are exploited for the delivery/ta
rgeting of antigen to the specialized cells.
These include follicular pathway, normal pores present in the sk
in,
lamellar lipid bodies and through corneocytes.
The skin is exploited as a route for immunization, i.e. topical
immunization because it shows specific (immunity) as well no
nspecific (inflammation) responses for foreign substances.
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These responses are a result of presence of
immunocompetent cells within the skin, which include
 Langerhan's cells (LC),
 Dendritic epidermal T-cells
 epidermotropic lymphocytes.
The mast cells also represent the immunocompetent cells of
dermis.
Other cells present in the skin are resident antigen presenting ce
lls and transient inflammatory lymphoid cells (e.g., polymorp
honucleocytes, monocytes and lymphocytes).
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Skin consists of SALT (skin associated lymphoid tissue) responsible for th
e specific and nonspecific responses.
The SALT composed of the epidermal antigen presenting cells (APC) and
migratory T- lymphocytes in circulation, which have avidity for epidermal
tissues.
The existence of SALT in the skin is supported by the cytokinin's,
which have capacity to regulate the immune responses.
The antigens that come in contact with the epidermis and hence in co
ntact with the antigen presenting cells are taken to the lymph nodes by me
ans of the lymphatics, because migratory T‐cells are attracted towards the
peripheral lymph nodes.
After binding to high endothelial venules (HEV) they enter into the lymphno
des. The accumulation of T-lymphocytes gives rise to immunological
response.
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APPROACHES
Physical
approach
Electroporation
can be used for
the transfer of
bioactive
molecules across
stratum corneum.
Electroporation is used
for the delivery gene to
the keratinocytes for
the immunization as
well as for thr gene
therapy without
compromising the
viability of cell.
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2. Chemical approach:
The majority of protocols to increase the permeability of the
epidermis (stratum corneum ) include utilization of the chemical
such as ; surfactant, alcohol and polyols.
• They increase the permeability by following mechanism;
• Increasing the fluidity of skin lipids.
• Hydrating the polar pathway.
• Opening the heterogeneous multiaminate pathways.
• Keratolytic action.
Disadvantages: the chronic use of these chemicals for the
permeability enhancement may have dangerous side
effects.
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3. Vesicular approach
This approach is gaining wide acceptance nowadays.
It include utilization of vesicles, virosomes and reconstituted
viral envelop since they are efficient in transfer of immunogens
across the skin.
These carrier target either through keratinocytes or through
follicles.
The vesicles that enhance skin permeability of bioactive inc
lude;
liposomes, niosomes, transfersomes, reconstituted sendai virus
envelop (RSVE), adenovirus vector, herpes simplex virus (HSV) a
nd amplicon vector.
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a.Liposomes:
It have been studied extensively transdermal delivery.
It promote antigenic response of various bacterial, viral and
tumor cell antigen.
This inherent immunoadjuvant action of liposome depends on
their structural characteristic, which control their fate in the
body.
b. Niosomes:
nonionic surfactant based vesicles that can be utilized as a topic
al carrier for immunogens (Antigens or DNA) for trans
dermal delivery.
Niosomes of decycloethyleneoleylether are found to fuse with th
e corneocytes.
This fusion to corneocytes and formation of lipid stocks indicate
that niosomes are most promising vesicular carriers for transder
mal delivery of lipophilic molecules.
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c. Transferosomes:
Transferosomes are specially designed lipid surfactant vesicles f
or transdermal of bioactive molecules.
They are ultradeformable carrier system having high capacity of
changing their shape and passing through the natural pores i
n the stratum corneum.
They are highly efficacious in transferring the bioactive
molecules across the stratum corneum.
They can pass through the small pores present in the skin
having diameter five times less than their own diameter.
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d. Viral vectors:
Viral vector is another class of topical vaccine carriers.
They can be utilized for epidermal transfer of the DNA or other su
itable antigen.
These include adenovirus vector and HSV amplican vector.
Reconstituted viral vectors or virosomes have also been utilized
for intracellular targeting of encapsulated DNA/antigen.
The reconstituted sendai virus envelops (RSVE) can be applied t
opically for efficient gene or antigen transfer.
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TECHNIQUES FOR TRANSDERMAL
DELIVERY SYSTEM
Sonophoresis
Microneedle-
assisted
delivery
Iontophoresis
Elastic
liposomes
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SONOPHORESIS
uses ultrasound to permeabilize the stratum corneum layer of the skin.
ultrasound travels through a coupling fluid, it produces cavitation
bubbles. These bubbles oscillate and increase in size over many cycles
of the pressure wave.
The main mechanism for sonophoresis-enhanced permeability of the
skin is particular inertial cavitation, whereby cavitation bubbles can
implode when they are close to a liquid–solid interface, generating an
intense local shockwave.
This produces a jet of liquid that can penetrate the stratum corneum.
And, because the cavitation effect inversely correlates with ultrasound
frequency, this technique is efficient for permeabilization of the skin.
for administration of tetanus toxoid in mice and hepatitis B surface
antigen in pigs
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The SonoPrep® ultrasound device
Disadvantage
technique may cause
burning of the skin in
some cases, and
epidermal necrolysis
may occur at high
intensities.

MICRONEEDLE-ASSISTED
DELIVERY
microneedles (MN) are needles with lengths in the micrometer range
(typically less than 1000 micrometers) which create pores in the skin
and enable medications or vaccines to be delivered locally or
transdermally into systemic circulation.
MNs can be categorized as hollow, solid, coated, dissolving, or
hydrogel-forming.
It has has been applied to DNA vaccines to help resolve the problem of
their poor immunogenicity.
It has been used to administer polio vaccine to volunteers. It has also
been used to investigate delivery of the bacillus Calmette-Guérin
(BCG) vaccine and the tetanus toxoid in animal models.
However, it can be challenging to deliver high doses of medications
using MNs.
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SOLID MNS FOR
INCREASING
THE
PERMEABILITY
OF A DRUG
FORMULATION
BY CREATING
MICRO-HOLES
ACROSS THE
SKIN
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Coated MNs for
rapid dissolution of
the coated drug
into the skin

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Dissolvable MNs
for rapid or
controlled
release of the
drug
incorporated
within the
microneedles
Hollow MNs used
to puncture the
skin and enable
release of a liquid
drug following
active infusion or
diffusion of the
formulation
through the
needle bores.

The first two commercially marketed MN-
based products are Intanza® and
Micronjet®
1.Intanza is the first influenza vaccine that
targets the dermis, a highly immunogenic
area.
It was developed and licensed by Sanofi
Pasteur MSD Limited and is being marketed
in two strengths; Intanza® 9 µg for adults
aged between 18 and 59 years
Intanza® influenza vaccine system has a
needle length of 1.5 mm.
2. MicronJet is a single use, MN-based
device for intradermal delivery
of vaccines and drugs. It was developed and
licensed by NanoPass. ®15 µg for adults of
60 years and above.
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IONTOPHORESIS
Iontophoresis involves application of a small electric
current to permeabilize the skin.
It is a non-invasive and efficient technology for
transdermal vaccine delivery, and is particularly helpful
because, when using transdermal vaccine delivery, it can be
challenging to accumulate enough antigen in the epidermis
for effective exposure to the skin’s DCs.
In various animal studies, this technique has been shown to
effectively deliver and generate an immune response to
tumor antigens and hepatitis B vaccines.
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Phoresor, Lidosite, E-trans are examples of three
commercially developed iontophoretic delivery
system.
The first approved commercial iontophoretic patch
system was LidoSite®, which was developed to
deliver lidocaine for fast dermal anesthesia.
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LIMITATION:
Iontophoresis has a minor effect on
skin structure over short treatment
periods due to the low-voltage
nature of the applied electric
current, when compared to
electroporation.

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