Transdermal and mucosal vaccine delivery and latest technologies used in it.

1. MUCOSAL AND
TRANSDERMAL VACCINES
Presented by:
J Manjunath
1ST M-Pharm
Pharmaceutics department
AL-Ameen college of pharmacy, Bangalore.
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Presented To:
Suma R
Associate professor
Pharmaceutics department
AL-Ameen college of pharmacy, Bangalore.

2. CONTENTS
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Introduction
Mucosal Vaccines
Oral and Nasal Delivery
Design of Nanocarriers
Transdermal Vaccines
Design Of Transdermal Vaccine Delivery
References

3. INTRODUCTION
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• Vaccination is carried out to protect the individual from an infection by priming the
immune system to resist the infecting agent.
• Immunization also results in the system developing a "memory" of exposure to
antigens present on the pathogen and becoming prepared to respond to the same
without much delay upon subsequent encounter.
• Recent studies have shown that other routes of delivery such as intranasal, oral, and
transdermal delivery have also been effective. In some cases, vaccination through
mucosal routes resulted in better responses in IgA production. Because non-parenteral
vaccine delivery presents many obvious advantages, numerous attempts have been
made on the development of non-parenteral delivery of vaccines.
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MUCOSAL VACCINES
• The surface of the mucosa is the biggest path through which pathogens enter
the human body.
• The better impact of the mucosal vaccine over traditional injectable vaccines
are that they not only induce efficient immune reactions to the mucosa but
they are also comfortable in physical aspect & psychological aspect.
• As most of the pathogens first infect the mucosal surfaces, and growing
interest is expressed in establishing protective immunity from the mucosa,
which is accomplished through mucosal paths through vaccination.

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• Parenteral vaccination alone is quite often insufficient in
inducing mucosal immune responses, because stimulation
of the MALT usually requires direct contact between the
immunogen and the mucosal surface.
• An antigen interacting with localized lymphoid tissue can
stimulate IgA precursor cells that may then migrate to
other mucosal surfaces to elicit immune reaction in other
mucosal tissues. It is known that the mucosal immune
system produces 70% of the body’s antibodies.

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ORAL VACCINES
Oral vaccination is the most preferable mode of vaccination because of its ease of use and low cost of
manufacturing. Furthermore, the gastrointestinal (GI) tract provides the largest component of the
mucosal immune system that has been well-characterized. Oral administration of vaccines has high
acceptability, by avoidance of injection, to individuals of all ages.
The maximal intestinal immunization can be achieved by intra-Peyer’s patch immunization, and thus
this method can be used to screen oral vaccine candidate antigens without the added complication of
simultaneously testing oral-delivery systems
•Ex: Oral polio vaccine. The oral polio vaccine (OPV) was the first successful mucosal vaccine developed.
Live oral typhoid vaccine (Ty21a)

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REQUIREMENT OF ORAL VACCINE FOR COVID-19
• The major Covid vaccines available in the market or under evaluation
are all administered ‘systemically’. However, only a vaccine designed
to induce ‘mucosal’ immune response can protect against respiratory
viral infection.
• The respiratory tract that is already home to billions of
microorganisms.
• The systemic Covid-19 vaccines available or undergoing evaluation will
be able to induce IgG antibodies and other protective immune cells in
the blood, but are unlikely to induce mucosal IgA antibody
production.
• Only a mucosal vaccine can stimulate the production of IgA antibodies
which attaches itself to host cell. Only IgA antibodies can prevent the
shedding of viral particles by this route.
• Limitation rapid replacement of the memory cells in the mucosal
tissues.
Ig A

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• Intranasal vaccination route has received growing interest for non-invasive immunization. Intranasal
immunization has been quite effective for various vaccine-delivery systems. This route of vaccine
targeting is developed because the conventional intradermal vaccine causes many problems like
irritation, pain, and redness. Nasal vaccine delivery is known to be superior to oral delivery in
inducing specific IgA and IgG antibody responses in the upper respiratory tract.
• Example: influenza vaccines FluMist /Fluenz
NASAL VACCINE

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BBV154-ANOVEL ADENOVIRUS VECTORED,INTRANASAL VACCINEFOR
COVID-19
• An intranasal vaccine stimulates a broad immune
response – neutralizing IgG, mucosal IgA, and T cell
responses.
• Immune responses at the site of infection (in the nasal
mucosa) – essential for blocking both infection and
transmission of COVID-19.

11. DESIGN OF NANOCARRIERS: SUITABLE DELIVERY VEHICLES
FOR MUCOSAL IMMUNIZATION
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• Conventional transporters (liposomes, micelles, nanoparticles, etc.) were developed to serve as a
structure for the transport of mucosal antibodies to safeguard the immunizing antigen from the
threatening state of the mucosal lumen and to boost its absorption and transcytosis through the
mucosal system.
• Used extensively as controlled-release dosage forms for many drugs including antigens.
• Useful in oral delivery of antigens because encapsulation in microparticles can protect antigens from
acidic and enzymatic degradation in the GI tract, and thus serve as a stable vaccine vehicle with
extended shelf life.

12. • Virus-like particles (VLPs) consist of one or more viral-coat
proteins. They are very immunogenic molecules that allow for
covalent coupling of the epitopes of interest.
• Recently, parvovirus-like particles have been engineered to
express foreign polypeptides in certain positions, resulting in
the production of large quantities of highly immunogenic
peptides, and to induce strong antibody, helper T-cell, and
cytotoxic T-lymphocyte responses.
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VIRUS LIKE PARTICLES (VLP)

13. • The slow degradation of the polymer, releases antigens slowly from the
microparticles for long term and this results in enhanced immune responses.
• A number of approaches have been tried to achieve antigen release at desired
rates as one of the important roles of microparticles is the slow release of
antigens.
• The surface of microparticles can be modified to alter the adsorption and
desorption kinetics of antigens. Alternatively, the pore size can be varied to
control the release of antigens from microparticles
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POLYMER MICROPARTICLES

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LIPOSOMAL DELIVERY SYSTEM
• Liposomes are vesicles composed of naturally occurring or
synthetic phospholipids, the bilayer structure can be single- or
multicompartment.
• As liposomes can protect antigens from the GI tract and
deliver them to the Peyer’s patches, they have been
extensively used as effective delivery system for oral
vaccination.
• The surface charge of liposomes is known to affect the immune
responses.

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VIROSOMES
• Virosomes are liposomes containing viral fusion proteins that allow
efficient entering into cells fusion with endosome membranes. Viral
fusion proteins become activated in the low pH environment in the
endosome to release its contents into the cytosol.
• Hepatitis A and influenza vaccines constructed on virosomes elicited
fewer local adverse reactions than did their classic counterparts and
displayed enhanced immunogenicity.
• The virosomes have a great potential for the design of combined
vaccines targeted against multiple antigens and multiple pathogens.

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MICELLES
• Micelles are aggregates of detergent molecules in aqueous solution
• They also align at aqueous/non-aqueous interfaces, reducing
surface tension, increasing miscibility, and stabilizing emulsions.
Polymeric micelles made of block copolymers, such as poly
(ethylene oxide)-poly (propylene oxide)- poly (ethylene oxide),
have been used as a delivery system for hydrophobic drugs.
• They can also encapsulate antigens for vaccination.

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NIOSOMES
• Niosomes are non-ionic surfactant vesicles. They have been used
to develop a vaccine-delivery system by peroral and oral routes.
• Ovalbumin was encapsulated in various lyophilized niosome
preparations consisting of sucrose esters, cholesterol, and dicetyl
phosphate. Encapsulation of ovalbumin into niosomes consisting of
70% stearate sucrose ester and 30% palmitate sucrose ester (40%
mono-, 60% di/tri ester) resulted in a significant increase in
antibody titters in serum, saliva, and intestinal washings

18. TRANSDERMAL VACCINE
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 The most widely used methods for transdermal administration of the drugs are hypodermic
needles, topical creams, and transdermal patches. The effect of most of the therapeutic agents is
limited due to the stratum corneum layer of the skin, which serves as a barrier for the molecules
and thus only a few molecules are able to reach the site of action.
 A new form of delivery system called the microneedles helps to enhance the delivery of the drug
through this route and overcoming the various problems associated with the conventional
formulations.
 It appears that transdermal electroporation is a promising technique for non-adjuvant skin
immunization, especially with low-molecular-weight, weakly immunogenic antigens.

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Design And
Strategy For
Design Of
Transdermal
Vaccine Delivery
HARSHITHA SK (GCP) 2021

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MICRONEEDLES
• Microneedle device consists of needles of micron size, which are arranged on a small patch.
• Microneedle patch bypasses the stratum corneum barrier and delivers the drug directly into the
epidermis or upper dermis layer which delivers 100% of the loaded drug without pain
• In the microneedle drug delivery system, the skin is temporarily disrupted. The drug is directly placed
in the epidermis or upper dermis layer which then goes into the systemic circulation and shows a
therapeutic response on reaching the site of action.

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Advantages Disadvantages
Faster onset of action Skin irritation or allergy to
sensitive skin
Better patient compliance Breaking of microneedle
tips
Self-administration Remained inside the skin
Improved permeability
Improved therapeutic
advantages

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Microneedle
Patch For
Influenza
Vaccination

23. • DNA tattooing involves puncturing the skin thousands of times with a multiple needle
tattoo device or permanent make-up device to deliver plasmid DNA vaccine into the
dermis and epidermis.
• DNA tattooing has been associated with overall lower transgene expression levels but
higher or equal levels of immune responses in comparison with intramuscular
vaccination.
• The plasmid DNA appears to suffer little damage as a result of the tattooing process,
so it is unlikely that this is the root cause of the lower expression.
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DNATATTOOING

24. • Jet injection is a needle-free method that uses a stream of high - pressurized liquid to penetrate the
stratum corneum
• Multiuse-nozzle jet injectors have been in use since the 1960s for the delivery of the intradermal
vaccination for smallpox and the bacille Calmette-Gueri (BCG) vaccine for tuberculosis
• Examples of jet injection are Injex30 (Oxford, UK), Biojector 2000 (USA), Bioject ZetaJet (Bioject,
USA), the PharmaJet Stratis (USA)
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JET INJECTION

25. • Upon actuation the power source pushes the piston & rapidly increases the pressure within the
drug-loaded compartment.
• Thereby forcing the drug solution through the orifice as a high velocity liquid jet.
• When the jet impacts on the skin it creates a hole & allows the liquid to enter the skin.
• The process of hole formation and liquid jet deposition occurs within microseconds.
• The deposited liquid can then disperse within the tissues to illicit an immune response.
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WORKING OF JET INJECTORS

26. PERMEABILIZATION OF THE SKIN
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Direct alteration of the skin to make it more permeable to vaccines, thereby
circumventing the need for needles, has been attempted in numerous ways, including
thermal ablation, chemical enhancer addition, abrasion, electroporation, ultrasound,
and iontophoresis.

27. • Thermal ablation generates micron-size holes by use of lasers in the stratum corneum by selectively
heating small areas of the skin surface to hundreds of degrees. The heat is applied for micro- to
milliseconds so that heat transfer to the viable tissues is avoided, thus minimizing pain and damage.
• The lack of contact of the perforating device with the skin reduces cross-contamination risks and the
utilization of laser scanning technology allows for flexibility in the depth, number, and density of the
created micropores.
• Commercially available examples are 1) PassPort® system by altea therapeutics corp (altanta, ga)
2) Viaderm® device by transpharma ltd (israel).
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THERMAL ABLATION

28. • Chemical enhancers modify the stratum corneum to make it more amenable to the delivery of
agents into the dermal layers. Ideally, they should be non-toxic, non-allergenic, have a rapid and
predictable duration of activity, function unidirectionally, and be compatible with the structure and
mode of action of drugs and vaccines.
• Dimethylsulphoxide (DMSO) is one of the most well-known and studied penetration enhancers, as it
allows for the penetration of both hydrophilic and lipophilic compounds. DMSO is an organic
solvent and interacts with the lipids in the stratum corneum, leading to the partial extraction of
these lipids and an increase in lipid fluidity
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CHEMICAL ENHANCERS

29. • Abrasion of the stratum corneum is another method of circumventing the
impermeable outer layer of the skin. This can be achieved via the use of tape
stripping, sanding, a razor, a toothbrush, or microdermabrasion. Application of a drug
or patch to the abraded area can then allow easier passage of the drug into the
dermal layers.
• A more recent abrasion technique is an abrasive gel made from star-shaped particles
(STAR) particles, which are 17-mm-sized particles with micron-sized protrusions that
have been found to be well tolerated by patients. These particles form microscopic
pores through which drugs or vaccines can be delivered into the skin. 29
ABRASION

30. • Iontophoresis uses an electrical field to deliver drugs and vaccines into
the skin and is particularly effective for charged and polar molecules.
• Two electrode patches are applied to create an electric circuit through
the skin and by applying a small electric current across the skin, drug
permeation is increased. The electrode with the same charge as the
drug is used to drive the charged drug through the stratum corneum
into the skin.
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IONTOPHORESIS

31. • Electroporation is typically used to increase the immunogenicity of DNA vaccines, particularly
by improving the delivery of DNA to the cell nucleus. The stage of transfer into the nucleus has
been shown to be particularly inefficient for plasmid DNA.
• Electroporation relies on the generation of transient pores, induced by the application of an
electric field. These pores allow the DNA to enter cells in the target tissue . Electroporation
has been applied to enhance intramuscular DNA uptake, as the muscle seems a particularly
attractive target for electroporation, perhaps because of the unique electrophysiology of
muscle cells
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ELECTROPORATION

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33. • Low frequency sonophoresis involves application of ultrasound waves at frequencies between 20 to
100 khz to the skin surface to reduce the stratum corneum barrier and thereby increase skin
permeability.
• Pretreatment is given prior to the application of a drug solution or patch.-Low frequency ultrasound
(20 khz) was used to deliver a tetanus toxoid, eliciting a robust immune response in mice to mice.
• More recently, ultrasound-mediated cavitation has been shown to enhance drug penetration and
extravasation in cancer therapy by providing a convective stimulus to push the drug into and
throughout solid tumours
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ULTRASOUND

34. • Encyclopedia of PHARMACEUTICAL TECHNOLOGY Third Edition VOLUME 1 page no. 3917-3922
• Journal of Immunological Methods, Review Article; Rational application of nano-adjuvant for
mucosal vaccine delivery system: www.elsevier.com/locate/jim
• Biomedicine & Pharmacotherapy : A smart approach and increasing potential for transdermal drug
delivery system, Elsevier
• Review article Vaccination into the Dermal Compartment: Techniques, Challenges, and Prospects
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REFERENCES

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Thank You
HARSHITHA SK (GCP) 2021