NASAL VACCINE: A NOVEL APPROACH IN NASAL DRUG …

www.wjpps.com Vol 4, Issue 04, 2015.

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Sujay et al. World Journal of Pharmacy and Pharmaceutical Sciences

NASAL VACCINE: A NOVEL APPROACH IN NASAL DRUG

DELIVERY SYSTEM

Sujay Raut*, Manisha Sutar and Sonia Singh

Alard College of Pharmacy, Pune. Savitribai Phule University of Pune,

Maharashtra-411 057, India.

ABSTRACT

Delivery of drugs through nasal route has been potentially explored as

an alternative route for administration of vaccines and biomolecules

such as proteins, peptides and non peptide drugs, hence it has attracted

the interest of scientific community. Intranasal therapy has been

accepted form of treatment in the ayurvedic system of medicines. Due

to the high permeability, high vasculature, low enzymatic environment

of nasal cavity and avoidance of hepatic first pass metabolism are well

suitable for systemic delivery of drug molecule via nose. Nasal route

gives good absorption of small molecules, than that of large molecules

can be increased by absorption promoters. The nasal vaccine is another

very attractive application in terms of efficacy and patient acceptance.

Nasal mucosa is the first site of contact with inhaled antigens and therefore, its use for

vaccination, especially against respiratory infections, has been extensively evaluated. In fact,

nasal vaccination is a promising alternative to the classic parenteral route, capable of eliciting

strong systemic and local immune responses. It enhances the systemic levels of specific

immunoglobulin G and nasal secretary immunoglobulin A. In current status research is going

on the development of vaccines for cancer, influenza, pneumonia, tuberculosis, diphtheria

and also against papilloma virus. In this review paper, we describe the main physiological

hurdles to nasal vaccine delivery, survey the progress made in technological approaches to

overcome these hurdles. We also providing the information to the studies done and the

opportunities for improving nasal vaccines against various diseased conditions.

KEYWORDS: Nasal route, nasal vaccines, systemic circulation, nasal mucosa.

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*Correspondence for

Author

Sujay Raut

Alard College of Pharmacy,

Pune. Savitribai Phule

University of Pune,

Maharashtra 411 057,

India.

Article Received on

10 Fab 2015,

Revised on 05 March 2015,

Accepted on 29 March 2015

http://www.wjpps.com/


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INTRODUCTION

Intranasal Therapy has been an accepted form of treatment in the Ayurvedic system of Indian

Medicine. Nowadays many drugs have better systemic bioavailability through nasal route as

compared to oral administration. Biotechnological advancement has lead to the development

of a large number of protein and peptide drug for the treatment of several of diseases. Oral

administration of these drugs is not possible because they are significantly degraded in the

gastrointestinal tract or considerably metabolized by first pass effect in the liver. Intranasal

drug delivery offers a promising alternative route for administration of such drugs. Nasal

drug delivery system is also suitable for restricting and obstacles blood brain barrier so that

drug can be delivered in the biophase of CNS. The interest in intranasal route for therapeutic

purposes arises from the anatomical, physiological and histological characteristics of the

nasal cavity, which provides rapid systemic drug absorption and quick onset of action .Only a

few nasal delivery systems used in experimental studies are currently on the market to deliver

therapeutics into the nasal cavities, i.e. nasal drops as multiple or single-dose formulation,

aqueous nasal sprays, a nasal gel pump, pressurized MDIs and dry powder inhalers.

Intranasal delivery is currently being employed in treatments for migraine, smoking

cessation, acute pain relief, osteoporosis, nocturnal enuresis and vitamin-B12 deficiency.

Other examples of therapeutic areas under development or with potential for nasal delivery

include cancer therapy, epilepsy, antiemetics, rheumatoid arthritis and insulin-dependent

diabetes. Now a days, researchers are working on some of the infectious diseases.[1]

Mucosal

surfaces are enormous surface areas that are vulnerable to infection by pathogenic

microorganisms. The adaptive immune system is designed to distinguish antigens, pathogens

and vaccines that enter the body through mucosal surfaces from those that are introduced

directly into tissues or the bloodstream by injection or injury. Mucosal immune responses are

most efficiently induced by the administration of vaccines onto mucosal surfaces, whereas

injected vaccines are generally poor inducers of mucosal immunity and are therefore less

effective against infection at mucosal surfaces. In this Review, we provide an overview of the

events within mucosal tissues that lead to protective mucosal immune responses, and we

summarize current progress in the development of mucosal or the nasal vaccines.[2]

ADVANTAGE OF NASAL ROUTE FOR DRUG DELIVERY[3]

Rapid drug absorption via highly vascularized mucosa

Ease of administration, non-invasive

Improved bioavailability by means of absorption enhancer



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Improved convenience and compliance of patient

Self-administration

Large nasal mucosal surface area for dose absorption

Avoidance of the gastrointestinal tract and first-pass metabolism

Rapid onset of action and lower side effects

Drugs which cannot be absorbed orally may be delivered to the Systemic circulation

through nasal drug delivery system.

Alternate to parenteral route especially for proteins and peptides.

LIMITATIONS OF NASAL ROUTE FOR DRUG DELIVERY[4]

Some drugs may cause irritation to the nasal mucosa

Nasal congestion due to cold or allergies may interfere with absorption of drug.

Frequent use of this route leads to mucosal damage

The amount of drug reaches to different regions of the brain and spinal cord varies with

each agent.

Normal defense mechanisms like mucociliary clearance and ciliary beating affects the

permeability of drug.

Enzymatic barrier to permeability of drug.

Certain surfactants used as chemical enhancers may disrupt and even dissolve membrane

in high concentration.

There could be a mechanical loss of the dosage form into the other parts of the respiratory

tract like lungs because of the improper technique of administration.

ANATOMY AND PHYSIOLOGY

Total surface area of human nasal cavities is about 150 cm2 and the total volume is about

15ml. The nasal cavity is divided into two halves by the nasal septum. The volume of each

cavity is approximately 7.5 ml, having a surface area around 75 cm2. The nasal cavity

consists following three main regions: The vestibular region it is located at the opening of

nasal passages and is mainly responsible for restricting entry of air borne particles. It is

considered to be less important of the three regions with regard to drug absorption. The

respiratory region is the largest having the highest degree of vascularity. The respiratory

region contains three nasal turbinates: superior, middle, and inferior which project from the

lateral wall of each of the nasal cavity. The presence of these turbinates creates a turbulent

airflow through the nasal passages ensuring a better contact between the inhaled air and the



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mucosal surface. The respiratory region is considered as the major site for drug absorption

into systemic circulation. The mucosa consists of an epithelium resting on a basement

membrane and a lamina propria. The anterior part of respiratory region is covered with

squamous epithelium, while he posterior part covered by a pseudostratified columnar

epithelium. The cells of respiratory epithelium are covered by about 300 microvilli per cells.

The respiratory epithelium consists of four dominated cell types; ciliated columnar cells,

nonciliated columnar cells, goblet cells, and basal cells. The basal cells are situated on the

basal membrane and do not extend to the apical epithelium surface, as do the other three cell

types. The presence of tight junction between neighboring epithelial cells prevents the free

diffusion of hydrophilic molecules across the epithelial by the paracellular route. The

olfactory region is situated between the nasal septum and the lateral walls of each of the two

nasal cavities and just below the cribriform plate of the ethmoid bone separating the cranial

cavity from nasal cavity. The olfactory epithelium is a pseudostratified epithelium,

comprising olfactory sensory neurons and two types of cells; basal cells that are able to

differentiate neuronal receptor cells and sustentacular cells (supporting cell) that provide

mechanical support by ensheathing neuronal receptor cells and maintain the normal

extracellular potassium level for neuronal activity. The olfactory epithelium is covered by a

dense and viscous layer of mucus, which is secreted from the tubuloalveolar Bowman‟s

glands and the supporting cells. The olfactory epithelium constitutes only about 5% of the

total area of the nasal cavity in man. It is about 10 cm2 in surface area, and it plays a vital

role in drug delivery because it bypasses the BBB, delivering therapeutic drugs to CNS .It

should be noted that the blood supply to the nasal mucosa is pertinent with regards to

systemic drug delivery. The arterial blood supply to the nasal cavity is derived from both the

external and internal carotid arteries. The blood that is supplied to olfactory region by

anterior and posterior ethmoidal branches come from the ophthalmic artery supply, which is

branch of carotid artery. These vessels supply the anterior portion of the nose. When the drug

is administered intranasally, it can enter into the brain via three different paths. The first one

is the systemic pathway by which the drug is absorbed into the systemic circulation and

subsequently reaches the brain by crossing BBB (especially lipophilic drug). The others are

the olfactory region and the trigeminal neural pathway by which drug is transported directly

from the nasal cavity to CNS (cerebrospinal fluid and brain tissue). The trigeminal nerve

receptors which are present in the nasal cavity are responsible for most chemoperception and

are suggested to transport the drug directly to CNS of drugs to the brain and the CNS.[5]



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MECHANISM OF ABSORPTION

Passage of drug through the mucus is the first step in the absorption from the nasal cavity.

Uncharged as well as small particles easily pass through mucus. However, charged as well as

large particles may find it more difficult to cross.

Following two mechanisms have been considered predominantly. The first mechanism of

drug absorption involves an aqueous route of transport. This route is slow and passive. It is an

inverse log‐log correlation between the molecular weight of water‐soluble compounds and

intranasal absorption. Drugs with a molecular weight greater than 1000 Daltons shows poor

bioavailability.

The second mechanism includes transport of drug through a lipoidal route (transcellular

process). Transcellular route is responsible for the transport of lipophilic drugs that show a

rate dependency on their lipophilicity. Cell membranes may be crossed by drugs by an active

transport route via carrier mediated means or transport through the opening of tight junctions.

Example: Chitosan opens tight junctions between epithelial cells and hence facilitate drug

transport.[6]

FACTOR INFLUENSING ABSORPTION[7][8]

Various factors affect bioavailability of nasally administered drugs as follows.

I Biological Factors

• Structural features

• Biochemical changes

II Physiological factors

• Blood supply and neuronal regulation• Nasal secretions

• Mucociliary clearance and ciliary beat frequency

• Pathological conditions

• Environmental conditions

• Membrane permeability

III Physicochemical Properties of Drugs

• Molecular weight

• Size

• Solubility



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• Lipophilicity

• pka and Partition coefficient

• Chemical form of drug

• Polymorphism

• Physical and Chemical state

IV Physicochemical Properties of Formulation

• Physical form of formulation

• pH

• Osmolarity

• Volume of solution applied and drug concentration

• Viscosity

STRATEGIES TO INCREASE NASAL DRUG ABSORPTION

There are many barriers present in nasal cavity which interfere with absorption of various

drugs .There are some methods which have been successfully used for the improvement of

nasal drug absorption.

Nasal enzymes inhibitors: Various kinds of enzyme inhibitors are utilized to minimize

metabolism of drug in nasal cavity which minimize activity of enzymes present in nasal

cavity includes protease and peptidase, used as inhibitors for the formulation of peptide and

protein molecule.

Structural modification: Modification of drug structure can be done without changing the

pharmacological activity for improvement of nasal absorption. Permeation enhancers are of

different categories and have been investigated to improve the nasal absorption like

surfactants, fatty acids, phospholipids, cyclodextrin , bile salts, etc.

Particulate drug delivery: Carriers are used for the encapsulation of drug which prevent

exposure of a drug to nasal environment and improve the retention capacity in nasal cavity.

Some examples of carriers may include microspheres, liposomes, nanoparticles and

nanosomes.

Prodrug approach: Inactive chemical moiety is called prodrug which becomes active at the

target site. Prodrugs are mainly used to improve taste, odor, solubility and stability.



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Bioadhesive polymer: To improve the nasal residence and absorption of the drug

bioadhesive polymers are used. They improve the retention time of the drug inside the nasal

cavity is increased by making an adhesive force between formulation and nasal mucosa,

which leads to minimization of mucociliary clearance of formulation.

In situ gel: These are the formulations which get converted into gel upon instillation into

nasal cavity by the influence of stimuli includes temperature, pH and ionic concentration.

Consistency of the gel is thick which makes the formulation difficult to drain by the influence

of ciliate movement.[9][10]

DOSAGE FORMS

Liquid dosage forms

Nasal drops - Nasal drops are one of the most simple and convenient delivery systems

among all formulations. The main disadvantage of this system is the lack of dose precision.

Nasal sprays- Both solution and suspension formulations can be formulated into nasal

sprays. Due to the availability of metered dose pumps and actuators, a nasal spray can deliver

an exact dose anywhere from 25 -200 μl Nasal emulsions, micro emulsions Intranasal

emulsions have not been studied as extensively as other liquid nasal delivery systems. Nasal

emulsions offer the advantages for local application mainly due to the viscosity.

Semi-solid dosage forms

Semi-solid systems, for example gels, ointments and liquid systems containing polymers that

gel at particular pH changes are usually employed for designing the nasal drug delivery

systems.[11]

Nasal gels

Nasal gels are thickened solutions or suspensions, of high-viscosity. The advantages of a

nasal gel include the reduction of post-nasal dripping due to its high viscosity, reduction of

the taste impact due to reduced swallowing, reduction of anterior leakage of the formulation.

Solid dosage forms

Solid dosage forms are also becoming popular for intranasal drug delivery, although these

formulations are more suitable for pulmonary drug delivery and similar applications, since it

can cover the vasculature within the epithelium of nasal mucosa.[12]



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Nasal powders

Powder dosage forms may be developed if solution and suspension dosage forms cannot be

developed, mainly due to lack of drug stability. The advantages of a nasal powder dosage

form are the absence of preservative and superior stability of the drug in the formulation.

However, the suitability of the powder formulation is dependent on the solubility, particle

size, aerodynamic properties and nasal irritancy of the active drug and/or excipients.[13]

APPLICATIONS of nasal drug delivery

1. Delivery of non-peptide pharmaceuticals

Low molecular weight (below 1000 daltons) small non- peptide lipophilic drugs are well

absorbed through the nasal mucosa even though absence of permeation enhancer. Nasal

membrane containing epithelium is highly vascularized and it contains large surface area.[14]

2. Delivery of peptide-based pharmaceuticals

Peptides & proteins have a generally low oral bioavailability because of their physico-

chemical instability and susceptibility to hepato-gastrointestinal first-pass elimination like

insulin, calcitonin, pituitary hormones etc .These peptides and proteins are hydrophilic polar

molecules of relatively high molecular weight, are poorly absorbed across biological

membranes with bioavailabilities obtained in the region of 1–2% concentrations when

administered as simple solutions. To overcome this problem mainly we are using the

absorption enhancers like sufactants, glycosides, cyclodextrin and glycols to increase the

bioavailability. Nasal route is proving to be the best route for such biotechnological

products.[15]

3. Delivery of Drugs to Brain through Nasal Cavity

This delivery system is beneficial in conditions like Parkinson‟s disease, Alzheimer‟s disease

or pain because it requires rapid and/or specific targeting of drugs to the brain. The

development of nasal delivery system to brain will increase the fraction of drug that reaches

the CNS after nasal delivery. The olfactory region located at the upper remote parts of the

nasal passages offers the potential for certain compounds to circumvent the blood-brain

barrier and enter into the brain. The recent studies express neurotrophic factors such as NGF,

IGF-I, FGF and ADNF have been intranasally delivered to the CNS shows good results to

increase the bioavailability of drug in the brain.[16]



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4. Delivery of diagnostic drugs

Nasal drug delivery system also play very important role in the delivery of diagnostic agents

for the diagnosis of various diseases and disorders in the body. Because the intranasal route

better for systemic release of medicament into blood circulation, so can get quick results with

less toxicity. Phenol sulfonphthalein is a diagnostic agent used to diagnose the kidney

function of the patients. Pancreatic disorders of the diabetic patients were diagnosed by using

the „Secretin‟and the secretory function of gastric acid was determined by Pentagastrin,

diagnostic agent.

5. Delivery of nasal Vaccines

Mucosal sites gives first line of defense against the microorganisms entered into the body,

nasal mucosa act by filtering the pathogens from the inspired air by compaction and

mucociliary clearance. Nose with nose- associated lymphoid tissue (NALT) acts as an

effective site of immune system, it is called Waldeyer´s Ring in human beings and nasal

secretions mainly contains immunoglobulins (IgA, IgG, IgM, IgE), protective proteins such

as complement as well as neutrophils and lymphocytes in the mucosa.[17]

Main reasons for

exploiting the nasal route for vaccine delivery are.

The nasal mucosa is the first site of contacts with inhaled pathogens

The nasal passages are rich in lymphoid tissue

Creation of both mucosal and systemic immune responses

Low cost, patient friendly, non-injectable and safe

Nasal delivery of vaccines has been reported to not only produce systemic immune response,

but also local immune response in the nasal lining, providing additional barrier of protection.

Delivering the vaccine to the nasal cavity itself stimulates the production of local secretory

IgA antibodies as well as IgG, providing an additional first line of defense, which helps to

eliminate the pathogen before it becomes established.

NASAL VACCINES APPROACHES

Diabetes Vaccine

In March 2003, the National Health and Medical Research Council jointly funded the

Diabetes Vaccine Development Centre (DVDC) in collaboration with the New York based

Juvenile Diabetes Research Foundation. The anticipated success of this vaccine trial could

see it become commercialized as a preventive treatment worldwide. The INIT II Trial will



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determine if exposure of the immune system to insulin delivered as a spray to the mucous

membranes of nasal passages will prevent the immune attack on the insulin-producing beta

cells of the pancreas. The key aspect of this treatment is that intranasal insulin acts only on

the immune system and is not absorbed into the body. Insulin given in this way does not

affect blood glucose and will not cause hypoglycemia B1 and B2.[18]

Dental carries vaccines

Dental caries is a chronic infectious disease caused by the formation of biofilm on tooth

surfaces. Among the oral bacteria, mutans streptococci are considered to be causative agents

of dental caries. Streptococcus sobrinus as well as S. mutans are major pathogens of dental

caries. Both bacteria produce water-soluble and water-insoluble glucans from sucrose, by the

combined action of glucosyltransferases. The synthesis of the water-insoluble glucan is

necessary for the accumulation of these cells on the tooth surface and the induction of dental

caries. S. sobrinus produces a water-insoluble GTF-I. The GTF-I protein consists of two

functional domains: an N-terminal sucrose-binding domain and a C-terminal glucan-binding

domain. The activities of GTF-I are mediated through both catalytic and glucan-binding

functions. If an effective vaccine for the oral cavity is to be designed, careful consideration

must be given to the various immune responses and antigen-delivery systems.[19]

Diptheria vaccine

Bacillus anthracis is the causative agent of anthrax, a bacterial infection with a high mortality

rate. Although anthrax infection can be cutaneous, gastrointestinal or pulmonary, the

pulmonary form is the most deadly. Thus, the release of Bacillus anthracis spores that can be

inhaled represents a potent bioterrorism threat. Recently, the available vaccines were

developed to confer protection against cutaneous infection; despite this, these vaccines

demonstrated experimental efficacy against pulmonary infection in multiple animal models.

Nevertheless, there are many limitations for these vaccines to be considered successful and

effective vaccine, including the intensity of the required vaccination schedule, the

administration route and the presence of local adverse effects experienced after vaccination.

To develop more efficient vaccines against pulmonary anthrax, intranasal formulations with

adjuvant have been studied. These formulations have advantages because they are easy to

administer and because they are expected to induce both systemic and respiratory tract

mucosal immune responses.[20]



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Influenza vaccine

Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal

spray. It is an attenuated vaccine, unlike most influenza vaccines, which are inactivated

vaccines. LAIV is administered intranasally, while inactivated vaccines are administered by

intramuscular injection. Both live attenuated and inactivated vaccines are typically trivalent.

That is, they contain material from three different influenza virus strains recommended by

national and international public health agencies as most likely to be protective

against seasonal influenza in any given year. LAIV is sold under the trade name FluMist in

the United States and Canada and Fluenz in Europe. FluMist is manufactured

by MedImmune and was first and the only live attenuated vaccine for influenza available

outside of Europe.[21]

Cancer vaccine

Human papillomavirus (HPV) is a significant cause of cervical cancer-related deaths

worldwide. Because HPV is a sexually transmitted mucosal pathogen, enhancement of anti-

gen-specific mucosal immune response likely serves good strategy for vaccination. However,

mucosal vaccines generally do not induce strong enough immune responses. Previously we

proved that a bacterial flagellin, Vibrio vulnificus FlaB, induce strong antigen-specific

immune responses by stimulating the Toll-like receptor 5. Intranasal administration of the

E6/E7 peptide mixture with FlaB elicited a strong antigen-specific cytotoxic T lymphocyte

activity and antigen-specific interferon-γ production from splenocytes and cervical lymph

node cells. Furthermore, FlaB, as a mucosal adjuvant, conferred an excellent protection

against TC-1 tumor challenge with high survival rates in E6/E7 immunized animals. These

results indicate that FlaB can be a promising mucosal adjuvant for nasal HPV vaccine

development.[22]

HIV vaccine

The role of mucosal immunity in protection against HIV. HIV might be considered as a

mucosal pathogen, because transmission occurs mainly through exposure of mucosal surfaces

to HIV and HIV-infected cells. Mucosal transmission of simian immunodeficiency virus

(SIV) in non-human primates, and presumably of HIV in humans, can occur without

epithelial-cell damage of the oral, rectal and genital mucosae.HIV presents a daunting

challenge to vaccinologists. It seems to exploit mucosal antigen-sampling mechanisms at

these sites, including vesicular transepithelial transport pathways of M cells and uptake by


http://en.wikipedia.org/wiki/Influenza_vaccine

http://en.wikipedia.org/wiki/Nasal_spray

http://en.wikipedia.org/wiki/Nasal_spray

http://en.wikipedia.org/wiki/Attenuated_vaccine

http://en.wikipedia.org/wiki/Inactivated_vaccine

http://en.wikipedia.org/wiki/Inactivated_vaccine

http://en.wikipedia.org/wiki/Intranasally

http://en.wikipedia.org/wiki/Intramuscular_injection

http://en.wikipedia.org/wiki/Influenza

http://en.wikipedia.org/wiki/Flu_season

http://en.wikipedia.org/wiki/United_States

http://en.wikipedia.org/wiki/Canada

http://en.wikipedia.org/wiki/Europe

http://en.wikipedia.org/wiki/MedImmune

http://en.wikipedia.org/wiki/Europe


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intraepithelial DCs. The mucosal tissues of the rectum and tonsils both contain abundant

mucosal lymphoid follicles and associated M cells, and M cells provide a short and rapid

pathway across the epithelial barrier. This could explain the observed transmission of HIV to

adults through infected semen, or to babies through infected milk Epithelial cells themselves

are not productively infected by HIV, but they serve as gateways for the delivery of

infectious HIV parasites to antigen-presenting DCs and macrophages. As mucosal antigen-

presenting cells interact with local CD4+ T cells, they unwittingly infect and ultimately

disable the very cells that are needed to mount an effective immune response. Infection of

local target cells can occur rapidly after deposition of virus on mucosal surfaces. However,

dissemination of virus to regional lymph nodes and other tissues might be delayed, for up to

several days, providing a window of opportunity for local control of the infection by mucosal

immune effectors. In any case, whether transmitted mucosally or injected, HIV and SIV

replicate preferentially in mucosal tissues, such as the intestinal mucosa, that are rich in

CD4+ T cells. Therefore, the ultimate goals of anti-HIV vaccines should be first to interrupt

mucosal transmission at its earliest stages, before the virus has crossed the epithelial barrier

and infected its first target cell, and then to prevent the establishment of viral reservoirs in

mucosal tissues. To achieve these goals, HIV-specific vaccines must generate multiple

immune effectors, including HIVenvelope- specific antibodies in mucosal secretions, and

CTLs and neutralizing HIV-envelope-specific antibodies in the mucosa and circulation.

Given what we know about the induction of mucosal immune responses, it is unlikely that

injected HIV vaccines alone will induce the mucosal responses that are required.[23]

Nicotine vaccines

The nicotine vaccine induces the formation of specific antibodies that bind with high affinity

to nicotine in plasma and extracellular fluids, thus preventing nicotine from reaching the

brain. There are no side effects. The conjugates formed are too big to cross the blood-brain

barrier, but antibodies can also lower the rate with which nicotine molecules reach the brain

through other mechanisms which are still not entirely understood. The effect of a nicotine

vaccine administered both intranasally and subcutaneously to rats, concluded that the vaccine

could break the vicious circle of gratification caused by nicotine in the brain. It is found that

the protection afforded by intranasal administration is at least as effective as that afforded by

subcutaneous administration. The antibodies indsuced after nasal administration bind less

extensively to nicotine in serum than those induced after subcutaneous administration but this

would be compensated by greater production of immunoglobulin A in saliva and the



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respiratory tract. A combination of the two routes of administration would therefore further

boost protection.[24]

Pneumonia vaccine

The polysaccharide vaccine most commonly used today. Consists of purified polysaccharides

from 23 serotypes (1, 2, 3, 4, 5, 6b, 7F, 8,9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F,

19A, 20, 22F, 23F, and 33F). Immunity is induced primarily through stimulation of B-cells

which release I‟m without the assistance of T cells. This immune response is less robust than

the response provoked by conjugated vaccines, which has several consequences. The vaccine

is ineffective in children less than two years old, presumably due to their less mature immune

systems. Non-responders are also common amongst older adults. Immunization is not

lifelong, so individuals must be re-vaccinated at age 65 if at least 5 years after initial

vaccination.]Since no mucosal immunity is provoked, the vaccine does not affect carrier

rates, promote herd immunity, or protect from upper or lower respiratory tract infections.]

Finally, provoking immune responses using unconjugated polysaccharides from the capsules

of other bacteria, such as H. influenza, have proven significantly more difficult.The

conjugated vaccine consists of capsular polysaccharides covalently bound to the diphtheria

toxoid CRM197, which is highly immunogenic but non-toxic. This combination provokes a

significantly more robust immune response by recruiting CRM197-specific type 2 helper T

cells, which allow for immunoglobulin type switching (to produce non-IgM immunoglobulin)

and production of memory B cells. Among other things, this results in mucosal immunity and

eventual establishment of lifelong immunity after several exposures. The main drawbacks to

conjugated vaccines are that they only provide protection against a subset of the serotypes

covered by the polysaccharide vaccines.[25]

Tuberculosis vaccine

mRNAs are highly versatile, non-toxic molecules that are easy to produce and store, which

can allow transient protein expression in all cell types. The safety aspects of mRNA-based

treatments in gene therapy make this molecule one of the most promising active components

of therapeutic or prophylactic methods. The use of mRNA as strategy for the stimulation of

the immune system has been used mainly in current strategies for the cancer treatment.

Where messenger RNA of Hsp65 protein from Mycobacterium leprae and show that

vaccination of mice with a single dose of 10 μg of naked mRNA-Hsp65 through intranasal

route was able to induce protection against subsequent challenge with virulent strain of



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Mycobacterium tuberculosis. Moreover it was shown that this immunization was associated

with specific production of IL-10 and TNF-alpha in spleen. In order to determine if antigen

presenting cells (APCs) present in the lung are capable of capture the mRNA, labeled

mRNA-Hsp65 was administered by intranasal route and lung APCs were analyzed by flow

cytometry.[26]

In spite of the large effort that has been directed to developing nasal vaccines,

only one nasal vaccine is currently on the market (Table 1). Furthermore, nasal vaccine

delivery may be compromised in patients with respiratory infections and the need for an

effective delivery device should not be overlooked. In attempts made to improve the

immunogenicity of nasal subunit vaccines, the vaccine formulation plays a crucial role, as

will be further discussed below.[27]

Table 1: Nasal Vaccines Currently On The Market

CONCLUSION

Nasal drug delivery is a novel platform and it is a promising alternative to injectable route of

administration. There is possibility in the near future that more drugs will come in the market

in the form of nasal formulation intended for systemic treatment. Development of a drug with

a drug delivery system is influenced by several factors. Although research and development

of nasal vaccines has gained momentum over the last years, only one nasal vaccine is

currently approved for human use, indicating that advances towards new effective vaccines

have been slow, in particular for inactivated/subunit vaccines. The opportunities in nasal

vaccination are not in a single research field, but require the integration of immunology,

biotechnology, microbiology and pharmaceutical sciences. Mechanistic insight into the

hurdles that limit the efficacy of nasal vaccination will create opportunities for rationally

designed nasal vaccines that can overcome these barriers. This could lead to “tailor made”

vaccines that provide similar or even superior protection to diseases as provided by classical

parental vaccines. The biggest challenge will be to combine these techniques in such a way

that they do not interfere with one another, but synergistically enhance vaccine efficacy. The

DISEASE PATHOGEN Vaccine type PHASE

Influenza Influenza virus Live attenuated On market

Hepatitis B Hepatitis B virus Subunit vaccine Phase 1

Influenza Parainfluenza virusType 3 Live attenuated Preclinical

Anthrax Bacillus anthracis Killed/inactivated Preclinical

Bronchiolitis Respiratory syncytial virus Killed/inactivated Preclinical

Herpes Herpes simplex virus Killed/inactivated Preclinical

Cervical cancer Human papillomavirus Subunit vaccine Preclinical



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nasal delivery of vaccines is an attractive option. This route of delivery avoids the discomfort

and hazards associated with injection and provides improved local immune protection and

cross protection in distant mucosal sites. It is important however to improve distribution to

the nasal mucosa, while at the same time limiting deposition outside the target sites.

Achieving this balance is essential in improving the reproducibility, safety, clinical efficacy

and patient compliance of nasally delivered vaccines and potent drugs. In contrast, a huge

amount of money is investigated by pharmaceutical companies in the development of nasal

products, because of growing demand of nasal drug products in global pharmaceutical

market. So for the avoidance of side effect and improve effectiveness of nasal products we

should pay attention to basic research in nasal drug delivery.

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2. Alagusundram M, Chengaiah B, Gnanaprakash K. (Nasal Drug Delivery System‐An

Overview). International Journal of Research in Pharmaceutical Sciences., 2010; 1(4):

454‐465.

3. Sharma PK, Chaudhari P, Kolsure P, Ajab A, Varia N. (Recent Ttrends In Nasal Drug

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