INTRODUCTION:

Active adaptive immunity against specific diseases is induced by certain biologics called vaccines.⁽¹⁾⁽²⁾

They generally consist of drug, which resembles the micro-organisms that cause the disease and are usually prepared from killed or weakened micro-organism, their surface proteins or their toxins. Vaccines are administered through nasal, oral or parental route. They stimulate the immune system⁽³⁾, identify the antigens and abolish them.⁽⁴⁾

Most of the infections affect or start from the mucosal surface, to produce protective immune response for which mucosal route of vaccination is required.⁽⁵⁾⁽⁶⁾⁽⁷⁾

Table 1: Different types of infections and their causing pathogens are listed below:

Type of infection	Pathogens
Gastro intestinal infection	Helicobacter pylori
	Enterotoxogenic Escherichia coli
	Shigella spp
	Vibrio cholera
Respiratory infection	Influenza virus
	Mycoplasma Pneumoniae
	RSV
STD (genital)	Neisseria gonorrheae
	Herpes simplex virus
	Chlamydia trachomatis
	HIV (Human immunodeficiency virus)

Vaccine Types:

LAV (Live attenuated Vaccine):

They consist of weakened living pathogen. Hence there is no chance that it can cause any severe disease in a healthy person.⁽⁸⁾LAV can be prepared by different methods. In the common method of preparation, the virus is passed through cell cultures in a series. Viruses are weakened by growing in cells, which normally do not grow in for several generations. Each time the virus is passed in a cell culture, it replicates better in the new cell, but not in the human host.

Ultimately, the weakened virus will not be capable of living in human host and hence used in vaccines. Mutants which are better for growth under unusual culture conditions which is unsuitable to grow in natural hosts are selected in this method.

Hence, when attenuated virus is administered to human, they do not replicate enough to cause illness, yet it exacerbates immune system to protect us from future infection. Using In-vitro method Oral polio vaccine, MMR vaccines and varicella vaccines are prepared.⁽⁹⁾⁽¹⁰⁾⁽¹¹⁾⁽¹²⁾

Advantages:

· Live vaccine is very similar to natural infection. Hence it is perfect to teach the system against viruses.

· Usually it requires single immunization. Hence the use of repeated boosters can be eliminated.

· For certain virus’s preparation of these vaccines are easy.

Disadvantages:

· The Sabine polio vaccine which is administered orally to kids in either liquid or cube form of sugar, consists of three strains of attenuated poliovirus. As the weakened polio viruses in vaccine meddle replication of each other, polio vaccine requires a booster whereas other vaccines require only one immunization dose.

· There is always the chance of reverting to original form and cause disease.

· Not suitable for a people with weak immune system.

· They could be linked with problems similar to those in the ailment.

Table 2: Some of the live attenuated vaccines

Vaccines	Target disease	Introduced in
MMR	Measles, mumps, rubella	1971
Rotavirus	Diarrhea (in children)	1998(Renewed version in 2006)
Oral polio	Poliomyelitis	1961
Varicella	Chicken pox	1995
Influenza (Flu Mist)	Flu	1930
Yellow fever vaccine	Yellow fever (in Africa and south America)	1912
Vaccinia	Small pox	1796
Shingles	Shingles and PHN	2006
Adenovirus oral vaccine	Febrile acute respiratory disease	2011

Inactivated vaccine:

In this technique, the pathogen is inactivated by heat or chemical method. Pathogen’s ability is abolished by this method but still it maintains intact so that the system can still notice it. Critical part during inactivation is maintaining the epitope structure on epitope. Because of denaturation of protein in large amount heat inactivation is usually unacceptable. Hence epitope which depends on high level protein structure changes considerably. It is to be noted that inactivation with formalin results in success. Polio vaccine is prepared using this method. Since inactivated pathogen can neither replicate nor revert to virulent form, they provide an ephemeral protection than attenuated vaccines. Nevertheless, it requires booster doses.

An oral vaccine of inactivated Cholera-bacteria with/without the B-subunit has been designed. Madsen tested whole cell whooping cough vaccine, which was inactivated by formalin. It was found almost effective.⁽¹³⁾⁽¹⁴⁾⁽¹⁵⁾⁽¹⁶⁾⁽¹⁷⁾

Table 3: Examples for inactivated vaccines

Vaccine	Uses	Introduced in
Viral Inactivated polio vaccine	Poliomyelitis	1955
Influenza vaccine	Influenza infection	1967 (revised in 1978, 1990, 2003)
Bacterial Inactivated Typhoid vaccine	Typhoid fever	1966
Inactivated Cholera vaccine	Cholera	Late 1800s
Inactivated Plague vaccine (less effective)	Yersinia pestis	1890s
Inactivated Pertussis vaccine	Whooping cough	1920

Subunit recombinant polysaccharide conjugate vaccine

Though small-pox vaccine contains live weakened viruses, it doesn’t cause any disease in human beings. The live vaccines are in use include yellow fever, measles and few influenza vaccines. Inactivated toxins are used for other vaccines. It won’t cause disease and will prevent possible infections.

Many types of vaccines are designed by using new techniques. Biosynthetic vaccines include subunit, recombinant, polysaccharide and conjugate. They contain artificial substances which are almost same as fragments of the bacteria or viruses.

They show a robust immune response as they use specific pieces of germ which targets the chief part of the micro-organism. They can be administered to almost everyone, including folks with weak immune system and with serious disease. They can prevent some risks with live or inactivated vaccines.

Disadvantages:

· Need for the booster dose.

· These vaccines require one subclass of the target pathogen to arouse the response of the immune system. This method is carried out by separating a specific protein as an antigen.

· Examples include acellular pertussis vaccine and influenza vaccine. (injection form).

· They can be prepared using genetic engineering and propagation of vector virus also.

· Another vaccine designed using this method is Human Papillomavirus (HPV). Gardasil and Cervarix are 2 types of vaccine available in market.

· Baculovirus can be used as a vector, as it infects insects only⁽¹⁸⁾^. Genes for immunogenic surface proteins can be introduced into it. After the modified virus is administered into a person, immunogen produces response against the one from which it’s derived. It is found that HAV(human adenoviruses) are potential carriers, mainly against diseases like acquired immunodeficiency syndrome.⁽¹⁹⁾

Advantages:

· The encoded protein has no change or denaturation and is in its native form. Hence immune response is same as antigen expressed by the pathogen.

· Cost and transportation problems are reduced to a larger extent as there is no need for refrigeration.

· Currently human trials are going on with a number of DNA vaccines, for the eradication of diseases like malaria, AIDS, influenza, and herpesvirus.

· Conjugate vaccines and recombinant vaccines are almost same. They are prepared by combining of two constituents.

· The conjugate vaccine is prepared by the use of fragments from the coverings of bacteria and they are linked chemically to a carrier.

These vaccines are used to protect from the following⁽²⁰⁾⁽²¹⁾⁽²²⁾⁽²³⁾

Table 4: Examples for Subunit recombinant polysaccharide conjugate vaccine

Vaccine	Uses	Introduced in
Human papillovirus vaccine	Prevention from certain types of HPV infection	2006
Hepatitis B (24)	Prevention of hepatitis B	1986
Haemophilus influenza type B (conjugate vaccine)	Prevention of Hib	1987

Toxoid:

They are prepared from selected toxins, which are weakened, still can induce a humoral response. The toxins show various symptoms of the ailment.

Initially bacterial toxins are purified and later using formaldehyde it is inactivated.

Inoculating with a toxoid induces an antibody which has the ability to bind toxins and nullifying their effects. Duration of immunity is less compared to attenuated viral vaccines. Hence there might be a need for a booster shot. Booster dose may be needed many times, based on individuals.

Table 5: Some of the toxoid vaccines

Vaccines	Target disease	Introduced in
Tetanus vaccine (25)	Tetanus	1948(re launched in 1992)
Pertussis vaccine	Whooping cough	1980s
Diphtheria vaccine	Corynebacterium diphtheria	1940s

Mucosal vaccination:

Since the chief entrance of many pathogens is mucosa. It acts as the primary guard against pathogens.

Many researches have been focused on designing mucosal vaccines capable of inducing systemic as well as mucosal immune responses, providing more than one layer of host protection. Compared to injectable vaccination mucosal vaccination is important as it can provoke immune responses, predominantly SIgA antibodies. These antibodies are situated at the entry of most of the infectious agents⁽²⁶⁾as the administration route has a major effect on immune responses.⁽²⁷⁾⁽²⁸⁾⁽²⁹⁾⁽³⁰⁾⁽³¹⁾⁽³²⁾

Skin and mucosal surfaces, borders with the external surroundings. These are suitably enclosed with special epithelial layers and these barriers are a line of exogenous challenge to pathogens and soluble antigens. The mucosal immune system is independent to the systemic immune apparatus and possesses its own well organized immunological tissues.⁽³³⁾These maintain homeostasis and stimulate the production of anti-inflammatory immune defenses such as SIgA antibodies and enhance tolerance against innocuous soluble substances as well as commensal bacteria⁽³⁴⁾

Oral mucosa has gained importance recently, as the no difficulty of manufacture and administration.⁽³⁵⁾⁽³⁶⁾

Sublingual mucosa:

Recently, many researchers have discovered the potential of sublingual vaccination in provoking responses against various potential constituents.⁽³⁷⁾⁽³⁸⁾⁽³⁹⁾⁽⁴⁰⁾⁽⁴¹⁾⁽⁴²⁾⁽⁴³⁾⁽⁴⁴⁾

Advantages of sublingual route over others:

Among the oral routes, the sublingual is usually used in the treatment of allergies. As absorbing antigen in this route is quick and entry into the systemic circulation is direct.⁽⁴⁵⁾⁽⁴⁶⁾⁽⁴⁷⁾

Anaphylactic shock is not seen.⁽⁴⁸⁾⁽⁴⁹⁾⁽⁵⁰⁾

Protein antigen delivery:

At present, sublingual route is broadly used in type 1 hypersensitivity. Immune response was induced by multi dose of an allergen, which mediatesTh₁ induction and/or Th₂ activation’s skewing of. There is a significant decrease in allergic symptoms followed by next exposure.⁽⁵¹⁾⁽⁵²⁾

Kildsgaard et al, carried out a study which showed the increased T cell proliferation in allergen sensitized mice when treated through sublingual immunotherapy with suitable detection of allergen specific levels of IgAs in Broncho alveolar lavage and nasal lavage and no significant detection of allergen-specific IgEs.⁽⁴⁵⁾

According to one more study, which was carried out by Brimnes et al, the symptoms such as eosinophilia, and allergen-specific Nasal lavage and serum IgE levels upon allergen challenge are reduced in allergen sensitized mice when treated sublingually.⁽⁴⁶⁾sublingual immunotherapy treatment in allergen-sensitized mice reduced the allergic symptoms, eosinophilia, and allergen-specific Nasal lavage and serum IgE levels upon allergen challenge.

Mainly, administration of antigen through sublingual route has been harmless. Since anaphylactic shock was not reported in clinical studies conducted on children. ⁽⁵⁰⁾⁽⁴⁹⁾But according to a phase 1 mild study local adverse effects were seen in evaluation of toxicity of grass pollen tablets.⁽⁵³⁾

Influenza virus:

Sublingual vaccination has been adopted for the protecting respiratory pathogens on the basis of several studies explored on the same.⁽³⁷⁾⁽³⁸⁾⁽³⁹⁾⁽⁴⁰⁾⁽⁴²⁾⁽⁴¹⁾⁽⁴³⁾⁽⁴⁴⁾

Table 7: Adjuvants in sublingual vaccines:

Antigen	Adjuvant	Protection	Reference
Heterologous antigen expression Live vaccine:			⁽⁵⁵⁾
Nucleoprotein of influenza APR8	rAd5	-	⁽⁵⁶⁾
HA soluble globular head	rAd5	+	⁽⁵⁷⁾
RSV - sFsyn2	HDAd2	+
SARS-S	rAd	n.d.	⁽⁵⁸⁾
HIV-Env (Envelope glycoprotein)	rAd5	n.d.	⁽⁵⁹⁾
HIV-Gag	rAd5 rEA	n.d.	⁽⁶⁰⁾
SIV En or rev SIV Gag	rAd5	n.d.	⁽⁶¹⁾
Ebola ZGP (Zaire glycoprotein)	rAd5	+	⁽⁶²⁾
Tetanus toxin fragment C	Bacillus subtilis mLT	+	⁽⁶³⁾
Streptococcus mutans P1	Bacillus subtilis	n.d	⁽⁶⁴⁾
Inactivated vaccines Influenza WIV (formalin)	mCTA-LT3	+	⁽⁶⁵⁾
Influenza WIV (formalin)		+	⁽⁴⁴⁾
Influenza HA subunit	LTK634	n.d.	⁽⁶⁶⁾
Influenza A Virosome	c-di-GMP5	n.d.	⁽⁶⁷⁾
Influenza-3M2eC	CT	+	⁽⁴¹⁾
HPV16L1 VLP	CT	+	⁽⁶⁷⁾
HPV16L1 VLP	CTB	n.d	⁽³⁸⁾
RSV G protein	CT	+	⁽³⁷⁾
HIV-1 Pol	CTB CT	n.d	⁽⁶⁸⁾
HIV-1 gp41	CT	n.d	⁽⁴³⁾
HIV 1 CN54gp140	FSL 1, Poly I C, MPLA, Pam3CSK4, R848, CpG B	n.d	⁽⁴³⁾
HIV-1 CN54gp140 (gp140)	Chitosan	n.d	⁽⁶⁹⁾
Salmonella proteins	CT, CpG	+	⁽⁷⁰⁾
Pneumococcal (chloroform)	dmLT	+	⁽⁷¹⁾

Abs: antibodies; ASC: antibody secreting cells; CTL: cytotoxic T cell; HA: hemagglutinin; HIV: human immunodeficiency virus; (m)CT: (mutant) cholera toxin; CTA/B, A/B subunit of CT; (m)LT: (mutant) heat labile toxin; LTB, B subunit of LT; dmLT, double mutant LT; MPLA: monophosphoryl lipid A; rAd: recombinant adenoviral vector; rEA: recombinant Eimeria tenella; RSV: respiratory syncytial virus; SARS: severe acute respiratory syndrome-associated coronavirus; SIV: simian immunodeficiency virus; WIV: whole inactivated virus

CONCLUSION:

There are still many unanswered questions on sublingual immunization, like use of appropriate adjuvants and optimization of formulation to increase the efficiency. Promising features of sublingual immunization has been discussed in this review. Studies have shown sublingual route of vaccination is safe and effective in creating high responses against the antigen. According to the studies sublingual route of vaccination could be better than parenteral route against respiratory and genital pathogens. Collectively, outcomes defined in this review provide a base for further assessment of sublingual immunization.

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Received on 22.10.2019 Modified on 17.12.2019

Research J. Pharm. and Tech. 2020; 13(8):3957-3962.

DOI: 10.5958/0974-360X.2020.00700.3

Vaccine	Adjuvant	Pathogen	Mucosal immunity response	Protection	Reference
sHA1	CT	Influenza	+++	YES	⁽⁵⁰⁾
3M2eC	CT	Influenza	+++	YES	⁽⁴⁹⁾
Delta H1N1	-	Influenza	+++	YES	⁽⁴⁶⁾
FI PR8	mCTA or(LTB)	Influenza	+++	YES	⁽⁵⁴⁾
Live PR8	-	Influenza	+++	YES	⁽⁵⁴⁾
rADV S	-	SARS	+++	YES	⁽⁵³⁾
Gcf	CT	RSV	+++	NOT DETERMINED	⁽⁵¹⁾
gp41	CTB	HIV-1	+++	NOT DETERMINED	⁽⁴²⁾
HPVLP	CT	HPV	+++	YES*	⁽⁴⁰⁾