INTRODUCTION:

“Vaccines are tugboats of preventive health”.

William Foege

Before the era of modern medicine the only way to develop immunity was to become infected by an infectious agent and survive it. The experiments of Edward Jenner, pioneer of small pox vaccine lead to the concept of a new form of immunisation called vaccination. India’s vaccination policy is one of the most successful immunisation programmes in the world. The eradication of small pox and polio are proof of its success. India’s vaccination policies are in accordance with WHO and UNICEF.

WHO defines immunisation as “The process whereby a person is made immune or resistant to an infectious disease, typically by the administration of a vaccine”¹.

Vaccines being antigenic stimulate antibody production in the body and also generate a memory in the body so that a powerful response can be produced by the body upon subsequent infection of pathogens carrying same antigen. A more precise definition given by WHO states that ‘vaccines are biological preparation that improves immunity to a particular disease”². A vaccine typically an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms contains 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”. The process of administering vaccines for developing immunity is called vaccination

Each country has its own immunisation schedule and it is updated regularly by the respective authority. Prevalence of infectious diseases, their public health importance, availability of suitable vaccines and their cost benefit factors and logistics are the important criterion for these updates.

National immunisation programmes commenced in India with the launch of Expanded Programme on Immunization (EPI) in 1978.³ The immunisation programmes were inspired by the eradication of small pox in 1977. The programmes which targeted infants lead to the introduction of DPT, OPV, BCG and typhoid paratyphoid vaccines in the country. As years passed by the programme underwent major changes. Typhoid-Paratyphoid vaccines were omitted from the programme because of low efficacy and allergic reactions. Later tetanus toxoid for pregnant women became part of the EPI. In 1985 major changes were done to the EPI and it was changed to a new programme called Universal Immunisation Programme (UIP). ³ The programme was launched with the aim of preventing 6 diseases namely tuberculosis, Diphtheria, Pertussis, Tetanus, Polio and measles. The vaccines under this programme included BCG, DPT, OPV and measles vaccine. Later Japanese encephalitis vaccine, Hepatitis vaccine were all included in the UIP. Universal Immunization programme in children include 6 vaccines namely BCG, DPT, Polio, DT and TT known as primary vaccines. Now a days the programme is known as Routine Immunisation Programme (RI). ⁴

These programmes have also shown success in the reduction in infant mortality and child mortality rates in India.⁴

Overview of the immune system:

Human immune system is divided into an innate/general resistance system and the adaptive system.

Innate/ General Resistance:

Innate system is the first line of defence against a pathological agent. This is a non-specific type of immunity although the system is able to differentiate between host and foreign cells. This system involves anatomical barriers like skin, mucous membranes which prevents the pathogen entry and also physiological barriers like fever, gastric acidity, lysozyme, interferons, compliment pathway and collectins which create unfavorable conditions for the pathogen. ^{4, 5}

Adaptive immunity:

Adaptive immunity involves the activity of B cells and T cells. It is a very specific type of immunity. The B cell antibodies compose humoral immunity and the T cells are involved in cell mediated immunity (CMI).

Vaccine induced immunity mainly targets the adaptive immunity, more specifically humoral immunity- B cells are involved in the process. After its production in the bone marrow the B cells migrate to the lymph nodes where they are exposed to the pathogens and toxic substances. In the lymph nodes the B cells recognise the antigenic material and produce antibodies against it. If an antigen can be recognized in its native form by the B cells it is called T independent antigen, include polymeric flagellin, dextran etc. There are another types of antigens which require processing by T cell before B cell activation. These antigens are called T dependent antigens.

These activated B cells produce their clones which in turn give rise to plasma cells which produce specific antibodies against a particular pathogen. Clone production occur during the primary immune response, these clones are retained in the lymph node and are used to produce immune response on subsequent exposure to the same pathogen.

B cell activation with T helper cell activation is very important for developing better response and effective memory, this long term effective immune response is a type of reaction that is the goal of immunization^{5, 6}

Immunisation:

The two different types of immunization are active immunization and passive immunization.

Passive Immunisation:

In passive immunization antibodies are directly injected into the body against a specific pathogen. It is a fast acting immunization and only requires a few hours for its effect to take place. However the duration of immunity is very less. This type of immunization containing human immunoglobulin is used against diphtheria, hepatitis A, hepatitis B, rabies and tetanus. It is used when fast action is needed or when there is a genetic defect in Antibody production.⁷

Active Immunisation:

Active immunization mainly includes vaccination. The three different forms of vaccines are

1) Killed pathogen/ Inactivated vaccines

2) Attenuated strains of pathogenic species

3) Chemically modified toxins or toxoids.

4) Conjugated vaccines

5) Recombinant vaccine

6) DNA vaccine

7) Subunit vaccine

8) Combined Vaccine

1) Killed pathogens/ inactivated vaccine:

The term killed is used for bacterial vaccine and the term inactivated is used for viral vaccines^{7, 8}. After the killed/ inactivated pathogen is injected into the body the dendritic cells phagocytise it and produce various antigenic fragments. These fragments are presented on the cell surface as MHC II antigenic fragment complexes^6,
7. The inactivation of the pathogen is done by radiation, heat or chemicals⁷. These types of vaccines are very safe for usage as the pathogens are either dead or in an inactivated state. Also because of the inactivated nature of the vaccine storage and transportation is hassle free, usually done in a freeze dried form. The major disadvantage with this vaccine is immune response stimulation is weaker compared to live vaccines, subsequent administrations and booster doses are required for the immunity to take effect. This result in reduced patient compliance in areas where health care facilities are inaccessible. Hypersensitivity reactions against the adjuvants used as a local response are also seen in some cases. Vaccines against Cholera, Influenza, Hepatitis A, Plague, and Rabies are come under killed vaccines.⁴

2) Attenuated vaccines:

Organisms that have lost their pathogenicity but which retain immunogenicity to generate immune response and generate memory cells are said to be attenuated ⁴. Attenuated vaccines contain such pathogens. Viral attenuated vaccines production involves growing the virus in a foreign host or a growth medium and selecting strains of virus that show virulence in human host or having a slow multiplication rate. This allow immune system to recognise and act on the pathogen and generate memory without occurrence of the disease. These vaccines are much more effective on comparison with killed vaccines. This is due to the multiplication of the pathogen in the host resulting in a greater amount of antigen than that was injected. The major disadvantage is due to the risks of pathogen regaining its virulence and causing the illness. ^{4, 7, 8} BCG vaccines, vaccines against polio, mumps, and measles come under this category.

3) Chemically modified toxins or toxoids:

Toxoids are used against pathogens whose toxins are responsible for the development of disease ^{4, 7, 8}. Bacterial endotoxins are treated with formalin after its purification. These inactivated toxins are then used for vaccine production. Thus immunity is generated against the specific endotoxin produced by pathogenic bacteria rather than the bacteria itself. This allows the body to produce antibodies that neutralise the endotoxin on subsequent pathogen exposure and result in prevention of the disease. Toxoid vaccines are safe because there are no problems of virulence. Also they are very stable to environmental conditions like temperature, humidity, light etc. The major disadvantage of this vaccinations are multiple doses are required for proper immunisation and the requirement of adjuvant to potentiate the antigenicity of the toxoid. On some occasions adjuvants are known to cause undesirable local reactions. The main vaccines under this category are DPT (Diphtheria, pertussis, tetanus) vaccine, diphtheria toxoid and the tetanus toxoid. ⁷

4) Conjugate vaccines:

These vaccines are used against pathogenic bacteria that have external polysaccharide coats. These coats enable the bacterium to escape detection by the immune system, particularly in the case of infants. Vaccine production involves linking the polysaccharide to an antigen. The polysaccharides of such bacterium are extracted and conjugated to an antigen the body can detect and respond. Haemophilus influenza B vaccine is an example of this type of vaccine. Their efficacy is very high but usage is comparatively less. ^{4, 7, 8}

5) Recombinant Vaccines:

Genes responsible for the production of antigenic structures are incorporated into a bacterium which results in production of antigenic molecules. These molecules are then isolated, purified and then used as vaccines. Usage of purified proteins result in lesser chances of adverse reactions. Hepatitis vaccine was earlier a recombinant vaccine in yeast. ⁴

6) DNA vaccines:

Genes of some pathogens which code for their antigenic molecules are introduced into the body cells. This foreign DNA is taken up and incorporated by the cells and the antigen producing genes are expressed. This result in body cells producing antigens against the specific pathogens as if the body is making its own vaccine. This causes a strong response to free floating antigens produced by the cells and also to the antigens on the cell surface of specific pathogen.⁹

7) Subunit Vaccines:

Subunit vaccines contain very specific antigens or its parts. Only the parts of antigen to which the antibodies bind are selected for vaccine production. Only antigens that stimulate the immune system in a strong way are included in vaccines^{. 8} Usually produced from purified macromolecules derived from immunogenic components of pathogenic microorganisms by recombinant DNA technology. ⁴ Since only specifically selected antigens are included in the vaccines chances of adverse reactions are comparatively less. One of the major disadvantage seen is the requirement of an adjuvant to produce an immune response of required strength. Also usage of adjuvant is associated with local reactions and irritations in some patients. ⁶

8) Combined Vaccines:

These vaccines are used to provide protection against multiple diseases or multiple variants of a single disease.⁸ Most of the modern vaccines MMR, BCG and DTP are all combined vaccines.⁸Combined vaccines make patient compliance easier as only a single vaccine is required to gain immunity against multiple diseases, rather than using a separate vaccine for each disease.⁸ Combined vaccines also make the procedure cost effective and storage easier.

Effect or Mechanism of Vaccines:

Antibodies act against extracellular pathogens by binding to the pathogenic agent and activating secondary mechanisms. These secondary mechanisms include compliment fixation, inhibition of viral replications, opsonisation. CD8+ T cells are involved in direct and indirect killing of the pathogen. CD4+ T cell act by production of interferons and interleukins. Both CD8+ and CD4+ T cells are not involved in prevention, they rather clear the pathogens from the system. ^[9] The initial detection of the antigen presented by the vaccine is done by the innate system. B cells also have the ability to perform this function. The innate system opsonise and bind to the antigen aiding its recognition and engulfment by antigen presenting cells. Antigen presenting cell process the antigenic substance and insert it along with the MHC protein on the surface of these cells. Viral antigens bind to the MHC 1 protein and bacterial antigens bind to the MHC 2 proteins. Viral antigens after binding are presented to the CD8 cell. This will induce cell mediated immunity. Bacterial antigens after binding to the MHC 2 are presented to the CD4 lymphocyte will produce an antibody mediated immunity.^{4, 7, 9}

Vaccination Schedule:

For vaccination programmes for any country to become successful there must be a proper schedule for vaccination. For a vaccination schedule to become effective various factors are involved. An effective immunization schedule can prevent the spread of a disease or even result in its complete eradication. Vaccination schedule for a country should be capable of achieving maximum effectiveness with least side effects.⁸

The effectiveness of a vaccination depend upon 3 considerations. They are immunological, epidemiological and programmatic^.8

Immunological considerations include factors like minimum age, dosing and interval and boosters required. Epidemiological considerations include the prevalence of the disease in the country. It also includes susceptibility, severity and mortality associated with the disease.⁸ Programmatic consideration depends on the vaccination programme and include factors like compatibility with other vaccines and other scheduled interventions.⁸ Vaccination programmes and schedules must be able to prevent mortality and morbidity associated with infectious and communicable diseases.

Table1: Table of important vaccines and associated information

Vaccine Name	Type	Dosage( children)	Dosage ( adult)	Storage conditions	Side effects
Tetanus, Diphtheria, Pertussis	Combined vaccine	1^st dose: 2months 2^nd dose: 4 months 3^rd dose: 6 months ^10,11,13	Administer diphtheria boosters every 10 years¹²	Between 2-8˚ C in refrigerator ^8,14	Local side effects include pain at the site of injection. Systemic side effects reported were headache and fatigue^{. 8}
HPV vaccine	VLPs (virus like particles)	2 doses for females aged 9-14 3 doses for females older than 15.Doses should be administered in 6 months interval^10,11,13	3 doses in a period of 19-26 years.¹²	Store in refrigerator between 2-8˚ C ^8,14	No serious ADR reported. Local effects include pain at the site of administration, fever, headache, myalgia, gastro intestinal symptoms^.8,15
Hepatitis A (HepA)	Killed Vaccine	2 doses in series in 12-23 months^10,11,13	2-3 doses ¹²	Store in a refrigerator between 2-8˚ C ^[8,14]	Common side effects include sore arm from the shot, tiredness, headache, fever, loss of appetite^.8
Hepatitis B (Hep-B)	Protein	First dose administered at birth (within 24hrs) Second dose administered at 6 weeks. Final dose should be administered at 6 months.^10,11,13	3 doses ¹²	Store in a refrigerator between 2-8˚ C ^8,14	Side effects are very mild. A sore arm and fever are the ADR’s. Occur in rare conditions^.8
Inactivated polio virus (IPV)	Live attenuated	If started at 6 week 2 doses should be administered. 3 doses if started at 8 weeks, 8 week interval between the two doses. Second dose is given at 10 weeks of age. 3^rd dose is given around 14 weeks of age. ^10,11,13	Immunisation not possible in adult.¹²	Stored in a refrigerator between 2-8˚ C ^8,14	No common side effects seen. Fainting, ringing in the ears are seen in some extremely rare cases. Some rare cases live attenuated vaccine can cause the disease but the incidence is very rare.⁸
Measles, Mumps, Rubella	Combined Vaccines	Dose 1 should be started around 9 months of age. Should not be administered before this period. 2^nd dose must be administered at 2 years of age at 15 months. 3^rd dose should be administered at 4-6 years of age. ^10,11,13	1-2 dose depending on indication at a period of 19-59 years.¹²	Store in a refrigerator between 2-8˚ C ^8,14	No severe ADR reported. Local ADR : Pain, redness, swelling Fever and swelling of parotid gland was also reported.^{8, 16}
Varicella (VAR)	Live attenuated	1^st dose started around 15 months. 2^nd dose administered at 4-6 years.^10,11,13 Recommended dosing for 13 year or older should take 2 doses with an interval of 28 days in between 2 doses	2 doses ¹²	Store in a freezer at temperatures of -15 to -50˚ C ^8,14	Soreness or swelling in the site of administration was seen in some cases, mild rash, fever are minor problems. Major problems are very rare and include seizures and pneumonia. ⁸
BCG	Live bacterium	At birth to all newborns. Administered before hospital discharge ^10,11,13	Less effective in preventing respiratory disease in adults.¹²	Frozen form at -15 to -50˚C in freezer^8,14	ADR is uncommon Abscess at site of injection⁸
Haemophilus influenzae type B (Hib)	Killed subunit	First dose around 6 weeks Second dose at 10 weeks Third dose at 14 weeks Fourth dose at 15-18 months^10,11,13	1-3 doses depending on the indication ¹²	Store in refrigerator between 2-8˚ C ^8,14	Soreness, redness, fever , headache are the minor ADRs associated with the vaccination, hypersensitivity and localised lymphadenopathy are local effects. Appearance of disease itself occur in very rare conditions.⁸

Table2: Immunological products and their cost in amrita institute of medical sciences

VACCINE BRAND NAME	DESCRIPTON	COST (IN RUPEES)
Biovac A 9.5ml	Freeze dried live attenuated hepatitis A vaccine. Manufacturer : WOCKHARDT	1395
Menactra 0.5ml Injection	Polysaccharide diphtheria conjugate toxoid vaccine. Manufacturer: SANOFI PASTEUR	4950
TubervacInj	Live freeze dried BCG vaccine. Manufacturer: SERUM INSTITUTE OF INDIA	59.1
Plasmahep 100IU Injection	Hepatitis B Immunoglobulin Manufacturer: PLASMA LIFESCIENCES	6950
Genevac B multidose injection 10ml	Recombinant Hepatitis B vaccine IP Manufacturer: SERUM INSTITUTE OF INDIA	820.4
Revac B adult injection 1ml	Recombinant Hepatitis B vaccine IP Manufacturer: BHARATH BIOTECH	106
Revac B paediatric injection 0.5ml	Recombinant Hepatitis B vaccine IP Manufacturer: BHARATH BIOTECH	52
Plasmarab 300 IU/2ml injection	Human Antirabies immunoglobulin injection Manufacturer: PLASMOGEN BIOSCIENCE	6579.19
Tresivac 0.5ml injection	Live freeze dried measles mumps rubella vaccine. Manufacturer: SERUM INSTITUTE OF INDIA	140.75
M-Vac Injection	Freeze dried measles vaccine Manufacturer: SERUM INSTITUTE OF INDIA	₹65.25
Influvae 0.5ml Injection	Influenza vaccine Manufacturer : ABBOTT	₹810
Pneumovax 23 Injection	Pnuemococcal vaccine polyvalent Manufacturer: MERCK & CO, INC	₹1495
Boostrix 0.5ml vaccine	Tetanus, diphtheria, acellular pertussis vaccine (Tdap) Manufacturer : GLAXOSMITHKLINE	₹999
Typbar vaccine 0.5ml	VI polysaccharide typhoid vaccine Manufacturer : BHARATH BIOTECH	₹150
Hexaxim vaccine 0.5ml	DTPa-hepB-IPV-Hib Diphtheria, Tetanus, pertussis (acellular component), Hepatitis B (rDNA), Poliomyelitis (Inactivated) and haemophilus influenza type B conjugate vaccine(Adsorbed) MANUFACTURER:	₹4800
Bio-Hib Vaccine	Haemophilus Influenza type B vaccine MANUFACTURER: BHARATH BIOTECH INTERNATIONAL LIMITED	₹375

CONCLUSION:

Immunisation programmes have shown success in reducing mortality rates all over the world. India has also been successful in implementing immunisation programmes. India’s success in eradication small pox is an example for immunisation programmes all over the world. India’s routine immunisation programme covers all the major vaccines like BCG, DPT, Polio, DT and TT. Vaccination is a type of active immunisation and the body gains active immunity to fight off diseases. The different types of vaccines are killed vaccines, attenuated vaccines, toxoids, recombinant vaccines, DNA vaccines, subunit vaccines and combined vaccines. Most of the common vaccines are killed vaccines, attenuated vaccines, toxoids and recombinant vaccines. They produce a slow but long last immunity against a particular pathogen. Also there are other immunological products like immunoglobulins which are used for passive immunisation. They produce a short lived but quick response. Human antirabies immunoglobulin is an example of such preparation. Although immunisation programmes are a great success all over the world still poor countries are lagging behind in such programmes. High cost, lack of knowledge, misconceptions and fear of adverse reactions are some of the obstacles faced by immunisation programmes all over the world. With proper planning, implementation and education these problems can be solved. The success of sabin polio vaccine given orally is an example of this success. Even though there were initial resistance by the community to vaccination, the programme gained acceptance later and polio was completely eradicated. [17]. International agencies and governments are working together to clear these obstacles and ensure vaccines will reach everyone. Also research is advancing on developing vaccines on diseases like Rheumatic heart disease and other conditions for which treatment is difficult and dependent on antibiotics. Vaccination in the long run helps to reduce the burden on the health care system as spread of infections and epidemics are minimized. As always prevention is better than cure.

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Received on 09.05.2017 Modified on 07.06.2017

Research J. Pharm. and Tech. 2017; 10(9): 3205-3210.

DOI: 10.5958/0974-360X.2017.00569.8