The term vaccine was initially coined by Louis Pasteur to facilitate the first ever successful small pox immunization done by Edward Jenner. The word vaccine is derived from the word, “vacca” which means cow as Jenner used the vaccinia virus (cowpox) for the prevention of smallpox infection. Generally, vaccination involves repeated exposure to antigens which cause disease under such conditions that it does not lead to the development of the disease. The main aim of the vaccine is to induce active immunity in the organism against that particular microbe so that on subsequent exposure to the same microbe, the body can call its sentry memory cells to fight off the infection and prevent disease induction. Usually, protective immunity involves neutralizing antibody secretion or memory production by cytotoxic T lymphocytes Th1 cells. In the current scenario, vaccines have been extended to facilitate immunization against fertilization and tumours. Basically, a vaccine is a suspension of a whole (inactivated or live) or fractionated viruses or bacteria that have been made non-pathogenic and given to an individual with the purpose of inducing immune response for the prevention of the disease.
Properties of an ideal vaccine:
- It should be capable of providing long lasting immunity.
- Should also be able to induce both cellular (T cell mediated) and humoral (B cell mediated) immunity
- It should never induce hypersensitivity or autoimmunity in the administered individual
- Its production should be inexpensive making it easily accessible to the masses.
- It should be easy to store, transport and administer.
- It should also be safe and not cause disease in the individual.
Tuberculosis is a huge threat to public health. As per the world health organisation, an estimated 8.7 million people were infected with TB in the year 2011. The causative organism of this disease is Mycobacterium tuberculosis. The most effective and licensed vaccine against TB is Bacillus-calmette Guerin (BCG) which has been developed from mycobacterium bovis. This vaccine has a protective effect in adolescents and children against various early results of tuberculosis infection like systemic infections and meningitis. But it cannot protect against infections which become latent. Thus, it can leave the door open for TB to get reactivated. Thus the efficacy and reliability of the BCG vaccine in prevention of pulmonary diseases in adults has been under scrutiny. In this regard, other vaccine strategies have been explored such as (I) developing a more successful BCG vaccine and (II) using attenuated strains of mtb (III) using subunit vaccines which are based on recombinant mtb proteins and its design includes combination with adjuvants for eliciting a protective effect.
BCG can be given anytime from the time of birth to 15 days of life. It is given along with the 0th dose of the polio vaccine which is administered orally. Usually BCG vaccine is available in an ampoule as a lyophilised powder. Buffered saline is used as a diluent to dissolve it for administration. Usually BCG vaccine stocks are stored in freezer compartments. Once prepared, it is advisable to use the vaccine within 2-3 hours and discard it after that.
In India, where tuberculosis is endemic, children usually catch the germs early in their life and develop a primary complex. In younger children, around 3-5 years of age, the germ can spread leading to serious and severe forms tuberculosis affecting children like tuberculosis meningitis, military tuberculosis, disseminated tuberculosis, organ tuberculosis like urinary tract, kidney etc. Since BCG is a live vaccine, it induces a benign primary complex but the spread of infection is prevented by the previous dose of BCG immunity. Such children do not develop childhood tuberculosis, however in later stages if they get affected they will develop the disease.
A second major option for developing better TB vaccines is dependent on the development of subunit vaccines. These vaccines are basically non-live or non-replicating vaccines which can be safely delivered to the human host regardless of the state of immunocompetence. Mostly, in case of TB, subunit vaccines are a combination of recombinant proteins mixed with adjuvants or attenuated viral vectors.
The upcoming 10-15 years are very crucial for the development of TB vaccines. It should also be realised that these first generation vaccines are not designed for infection prevention or to eradicate TB. They just aim at delaying or inhibiting TB reactivation. Currently what is needed are better TB vaccines which can help in complete disease eradication and healthier lifestyle.
There should be no doubt that small pox has frequently changed the course of human history by countless deaths in the old as well as new world. Some of the greatest achievement in world history is the development of small pox vaccine by Edward Jenner and its global eradication. The overall mortality rate has been estimated to be around 30% and most deaths occurs during second week of illness. Small pox is generally caused by variola virus of Orthopoxvirus gene. Vaccinia induces both cellular as well as humoral immunity to individuals. Usually the NYCBOH strain is used either cultured from human embryonic lung cell culture or in African green monkey (vero) cells. This vaccine’s efficacy has not been checked in controlled studies though epidemiological data actually suggest that high level protection may persist till 5 years after vaccination with partial immunity surviving longer.
Though there are several disadvantages to the same. Mild reactions include satellite lesion formation, muscle ache, fever, fatigue, nausea, headache rashes etc. at the site of vaccination. Individuals may also suffer from progressive vaccinia, which is defined as uncontrolled vaccine virus replication leading to a slow and progressive necrosis of the surrounding tissue. Inadvertent inoculation is another problem with smallpox vaccination. Usually occurs when the vaccinia virus gets transferred from vaccination site to other sites like mouth, eyes, nose etc.; other problems associated with vaccinia virus vaccination are eczema vaccinate, post-vaccine encephalitis, generalized vaccinia etc.
The vaccinia virus Lister/Elstree strain was used during the world wide eradication of small pox. Immunogenicity of the vaccinia virus Lister has been evaluated with and without p53 human gene insert and compared to the modified vaccinia virus Ankara (MVA) which is referred to as the gold standard of recombinant vaccinia virus in clinical development. With p53 gene insert it has been observed to show better product safety. On comparison with replication competent vaccinia virus, MVA has been shown to provide similar levels of gene expression even in case of nonpermissive cells. Animal models has shown MVA to be protective and immunogenic against different kinds of infectious agent inclusive of influenza, parainfluenza, immunodeficiency viruses, plasmodium parasites, measles virus, flavivirus etc.
Waning of the herd immunity is also coming into picture thanks to the small pox vaccine. Earlier when maximum number of people were vaccinated, the minor population who did not receive the vaccine did not get affected by small pox. Now, as vaccination in the population level is decreasing the level of individuals without the proper vaccination is increasing, thus widening the window for smallpox to strike again and proliferate in its human hosts.
Meningiococcal disease is a severe illness caused by a bacteria named Neisseria meningitides. Meningitis is an infection of the brain lining and the spinal cord. The disease can spread though close contact (kissing or coughing) amongst people sharing the same household. 12 typed of N. meningitides have been found of which serogroups A, B, C, W and Y are responsible for causing the maximum cases of meningiococcal disease. The vaccine acting against meningiococcal disease are referred to as meningiococcal conjugate vaccine ACWY which basically acts against A, C, W, Y serogroups and meningiococcal polysaccharide vaccine (MPSV4).
Usually the side effects to the meningiococcal vaccine are mild. However, they may include mild pain and redness at injection spot accompanied by slight fever. It may also lead to a severe allergic reaction which can be identified by hoarseness, itching, hives, redness, warm skin, paleness, difficulty in swallowing etc. The immunity provided by Menomune (MPSV-4) is approximately 3 years or even less in children under 5 years of age as it does not play any role in generation of T cells. Boosters are not recommended in this vaccine as they lead to reduced antibody response.
pestis has the ability to overcome host defense mechanisms. Btu a safe and effective pneumonic plague vaccine has been designed (Smiley, 2008):
Killed whole cell plague vaccine: this vaccine was designed in 1897 and could protect against bubonic plague. The drawback was these vaccines were highly reactogenic and could not protect against bubonic plague. These vaccines also caused significant adverse reaction especially after administration of booster doses which are required to maintain the protection (Parent, 2005).
Subunit plague vaccine: this vaccine was developed in 1952 which combined capsular proteins of F1 and Y pestis. Vaccination which combines purified LcrV and F1 proteins are able to protect mice against sub cutaneous Y. pestis. This combination vaccine of F1 and LcrV have been found to be more effective than compared to either subunit alone. It is also found to protect mice against pulmonary Y. pestis.
Live attenuated plague vaccine: Live attenuation of organisms provide the theoretical advantage of priming immunity against many antigens simultaneously. Thus this can be used to reduce opportunity for circumvention by weapon engineers. It has also been observed that live attenuated vaccines can also protect humans against bubonic plague. The live attenuated vaccines are derived from the virulent Y pestis which contain mutation that have occurred spontaneously using the pigmentation locus (PGM). Disadvantages are that these vaccines are quite unstable and can also display virulence in non-human primates. They may also cause debilitating fever, lymphadenopathy and malaise in humans. Some groups have recently described attenuated strains of Y. pestis which have well defined genetic modifications which may play a useful role in live vaccinations. Vaccines with mutations in pla and pgm loci have sown to safely induce humoral immunity responses in monkeys. It has also been observed that strains with mutations in the lpxM or pcm loci can protect mice against subcutaneous challenge. YopH mutant has shown to protect mice against pulmonary as well as subcutaneous challenge (Titball & Williamson, 2004).
Passive immunity against plague is received by the new-born rodents from the mother’s immune system. So far studies have not been able to demonstrate any appreciable bactericidal activity of the immune serum of plague and suggest that the antibody mediated defense which has been observed against plague is a reflection of the collaboration between the cellular and humoral immune response mechanisms of the host. One other possible mechanism of antibody action can be via opsonic mechanisms (opsonisation is the process by which the viral antigens are coated by certain molecules which can be easily recognised by the neutrophils and other scavengers thus neutralizing them and removing them from immune circulation). LcrV expression has been seen on the bacterial surfaces and antibodies specific to the molecule LcrV help the neutrophils and macrophages phagocytose the Y. pestis . it’s being speculated that contact with the bacilli Y. pestis may activate macrophage apoptosis in vivo via Yop dependent mechanism and the antibodies to LcrV suppress macrophage apoptosis and Yop translocation. There are not many studies available which shed light on the role of T cells and acquired cellular level immunity due to the difficulties in the methodology for studying cellular immunity. Nowadays there are a number of factors suggesting a role of cytokines like IFN gamma and TNF alpha. Pre-treatment with IFN gamma and TNF alpha has shown to restrict the intracellular replication.
As it is known that, cellular and humoral immunity often use complementary defense mechanisms and understanding their clear potential for energy, the next generation vaccines for encountering disease like plague should work towards being prime in both cellular and humoral immunity.
Parent MA. (2005), Cell-mediated protection against pulmonary Yersinia pestis infection. Infect Immun., 73(11), 7304-7310.
Smiley, ST (2008), Immune defense against pneumonic plague, Immunol Rev. 2008 Oct; 225: 256–271.
Titball RW, Williamson ED.(2004), Yersinia pestis (plague) vaccines. Expert Opin Biol Ther., 4(6), 965-973.