Leprosy is endemic in several regions of the world. Currently the only protection has come from vaccination with BCG (Bacillus Calmette-Guerin), a single dose of which gives 50 percent or higher protection against the disease. BCG is a component of the Expanded Program on Immunization and confers some degree of protection against tuberculosis, which is caused by a mycobacterium allied to M. leprae.
Closeup hand of old man suffering from leprosy, amputated hand, on wheelchair - Image Credit: Tidarat Tiemjai / Shutterstock
For this reason, BCG vaccination is used routinely in childhood in countries where leprosy is endemic, as well as for the household contacts of diagnosed leprosy patients. When the individual has developed a scar following the first vaccination, a second dose of BCG confers 50 percent protection in addition to that resulting from the first dose.
It has become the most widely used vaccine in the world, yet the degree of protection it confers is still controversial. The meta-analysis of several experimental studies concludes that on average, 26 percent protection against leprosy is afforded by the vaccine. The protection level goes down over time. When more than one dose of vaccine is used, better protection is offered.
It has been suggested that BCG vaccination causes the host immune system to undergo alterations which, in turn, leads to different levels of protection against multibacillary and paucibacillary forms of leprosy. Higher cellular immunity may be associated with more cases of paucibacillary disease.
Mechanism
In the late 1930s, it was shown that BCG vaccination led to the occurrence of a positive Mitsuda reaction, a late hypersensitivity reaction to the intradermal inoculation of lepromin. Lepromin is a standardized extract of inactivated lepromin bacilli. The cell-mediated Mitsuda reaction occurs after 28 days in individuals who have strong cell-mediated immune reactions to the mycobacterium. It is marked by the formation of a granuloma at the inoculation site. It is positive when a wheal of 3-10 mm is produced within 28 days. It is positive in tuberculoid and borderline tuberculoid leprosy, but always negative in lepromatous leprosy. Thus it correlates cell-mediated immunity with the tuberculoid form of leprosy.
When an individual who was earlier unresponsive to intradermal lepromin injection becomes positive for the lepromin test later, the phenomenon is referred to as lepromin conversion. This occurs following BCG vaccination, and it was this finding which led to the concept of using the vaccine to prevent leprosy. Animal studies have shown that the maximum effect of BCG seems to occur at two points:
- Immediately before exposure to M. leprae
- Just before the organism enters the logarithmic proliferation phase
BCG vaccination leads to increased cell-mediated immunity among contacts of leprosy patients.
Preventive strategies
The prevention of new leprosy cases depends upon:
- wider coverage of infants in endemic regions with the BCG vaccine
- secondary prevention by tracing contacts, making an early diagnosis, and treating infection early
- offering chemoprophylaxis to healthy household contacts
- additional vaccination of leprosy patients with BCG (though this may speed up the onset of paucibacillary leprosy)
Reasons for Variable Efficacy of BCG Vaccination
There are many influences upon the studies which have been conducted on the protective effect of BCG. These include:
- poor quality trials (in terms of randomization or blinding) which generally report a lower efficacy
- environmental mycobacterial may alter the cellular immune response to BCG which could in turn affect the response to leprosy
- higher latitudes may be associated with lower protection against leprosy
- different strains used in BCG may account for differences in the rate of protection
- genetically different populations contribute another confounder, that due to variance in genetic susceptibility to leprosy
- differences in the nutritional status of populations can result in varying rates of leprosy and in heterogeneous clinical manifestations
Variants of Vaccination
Adding killed M. leprae to BCG
Various modifications have been suggested, such as the addition of killed M. leprae to BCG. While it has not been conclusively proved to increase the protection rate, some studies have suggested that it almost doubles the vaccine efficacy in some populations. It fails, however, to increase the protection rate for patients below 15 years.
Vaccination with M. indicus pranii
Earlier known as Mycobacterium W, this strain has been proved in one study to provide protection for up to nine years in both contacts and index cases. Unfortunately the immunity wanes with time and is higher for contacts than for cases.
Indian cancer research center (ICRC) bacilli
ICRC bacilli are thought to belong to the M. avium intracellulare group, and in one trial, they induced lepromin conversion in lepromatous leprosy patients and in lepromin-negative leprosy-free individuals. Its efficacy was reported to be 65.5 percent.
M. vaccae
This soil-dwelling mycobacterial species has been combined with BCG to provide greater protection, but a Vietnamese trial showed no such effect.
M. habana
This organism induced lepromin positivity in monkeys, and protected mice against the development of leprosy. It has been reported to induce lepromin conversion when used in a live vaccine.
However, none of these organisms has replaced the BCG vaccine in common use.
Other refinements on this vaccine include:
- Purified antigens including 35kD, Ag85B, and hsp65
- Recombinant antigens in appropriate adjuvants
- Recombinant BCG strains in order to increase its immunogenicity and duration of protection
Post-Exposure Prophylaxis
Also known as chemoprophylaxis, this approach focuses on providing effective antibiotics to people at risk. Clusters of leprosy cases are found in all endemic regions, rather than being evenly dispersed over the whole area. These can be identified, and vaccination provided, in addition to secondary prevention strategies. These include focused surveillance, contact tracing, early diagnosis, and treatment. This can not just reduce the incidence but break the chain of transmission.
Additionally, vaccination could be used primarily for contacts of multibacillary patients, who have the highest risk of developing the disease. These are the targets of chemoprophylaxis and for whom pre-emptive treatment is offered in order to prevent the emergence of the clinical infection and its transmission to others. The limitations of this approach, in contrast with vaccination, include:
- High bacillary load by the time the treatment is started, making it impossible to eliminate the infection with one or two doses, in which case the recommendation may be to start a full course of multi-drug therapy for the contact in question. This will require a more specific screening test which can distinguish between contacts with high and low bacillary load.
- The possibility of infection after chemoprophylaxis is administered, which makes the latter redundant and contributes to unchanged case detection rates - or in other words, the short duration of protection (approximately two years).
Since chemoprophylaxis or multi-drug treatment wipe out the extant mycobacteria, it is impossible to combine immune- and chemoprophylaxis on a simultaneous basis. However, two doses of vaccine may be considered at a 30 day interval, with short-term chemotherapy being given in between, for individuals who have already been infected.
References
Further Reading
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