Revival of Leishmanization and Leishmanin

Abstract

Leishmaniasis includes a spectrum of diseases ranging from debilitating cutaneous to fatal visceral infections. This disease is caused by the parasitic protozoa of the genus Leishmania that is transmitted by infected sandflies. Over 1 billion people are at risk of leishmaniasis with an annual incidence of over 2 million cases throughout tropical and subtropical regions in close to 100 countries. Leishmaniasis is the only human parasitic disease where vaccination has been successful through a procedure known as leishmanization that has been widely used for decades in the Middle East. Leishmanization involved intradermal inoculation of live Leishmania major parasites resulting in a skin lesion that following natural healing provided protective immunity to re-infection. Leishmanization is however no longer practiced due to safety and ethical concerns that the lesions at the site of inoculation that can last for months in some people. New genome editing technologies involving CRISPR has now made it possible to engineer safer attenuated strains of Leishmania, which induce protective immunity making way for a second generation leishmanization that can enter into human trials. A major consideration will be how the test the efficacy of a vaccine in the midst of the visceral leishmaniasis elimination program. One solution will be to use the leishmanin skin test (LST) that was also used for decades to determine exposure and immunity to Leishmania. The LST involves injection of antigen from Leishmania in the skin dermis resulting in a delayed type hypersensitivity (DTH) immune reaction associated with a Th1 immune response and protection against visceral leishmaniasis. Reintroduction of novel approaches for leishmanization and the leishmanin skin test can play a major role in eliminating leishmaniasis.

Keywords: immunity; leishmaniasis; leishmanin; leishmanization; vaccine.

Figure 1

Leishmanization, immunization with live attenuated parasites and use of LST. Wild type L. major promastigotes (1) or live attenuted parasites (2) are injected intradermally through the skin. Wild type L. major parasites cause a skin lesion that can be controlled by radiofrequency-induced heat therapy (3). Injection with live attenuated parasites has shown no risk of skin lesions in pre-clinical models, however, radiofrequency-induced heat therapy can be used to mitigate this risk in clinical studies (3). Promastigotes transform into amastigotes and are internalized by dendritic cells, which travel to the draining lymph nodes to present the antigen to T cells (4). Different populations of effector and memory T cells are generated upon antigen presentation (5). Due to low parasitemia, these populations persist in the body and provide long term protection against sand fly challenge with virulent leishmania parasites (6). The leishmanin skin test (LST) can be used to evaluate cellular immunity and memory (7).