Despite intense efforts there is no safe and efficacious
vaccine against
visceral leishmaniasis, which is fatal and endemic in many tropical countries. A major shortcoming in the
vaccine development against blood-borne parasitic agents such as Leishmania is the inadequate predictive power of the early immune responses mounted in the host against the experimental
vaccines. Often immune correlates derived from in-bred animal models do not yield
immune markers of protection that can be readily extrapolated to humans. The limited efficacy of
vaccines based on
DNA, subunit, heat killed parasites has led to the realization that acquisition of durable immunity against the protozoan parasites requires a controlled
infection with a live attenuated organism. Recent success of irradiated
malaria parasites as a
vaccine candidate further strengthens this approach to vaccination. We developed several gene deletion mutants in Leishmania donovani as potential live
attenuated vaccines and reported extensively on the immunogenicity of LdCentrin1 deleted mutant in mice, hamsters, and dogs. Additional limited studies using genetically modified live attenuated Leishmania parasites as
vaccine candidates have been reported. However, for the live attenuated parasite
vaccines, the primary barrier against widespread use remains the absence of clear
biomarkers associated with protection and safety. Recent studies in evaluation of
vaccines, e.g.,
influenza and
yellow fever vaccines, using systems biology tools demonstrated the power of such strategies in understanding the immunological mechanisms that underpin a protective phenotype. Applying similar tools in isolated human tissues such as PBMCs from healthy individuals infected with live attenuated parasites such as LdCen(-/-) in vitro followed by human microarray hybridization experiments will enable us to understand how early
vaccine-induced gene expression profiles and the associated immune responses are coordinately regulated in normal individuals. In addition, comparative analysis of
biomarkers in PBMCs from asymptomatic or healed
visceral leishmaniasis individuals in response to
vaccine candidates including live attenuated parasites may provide clues about determinants of protective immunity and be helpful in shaping the final
Leishmania vaccine formulation in the clinical trials.