Vaccines for leishmaniasis and the implications of their development for American tegumentary leishmaniasis

Abstract

The leishmaniases are a collection of vector-borne parasitic diseases caused by a number of different Leishmania species that are distributed worldwide. Clinical and laboratory research have together revealed several important immune components that control Leishmania infection and indicate the potential of immunization to prevent leishmaniasis. In this review we introduce previous and ongoing experimental research efforts to develop vaccines against Leishmania species. First, second and third generation vaccine strategies that have been proposed to counter cutaneous and visceral leishmaniasis (CL and VL, respectively) are summarized. One of the major bottlenecks in development is the transition from results in animal model studies to humans, and we highlight that although American tegumentary leishmaniasis (ATL; New World CL) can progress to destructive and disfiguring mucosal lesions, most research has been conducted using mouse models and Old World Leishmania species. We conclude that assessment of vaccine candidates in ATL settings therefore appears merited.

Inoculation of the Leishmania infantum HSP70-II Null Mutant Induces Long-Term Protection against L. amazonensis Infection in BALB/c Mice

“…It is a consolidated concept that protection against L. amazonensis, as with other species of the parasite, is related to the generation of an IFN-γ-mediated response against the parasite prompted by vaccination [47]. Our results demonstrated that protection induced by LiΔHSP70-II was also correlated to the induction of a Th1 systemic response against leishmanial antigens, evidenced by an increase of IFN-γ production in the spleen ( Figure 3) and an increase in the titers of anti-SLA IgG2a circulating antibodies ( Figure 2).…”

Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis

“…Traditional strategies for vaccine development to control leishmaniasis have failed to reproduce the lifelong immunity to reinfection observed in patients clinically recovering from the disease but maintaining chronic infections (concomitant immunity) considered subclinical. This inability to design prophylactic vaccines that trigger long-lasting protection against Leishmania antigens in humans reflects the gap in the current understanding of the relationship between disease pathogenesis and host immune responses generated against Leishmania parasites, and the challenge of translating experimental evidence from animal models to human cases [18,153].…”

“…The inoculation of live and virulent Leishmania parasites termed leishmanization was a common vaccination strategy in endemic areas that conferred protection to natural and exacerbated Leishmania infections induced by sandfly transmission, but this practice was largely discontinued due to safety and reproducibility issues [154]. Attempts to emulate the anti-Leishmania responses acquired by "leishmanized" individuals with whole-killed or attenuated parasite-based formulations have raised concerns regarding the low immunogenicity and the potential reversion to a more virulent phenotype, respectively, in addition to variations in vaccine efficacy observed in clinical trials in different areas [153][154][155]. Yet, the use of adjuvants to tailor immune responses through activation of specific innate pathogen-recognition receptors (PRRs), such as TLRs, has been shown to enhance the generation of Th1 memory cells and parasite-specific responses to secondary challenges [156].…”

“…An alternative and attractive vaccine approach is the delivery of recombinant nucleic acids (DNA and RNA) encoding Leishmania antigenic proteins that can be expressed in vivo and loaded into MHC molecules on transfected cells [162,163]. Some of the advantages of nucleic acid-based vaccines are their stability, the number of antigens and adjuvants that can be encoded by a single vector, the expression of structurally unaltered immunogenic proteins in recipient cells and the antigen-specific stimulation of CD4+ and CD8+ T cell responses [153,164]. Several tests with DNA-based vaccines have been conducted in experimental models of leishmaniasis using different routes of administration.…”

Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4+ T Effector and Regulatory T Cells in Cutaneous Leishmaniasis

“…Disease presentation ranges from the development of ulcers, which can spontaneously heal, to single or multiple chronic non-healing lesions, which are difficult to resolve (3). So far, drugs to control the disease are limited due to high costs and toxicity, and there is currently no safe and effective vaccine for application in humans (4,5). The complexity of the host immune response to Leishmania is also a key limiting factor for developments in this field (6)(7)(8).…”