Vaccination against Leishmania major in a CBA mouse model of infection: role of adjuvants and mechanism of protection

Abstract

Gp63 is a major surface protein of Leishmania promastigotes. Its protective efficacy has been tested in several experimental models using different mouse strains, gp63 forms, adjuvants and routes of immunization, giving rise to conflicting results. This investigation was designed to determine whether these discrepancies could be ascribed to differing experimental procedures, and to compare gp63-induced protection with that achieved using live promastigotes. Preliminary experiments demonstrated that gp63 was an extremely potent immunogen compared to a standard antigen (ovalbumin). Protection against Leishmania major infection afforded by gp63 inoculation was studied in CBA mice. Injection of gp63 in saline, or of CFA, BCG, and C. parvum without antigen, induced significant protection. When gp63 and adjuvants were combined, results differed depending on the site of vaccination relative to that of the challenge infection. Vaccination with gp63 plus adjuvants in the tail (i.e. close to the site of infection) led to a stronger reduction of lesion size than the basal level of protection elicited by adjuvants alone, except in the case of CFA. Surprisingly however, when the antigen was injected at a distance from the site of infection (immunization in the hind foot pads, infection in the rump), the protective effect of gp63 was decreased by the adjuvants. Finally, vaccination at either site using live parasites (radioattenuated or virulent promastigotes) resulted in most instances in better protection than achieved by any protocol using gp63 and adjuvants. While anti-gp63 T cells proliferated in vitro in response to L. major-infected bone marrow-derived macrophages, they were unable to activate macrophages for parasite killing. This is in contrast with lymphocytes from mice immunized with live parasites, which both proliferated and stimulated significant killing of the microorganisms within 48 h.

Leishmaniasis: Current Status of Vaccine Development

“…This study extends the data obtained with the mouse and dog models (2,72,82,83,114) and provides a basis for further human trials. However, because delayed-type hypersensitivity was not predictive of protection in this monkey model, the value of delayed-type hypersensitivity as a surrogate marker of protection in humans needs to be reassessed.…”

“…Such immunization will also deliver many more parasite antigens than the limited number possible with subunit or recombinant antigens. Summarizing a large amount of experimental evidence, Rivier et al (114) concluded that injection of attenuated organisms achieved better protection than any method involving recombinant gp63 as test antigen delivered with a variety of adjuvants and delivery systems. If this conclusion is shown to be generally applicable to other vaccine candidates, the prospect of using attenuated Leishmania vaccines in preference to subunit or recombinant approaches will gain favor.…”

Species Typing in Dermal Leishmaniasis

“…The metalloprotease glycoprotein 63 (GP63) is the major surface glycoprotein of Leishmania and is considered an important virulence factor and a strong immunogen (168). The gene is arranged as a tandemly repeated unit, and both the intra-and intergenic regions have been used for typing by RFLP analysis.…”

SIR2-Deficient Leishmania infantum Induces a Defined IFN-γ/IL-10 Pattern That Correlates with Protection

“…In addition, higher levels of parasite Ags are delivered at the site of the infection than when using subunit vaccines. Indeed, vaccination with avirulent organisms achieved better protection than classical immunizations with selected Ags whatever the adjuvants and delivery systems used (21). Several vaccination strategies that lead to obtaining live attenuated organisms have been attempted, including long-term in vitro cultures (22), selection for temperature sensitivity (23), chemical mutagenesis (24), and parasite culture under drug pressure (25).…”