Vervet Monkeys Vaccinated with KilledLeishmania majorParasites and Interleukin-12 Develop a Type 1 Immune Response but Are Not Protected against Challenge Infection

Abstract

Leishmania major is a protozoan parasite that causes chronic cutaneous lesions that often leave disfiguring scars. Infections in mice have demonstrated that leishmanial vaccines that include interleukin-12 (IL-12) as an adjuvant are able to induce protective immunity. In this study, we assessed the safety, immunopotency, and adjuvant potential of two doses of IL-12 when used with a killed L. major vaccine in vervet monkeys. The induction of cell-mediated immunity following vaccination was determined by measuring delayed-type hypersensitivity, in vitro lymphocyte proliferation, and gamma interferon (IFN-␥) production. Protection was assessed by challenging the animals with L. major parasites and monitoring the course of infection. At low doses of IL-12 (10 g), a small increase in the parameters of cell-mediated immunity was observed, relative to those in animals that received antigen without IL-12. However, none of these animals were protected against a challenge infection. At higher doses of IL-12 (30 g), a substantial increase in Leishmania-specific immune responses was observed, and monkeys immunized with antigen and IL-12 exhibited an IFN-␥ response that was as great as that in animals that had resolved a primary infection and were immune. Nevertheless, despite the presence of correlates of protection, the disease course was only slightly altered, and protection was low compared to that in self-cured monkeys. These data suggest that protection against leishmaniasis may require more than the activation of Leishmania-specific IFN-␥-producing T cells, which has important implications for designing a vaccine against leishmaniasis.Cutaneous leishmaniasis is a disease caused by obligate intracellular protozoa of the genus Leishmania and is characterized by cutaneous lesions that can be self-resolving with life-long immunity or chronic when accompanied by defective cellular immune responses (27). The disease is prevalent in many tropical and subtropical regions of the world, where it is transmitted via the bite of the sand fly. Treatment for leishmaniasis often involves the use of high doses of pentavalent antimony compounds or various formulations of amphotericin B. However, the increasing prevalence of drug-resistant organisms and the tendency for patients to relapse after an initially successive regimen of chemotherapy underscore the need for an effective prophylactic vaccine (27).Efforts towards vaccine development have involved both animal model studies and human research. The vervet monkey is an excellent animal model for studying Leishmania major infection (4,11,17,(23)(24)(25)27). Similar to many human patients with leishmaniasis, the vervet monkey has been shown to undergo spontaneous cure following both natural and experimental infection with L. major. Associated with healing was resistance to subsequent challenge with an appropriate dose of homologous parasites. Studies with the vervet monkey model for cutaneous leishmaniasis have demonstrated that resistance to leishmaniasis in this model is correlated w...

Protective immunity using MPL-A and autoclaved Leishmania donovani as adjuvants along with a cocktail vaccine in murine model of visceral leishmaniasis

“…Our results are in agreement with the studies which showed that mice immunized with autoclaved and heat killed antigen of L. donovani elicited strong DTH response correlated with the protection against infection in these groups (Nagill et al 2009). Similarly monkeys vaccinated with ALM?rIL-12 has been shown to elicit higher DTH responses (Gicheru et al 2001). Our studies are also in consistence with the studies which showed that MPL-A when used along with 78 kDa antigen for immunization further enhanced the DTH response (Nagill and Kaur 2010).…”

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

“…Taken together with our finding that immunization of vervet monkeys induces both of these immune responses without inducing significant resistance to infection (31), it is clear that reliable correlates of immunity for leishmaniasis have yet to be defined. Understanding how immunologic memory is induced and maintained should aid in defining useful correlates of immunity.…”

The utility of rhesus monkey (Macaca mulatta) and other non-human primate models for preclinical testing of Leishmania candidate vaccines

“…Neither study in the L. amazonensis (Kenney et al 1999) or L. major-macaque model , Amaral et al 2002, nor those in the L. major-vervet monkey model (Gicheru et al 2001), have resulted in a clear definition of what T-cell responses will be required for vaccine-induced protective immunity. Without such knowledge, vaccine design strategies will remain largely empirical, and further failures are likely to occur.…”