Clinical and parasitological protection in a Leishmania infantum-macaque model vaccinated with adenovirus and the recombinant A2 antigen

PLoS Negl Trop Dis. 2014 Jun 19;8(6):e2853. doi: 10.1371/journal.pntd.0002853. eCollection 2014 Jun.

Abstract

Background: Visceral leishmaniasis (VL) is a severe vector-born disease of humans and dogs caused by Leishmania donovani complex parasites. Approximately 0.2 to 0.4 million new human VL cases occur annually worldwide. In the new world, these alarming numbers are primarily due to the impracticality of current control methods based on vector reduction and dog euthanasia. Thus, a prophylactic vaccine appears to be essential for VL control. The current efforts to develop an efficacious vaccine include the use of animal models that are as close to human VL. We have previously reported a L. infantum-macaque infection model that is reliable to determine which vaccine candidates are most worthy for further development. Among the few amastigote antigens tested so far, one of specific interest is the recombinant A2 (rA2) protein that protects against experimental L. infantum infections in mice and dogs.

Methodology/principal findings: Primates were vaccinated using three rA2-based prime-boost immunization regimes: three doses of rA2 plus recombinant human interleukin-12 (rhIL-12) adsorbed in alum (rA2/rhIL-12/alum); two doses of non-replicative adenovirus recombinant vector encoding A2 (Ad5-A2) followed by two boosts with rA2/rhIL-12/alum (Ad5-A2+rA2/rhIL12/alum); and plasmid DNA encoding A2 gene (DNA-A2) boosted with two doses of Ad5-A2 (DNA-A2+Ad5-A2). Primates received a subsequent infectious challenge with L. infantum. Vaccines, apart from being safe, were immunogenic as animals responded with increased pre-challenge production of anti-A2-specific IgG antibodies, though with some variability in the response, depending on the vaccine formulation/protocol. The relative parasite load in the liver was significantly lower in immunized macaques as compared to controls. Protection correlated with hepatic granuloma resolution, and reduction of clinical symptoms, particularly when primates were vaccinated with the Ad5-A2+rA2/rhIL12/alum protocol.

Conclusions/significance: The remarkable clinical protection induced by A2 in an animal model that is evolutionary close to humans qualifies this antigen as a suitable vaccine candidate against human VL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Human / genetics
  • Adjuvants, Immunologic / administration & dosage
  • Animals
  • Antibodies, Protozoan / blood
  • Antigens, Protozoan / genetics
  • Antigens, Protozoan / immunology*
  • Disease Models, Animal
  • Drug Carriers*
  • Female
  • Genetic Vectors
  • Immunoglobulin G / blood
  • Leishmania infantum / genetics
  • Leishmania infantum / immunology*
  • Leishmaniasis / immunology
  • Leishmaniasis / prevention & control*
  • Liver / parasitology
  • Liver / pathology
  • Macaca
  • Male
  • Parasite Load
  • Protozoan Vaccines / administration & dosage
  • Protozoan Vaccines / genetics
  • Protozoan Vaccines / immunology*
  • Vaccination / methods*
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / genetics
  • Vaccines, Synthetic / immunology

Substances

  • Adjuvants, Immunologic
  • Antibodies, Protozoan
  • Antigens, Protozoan
  • Drug Carriers
  • Immunoglobulin G
  • Protozoan Vaccines
  • Vaccines, Synthetic

Grants and funding

The National Institute of Science and Technology for Vaccines (Brazil) (MCT/CNPq, grant #470269/2006-5) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG, grant # APQ-00304-10) supported this work. CNPq provided fellowship to MGLR and MSD. RTG is recipient of the Visiting Professor Scholarship from CAPES and the David Rockefeller Center for Latin America Studies at the Harvard School of Public Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.