Gene-deleted live-attenuated Trypanosoma cruzi parasites as vaccines to protect against Chagas disease

Abstract

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. This illness is now becoming global, mainly due to congenital transmission, and so far, there are no prophylactic or therapeutic vaccines available to either prevent or treat Chagas disease. Therefore, different approaches aimed at identifying new protective immunogens are urgently needed. Live vaccines are likely to be more efficient in inducing protection, but safety issues linked with their use have been raised. The development of improved protozoan genetic manipulation tools and genomic and biological information has helped to increase the safety of live vaccines. These advances have generated a renewed interest in the use of genetically attenuated parasites as vaccines against Chagas disease. This review discusses the protective capacity of genetically attenuated parasite vaccines and the challenges and perspectives for the development of an effective whole-parasite Chagas disease vaccine.

Keywords:

• Chagas disease
• immune response
• infectivity
• live vaccine
• parasite knock-out
• safety
• Trypanosoma cruzi

Acknowledgements

The authors greatly appreciate LA Parada for critical reading of the manuscript. The authors also gratefully acknowledge the contribution of the Fundación Bunge y Born and the ‘Mariano Levin Scholarship’ granted to Fernando Sánchez-Valdéz.

Financial & competing interests disclosure

This work was supported by grants from Howard Hughes Medical Institute, Agencia Nacional de Promoción Científica y Técnica, Fundación Florencio Fiorini and Consejo Nacional de Investigaciones Científicas y Técnicas. The funders had no role in study design, data collection and analysis, decision to publish, or in the preparation of the manuscript.

Key issues

• Chagas disease is a neglected tropical disease affecting more than 10 million people in the poorest regions of Latin America.

• For more than 40 years, Chagas disease treatment was based on the use of relatively toxic drugs that produce serious side effects and have restricted indications in adult patients and pregnant women.

• Chagas vaccine development is being justified by a progressive replacement of the autoimmune hypothesis by the notion that parasite persistence is the main inductor of pathogenesis.

• Live vaccines are likely to be more efficient in inducing long-lasting protection, but safety issues linked with their use must be addressed.

• Genetic manipulation techniques, through gene deletion by homologous recombination, have increased the safety of live vaccines.

• Only seven genetically modified Trypanosoma cruzi parasites have been used as immunogens in experimental models of Chagas disease, demonstrating the limited development of this area compared to leishmaniasis and malaria.

• All T. cruzi mutants tested so far (either mono- or biallelic) have displayed some degree of attenuation in their infective capacity.

• Before undergoing clinical trials, gene-deleted live attenuated T. cruzi vaccines will have to overcome several challenges.

• Prior immunization, with these tools, of intra- or peri-domiciliary mammal reservoirs (i.e., canines) may hinder transmission of the parasite to humans, besides its intrinsic veterinary therapeutic value.