Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi

Abstract

There are several unmet needs in modern immunology. Among them, vaccines against parasitic diseases and chronic infections lead. Trypanosoma cruzi, the causative agent of Chagas disease, is an excellent example of a silent parasitic invasion that affects millions of people worldwide due to its progression into the symptomatic chronic phase of infection. In search for novel vaccine candidates, we have previously introduced Traspain, an engineered trivalent immunogen that was designed to address some of the known mechanisms of T. cruzi immune evasion. Here, we analyzed its performance in different DNA prime/protein boost protocols and characterized the systemic immune response associated with diverse levels of protection. Formulations that include a STING agonist, like c-di-AMP in the boost doses, were able to prime a Th1/Th17 immune response. Moreover, comparison between them showed that vaccines that were able to prime polyfunctional cell-mediated immunity at the CD4 and CD8 compartment enhanced protection levels in the murine model. These findings contribute to a better knowledge of the desired vaccine-elicited immunity against T. cruzi and promote the definition of a vaccine correlate of protection against the infection.

Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

“…In the last few years, a better understanding of the protective immune responses that can effectively arrest T. cruzi survival in mammalian host provides the fundamentals for a rational design of a prophylactic and therapeutic vaccine against Chagas disease ( 22 ). Anti- T. cruzi strategies had been focused on targeting specific metabolic biochemical pathways or parasite-specific enzymes, as well as noninvasive immunization routes ( 23 , 24 ). Most of these strategies need potent adjuvant to obtain the desirable response to improve vaccine efficacy ( 43 ).…”

“…In our laboratory, we took advantage of attenuated Salmonella enterica serovar Typhimurium aroA that can be administered orally and is easily produced, facilitating its implementation in vaccination campaigns. We have previously demonstrated the efficacy of this transport system as prophylactic vaccines to T. cruzi infection ( 19 , 21 , 24 , 50 , 51 ). Based on these promising results, we have evaluated the therapeutic effect of Salmonella as a DNA delivery system of Cz upon the coadministration with GM-CSF as adjuvant with good performance ( 25 ).…”

“…Cz stimulates potent humoral and cellular immune responses during infection ( 18 ). Additionally, Cz has been reported as an efficient prophylactic vaccine as both protein and DNA vaccine, in different administration routes and coupled with several adjuvants ( 19 – 24 ). In addition, we had encouraging results using a therapeutic Cz DNA-based vaccine that has been able to decrease parasitemia, inflammatory cell infiltrate, and tissue damage in murine models of T. cruzi infection ( 25 ).…”

Heterologous Chimeric Construct Comprising a Modified Bacterial Superantigen and a Cruzipain Domain Confers Protection Against Trypanosoma cruzi Infection

“…For this purpose, after the last immunization animals were challenged with 3 × 10 5 blood trypomastigotes of the less virulent K98 clone (from CA-I strain) by intraperitoneal injection. Parasitemias were recorded weekly during the acute phase (19,35).…”

“…described that the N-terminal domain of Cz (Nt-Cz) displayed the highest protective role during immunization, bypassing ineffective responses towards the C-terminal domain (17). In previous work from our laboratory, an engineered chimeric immunogen named Traspain was designed containing Nt-Cz as one of the key parasitic molecules, with very promising results (18,19).…”