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Intranasal Trans-Sialidase Vaccine Mitigates Acute and Chronic Pathology in a Preclinical Oral Chagas Disease Model
Maria Florencia Pacini1, Camila Bulfoni Balbi1, Brenda Dinatale1
1Instituto de Inmunología Clínica y Experimental de Rosario (IDICER-CONICET), Rosario 2000, Argentina.
Insights
A novel mucosal vaccine using trans-sialidase (TS) and c-di-AMP (TS+A) shows promise against Chagas disease. This Trypanosoma cruzi vaccine candidate reduced parasite load and prevented both acute and chronic cardiomyopathy in preclinical studies.
Area of Science:
- Immunology and Infectious Diseases
- Vaccine Development
- Parasitology
Background:
- Chagas disease, caused by Trypanosoma cruzi, affects millions globally, leading to severe cardiac complications in 30% of cases.
- Current treatment options for Chagas disease are limited, and no licensed vaccine is available for prevention.
- Chagas cardiomyopathy, a chronic fibrosing condition, represents the most significant and debilitating manifestation of the disease.
Purpose of the Study:
- To evaluate the immunogenicity and prophylactic efficacy of a novel mucosal vaccine candidate against Trypanosoma cruzi.
- To assess the vaccine's impact on both acute and chronic cardiomyopathy development in a preclinical model.
- To investigate the immune responses, including mucosal and systemic immunity, elicited by the vaccine.
Main Methods:
- Nasal administration of a vaccine comprising trans-sialidase (TS) and c-di-AMP (TS+A) to mice.
- Assessment of mucosal (NALT IgA) and systemic immune responses (cytokine profiles, lymphocyte proliferation, DTH).
- Evaluation of prophylactic efficacy through oral infection with T. cruzi, measuring parasitemia, parasite load, organ damage, and cardiomyopathy markers.
Main Results:
- TS+A vaccination induced robust mucosal (NALT IFN-γ, IL-17a, IL-4 mRNA, IgA) and systemic immune responses (Th1/Th2/Th17 cytokines, DTH).
- Vaccinated mice exhibited significantly reduced parasitemia and parasite burden in heart, muscles, and intestines post-infection.
- TS+A significantly attenuated acute myocarditis and chronic cardiomyopathy, including fibrosis and electrocardiographic abnormalities, by reducing pro-fibrotic markers like TGF-β.
Conclusions:
- A mucosal vaccine based on trans-sialidase (TS) and c-di-AMP (TS+A) is a viable strategy for preventing T. cruzi infection.
- This vaccine candidate effectively reduces parasite load and prevents the development of Chagas cardiomyopathy, a major disease complication.
- The study demonstrates the potential of TS+A as a promising mucosal vaccine for controlling Chagas disease and its cardiac sequelae.
Abstract:
Chagas disease, caused by Trypanosoma cruzi, leads to severe complications in 30% of infected individuals, including acute myocarditis and chronic fibrosing cardiomyopathy. Despite the significant burden of this disease, there is currently no licensed vaccine available to prevent it. This study aimed to evaluate the mucosal and systemic immunogenicity as well as the prophylactic efficacy of a mucosal vaccine candidate and its impact on both acute and chronic cardiomyopathy. The results showed that the nasal administration of trans-sialidase (TS) plus c-di-AMP (TS+A) vaccine elicited a NALT expression of IFN-γ, IL-17a and IL-4 mRNA as well as a nasal-specific production of IgA. An in vivo challenge with TS also triggered increased proliferation of lymphocytes from the NALT, sentinel cervical lymph node, and spleen. TS+A immunization increased the plasma levels of Th1/Th2/Th17 cytokines and elicited an evident cellular response by which to judge enhanced delayed-type hypersensitivity responses following a TS footpad challenge. After oral infection, TS+A-vaccinated mice showed significantly reduced parasitemia and parasite load in the heart, muscles and intestines, while markers of hepatic and muscle damage as well as clinical manifestations of acute infection were strongly diminished. TS+A also attenuated acute myocarditis and the expression of inflammatory markers in the heart. The protection conferred by TS+A extended into the chronic phase, where it resulted in a clear reduction in chronic myocarditis, fibrosis and functional electrocardiographic abnormalities, associated with a decreased expression of the pro-fibrotic TGF-β. These results revealed that it is possible to develop a mucosal vaccine against T. cruzi based on TS and c-di-AMP that is capable of reducing the development of Chagas cardiomyopathy, the hallmark of Chagas disease.
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