Periodic Reporting for period 3 - CRUZIVAX (Vaccine for prevention and treatment of Trypanosoma cruzi infection)
Reporting period: 2023-03-01 to 2025-02-28
Chagas is a neglected disease caused by Trypanosoma cruzi with a huge social and financial impact. It is endemic in 21 Latin-American countries (>7,000,000 chronic infections) and became a worldwide concern due to migration in 19 nonendemic areas (>1.3 million carriers in EU/USA). Available drugs are only active in the early but primarily asymptomatic phase of infection, with 30-40% of patients progressing to chronic disease. There are no vaccines or effective treatments for chronic disease.
The main goal of CRUZIVAX was to develop and validate a novel intranasal needle-free vaccine against T. cruzi infection based on the trimeric synthetic antigen Traspain adjuvanted with c-di-AMP (CDA) as a prophylactic and/or therapeutic vaccine.
This goal was pursued by the following objectives:
(i) Determine the best formulation and vaccination strategy by evaluating immunogenicity and efficacy in prophylactic and therapeutic settings in three different animal species, which was achieved.
(ii) Establish the production processes to manufacture antigen and adjuvant. The production processes were established, but only the adjuvant was produced at GMP-grade.
(iii) Perform a pivotal GLP toxicology study, which was achieved showing vaccine safety.
(iv) Perform first in human studies. This was hindered by a production bottleneck, but crucial advances toward this end were achieved.
(v) Estimate the potential demand for the vaccine and the benefits associated with future implementation in endemic and non-endemic areas, which was achieved.
The main goal of CRUZIVAX was to develop and validate a novel intranasal needle-free vaccine against T. cruzi infection based on the trimeric synthetic antigen Traspain adjuvanted with c-di-AMP (CDA) as a prophylactic and/or therapeutic vaccine.
This goal was pursued by the following objectives:
(i) Determine the best formulation and vaccination strategy by evaluating immunogenicity and efficacy in prophylactic and therapeutic settings in three different animal species, which was achieved.
(ii) Establish the production processes to manufacture antigen and adjuvant. The production processes were established, but only the adjuvant was produced at GMP-grade.
(iii) Perform a pivotal GLP toxicology study, which was achieved showing vaccine safety.
(iv) Perform first in human studies. This was hindered by a production bottleneck, but crucial advances toward this end were achieved.
(v) Estimate the potential demand for the vaccine and the benefits associated with future implementation in endemic and non-endemic areas, which was achieved.
Preclinical studies performed in mice, dogs and non-human primates (NHP) showed that vaccination was safe and stimulated strong immune responses in animals of different sexes and ages. Vaccinated animals were protected against a lethal challenge with a highly virulent T. cruzi strain. The vaccine also prevented chronic phase-associated damage in a sub-lethal early chronicity model. Vaccinated animals showed less tissue damage and electrocardiogram (ECG) abnormalities, and reduced parasite burden. Experiments addressing the potential of the vaccine in therapeutic setting alone and in combination with an antiparasitic drug confirmed the beneficial effects resulting from administering the novel combination therapy. Treated animals showed i) less alterations in the ECG, normal levels of enzymes indicating myocardium damage, less inflammation and fibrosis in skeletal and/or heart muscle; and ii) improved vaccine-specific immune responses. The acute and chronic infection models established in NHPs are also invaluable tools for evaluating future vaccines and therapies. Finally, the pivotal toxicology study conducted in rabbits showed no alterations in all tested parameters, thereby demonstrating vaccine non-clinical safety and paving the road towards clinical development.
From a manufacturing perspective, the optimization of a CDA cost-efficient enzymatic synthesis production process in large quantities (up to 5 million doses per batch) marks a critical step toward vaccine accessibility and commercial viability. Although some hurdles still need to be addressed for large scale clinical-grade Traspain antigen production, foundational work was laid for process optimization. The submission of a patent for an improved derivative of Traspain further strengthens the project's innovation and protects future commercial applications. Complementing this, the trademark “CRUZIVAX” was secured in major jurisdictions, reinforcing strategic positioning for future deployment.
Experiments also quantified the importance that patients living in endemic and non-endemic areas, and communities living in endemic areas attribute to the selected vaccine characteristics. Further, it was found that Chagas disease significantly reduces Health-Related Quality of Life, and that the long-term costs associated with the management of Chagas disease is a non-negligible resource burden. On the policy front, CRUZIVAX proactively engaged with national and regional stakeholders, held consultations with international bodies, and was presented in global forums, spearheading also discussions on cost-effective and innovative combination therapies for Chagas. A policy brief targeting non-research audiences is also being prepared to disseminate the project's health-economic implications and inform public health planning.
From a manufacturing perspective, the optimization of a CDA cost-efficient enzymatic synthesis production process in large quantities (up to 5 million doses per batch) marks a critical step toward vaccine accessibility and commercial viability. Although some hurdles still need to be addressed for large scale clinical-grade Traspain antigen production, foundational work was laid for process optimization. The submission of a patent for an improved derivative of Traspain further strengthens the project's innovation and protects future commercial applications. Complementing this, the trademark “CRUZIVAX” was secured in major jurisdictions, reinforcing strategic positioning for future deployment.
Experiments also quantified the importance that patients living in endemic and non-endemic areas, and communities living in endemic areas attribute to the selected vaccine characteristics. Further, it was found that Chagas disease significantly reduces Health-Related Quality of Life, and that the long-term costs associated with the management of Chagas disease is a non-negligible resource burden. On the policy front, CRUZIVAX proactively engaged with national and regional stakeholders, held consultations with international bodies, and was presented in global forums, spearheading also discussions on cost-effective and innovative combination therapies for Chagas. A policy brief targeting non-research audiences is also being prepared to disseminate the project's health-economic implications and inform public health planning.
CRUZIVAX optimized vaccine formulations and an immunization scheme, and performed seminal work showing vaccine immunogenicity, safety and efficacy in three animal species. These studies validated the vaccine’s dual utility in prophylactic and therapeutic settings, preventing disease and improving treatment outcomes by reducing cardiac damage and enhancing immune responses. This represents a significant advancement in vaccine strategies for chronic Chagas disease, a domain historically marked by limited innovation. CRUZIVAX also established and validated T. cruzi infection models in NHPs, invaluable tools for evaluating future vaccines and therapies. Cost-efficient manufacturing processes, intellectual property rights, trade secrets and trademarks were generated, as a cornerstone toward vaccine commercial viability. CRUZIVAX also generated knowledge on key health economics parameters crucial for field implementation of Chagas vaccines, and engaged with national and regional stakeholders. Thus, CRUZIVAX catalyzed a multi-dimensional impact by generating actionable scientific data, advancing preclinical vaccine development, enabling regulatory and manufacturing preparedness, and fostering dialogue with policymakers. The groundwork laid by CRUZIVAX positions the vaccine as a strong prophylactic and therapeutic candidate in the development pipeline, and offers valuable tools and knowledge to the broader Chagas disease community. The fulfillment of this potential will result in a great impact in the quality of life, morbidity, disability and associated health care costs.