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Vaccine for prevention and treatment of Trypanosoma cruzi infection

Periodic Reporting for period 1 - CRUZIVAX (Vaccine for prevention and treatment of Trypanosoma cruzi infection)

Reporting period: 2019-06-01 to 2021-08-31

Chagas is a neglected disease endemic in 21 Latin-American countries caused by Trypanosoma cruzi (T. cruzi). It has a strong social impact and its annual treatment costs are a high financial burden for health care systems and patients. It is the largest parasitic disease burden in the Americas (>7,000,000 chronic infections). It became a worldwide concern because of mass migration with reports in 19 non-endemic areas (>1.3 million carriers in EU/USA). The available drugs are only active in the acute but primarily asymptomatic phase of infection, with 30-40% of patients progressing to chronic disease, mainly developing cardiomyopathies. Thus, Chagas has a strong social impact and represents a major financial burden.

The strategic goal of CRUZIVAX is to develop the trimeric synthetic antigen Traspain adjuvanted with c-di-AMP (CDA) as a prophylactic needle-free intranasal vaccine against T. cruzi infection, as well as to assess its therapeutic value. The vaccine will be advanced along the development pipeline by conducting preclinical studies and a clinical phase 1 trial.

The strategic goal of CRUZIVAX will be achieved by pursing the following specific objectives:
(i) determine the best formulation and vaccination strategy by evaluating the immunogenicity and efficacy in prophylactic and therapeutic settings in three different animal models,
(ii) establish the production processes to manufacture GMP-grade antigen and adjuvant,
(iii) perform the pivotal GLP toxicology study of the vaccine,
(iv) assess the safety and immunogenicity of the vaccine in a phase 1 clinical trial, and
(v) estimate the potential demand for the vaccine and the benefits associated with future implementation in terms of quality of life.
Intranasal (i.n.) immunization of mice using Traspain co-administered with CDA was well-tolerated and stimulated strong humoral and cellular immune responses. CDA resulted in a Th1-dominated immune response and induction of IL-10 producing cells, which are needed to efficiently combat T. cruzi infection and prevent tissue damage. The experiments demonstrated the need for adjuvantation and the superiority of the i.n. route for optimal cellular responses. Preliminary results showed that the selected best formulations conferred protection against a lethal T. cruzi challenge (WP1). Experiments to evaluate the therapeutic efficacy of the vaccine have just begun (WP2).

A dose-finding pilot study in dogs showed that the vaccine triggers humoral and cellular responses when administered by parenteral or intranasal route. For the main studies in dogs, animals immunized three times by i.n. route were physically well, and no cardiac, hematological or biochemical alterations were observed. Processing of samples for characterization of immune responses is ongoing. (WP3 & 4).

A pilot study is underway in non-human primates (NHP) to select the best formulation/scheme. To test vaccine efficacy, we established an infection model in macaques by comparing 2 T. cruzi strains, which will be now further refined (WP5).

For the safety assessment, a preliminary immunogenicity study in NZW rabbits is being conducted. After confirmation of suitable immune responses, the pivotal toxicity study will be carried out (WP10).

The upstream and downstream processing for producing research-grade Traspain to conduct preclinical experiments in mice were developed. Standard operating procedures for Western blot and SDS-PAGE were developed for identifying Traspain and determining its purity during manufacturing (WP7). For GLP and GMP production of Traspain, the critical and non-critical batch release assays defined in the analytical development plan were implemented. The master cell bank for Traspain production was also generated under GMP conditions. GLP-grade Traspain was produced in sufficient quantity and quality for preclinical studies in dogs and NHP (WP7). With respect to CDA, the production processes were optimized and several batches of GMP-compliant CDA were produced for use in preclinical work (WP7). A newly developed HPLC assay for CDA determination was validated (WP9).

A scientific advice meeting at the regulatory authority has been conducted in a very early project stage to address questions regarding the development strategy for GMP-compliant product and the intended non-clinical development program (WP11).

The potential demand for a vaccine is being estimated by discrete choice experiments among Chagas disease patients in Barcelona (a non-endemic area) and in Argentina (a T. cruzi endemic area), together with recording of information pertaining to health-related quality of life. To this end, study protocols, questionnaires, databases and tablets for electronic data collection were setup, interviewers were trained and pilot studies were carried out. We have finalized data collection in Spain and we are already mid-way in Argentina. Meanwhile, we have set-up the database for data collection among policy makers (Spain and Argentina) (WP14). For determining the potential supply of the vaccine, we have started gathering data on use of healthcare resources and cost of healthcare interventions (WP15).
CRUZIVAX will validate for the first time the safety and immunogenicity of a vaccine against Chagas disease in humans. The results obtained in preclinical models suggest that CRUZIVAX’s vaccine candidate is very promising for preventing T. cruzi infection. Furthermore, the design of the Traspain antigen and preliminary preclinical data suggest that CRUZIVAX’s vaccine could be also implemented as a therapeutic vaccine in combination with anti-parasitic drugs. Thus, CRUZIVAX can provide a significant contribution towards increasing treatment options and vaccines against a major neglected infectious disease in 21 Latin American countries that is rapidly spreading worldwide. CRUZIVAX’s comprehensive immune monitoring data obtained in preclinical studies and the clinical trial will also contribute towards the identification of biomarkers and correlates of protection, which can facilitate the development of diagnostics for stratification and follow-up of vaccines or patients.

The development of a prophylactic or therapeutic vaccine against Chagas disease will have a great impact upon the quality of life, resulting in reduced mortality, human suffering and disability, and associated care costs. Implementation as a therapeutic vaccine will also contribute to optimize established medical treatments (i.e. anti-parasitic drugs) by increasing efficacy, reducing length of treatment and decreasing adverse events, as well as health-care costs. The cost-efficient GMP manufacturing of the Traspain, due to its trivalent nature, together with the easy administration logistic (i.e. needle-free) will also facilitate implementation and uptake by health systems with limited resources in the endemic areas.