Periodic Reporting for period 2 - CRUZIVAX (Vaccine for prevention and treatment of Trypanosoma cruzi infection)
Periodo di rendicontazione: 2021-09-01 al 2023-02-28
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.
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 our adjuvant c-di-AMP (CDA) was well-tolerated and stimulated strong humoral and cellular immune responses. The experiments demonstrated the need for adjuvantation and the superiority of the i.n. route for optimal cellular responses. These results provided the immunization parameters in terms of dose and scheme for the subsequent in vivo studies in the different animal species (WP1).
Efficacy experiments rendered excellent results because the two selected vaccine formulations were able to confer protection against a lethal challenge with a highly virulent T. cruzi strain. This prophylactic vaccine was also able to prevent chronic phase-associated damage (WP1). Furthermore, we are conducting additional experiments addressing the potential of the vaccine in a therapeutic setting (WP2).
A dose-finding pilot study was carried out in dogs to establish the framework for the main dog study. The results demonstrated that CDA in combination with Traspain elicits humoral and cellular responses when administered by parenteral or intranasal route. In the subsequent main study in dogs, intranasal vaccination with Traspain+CDA conferred protection against T. cruzi challenge. Vaccination induced a specific humoral immune response and an antigen-specific cellular immune response. After the challenge, vaccinated dogs showed normal physical examination and ECG readings and the clinicopathological parameters were within normal values (WP3).
In NHP, a preliminary vaccine immunogenicity study revealed induction of a humoral and cellular response in 100% of animals immunized intramuscularly and 50% of the animals immunized intranasally at a high dose. This highlighted the interest of pursuing both intramuscular and intranasal routes as options for the prophylactic vaccination studies in NHP, and the possibility of increasing vaccine response with higher vaccine dosages. A larger experiment is being conducted to test the immunogenicity and efficacy of the prophylactic vaccine (WP5).
For the safety assessment of the vaccine formulation, preliminary immunogenicity studies were conducted in rats and New Zealand White rabbits. The IgG titers confirmed the rabbit as a relevant species for the toxicity study. A bio-distribution study was carried out in mice after a single intranasal administration of CDA with and without Traspain. The analysis of samples is in progress (WP10).
The upstream and downstream processing for producing Traspain were developed. Traspain was produced for the preclinical studies in mice, dogs, rabbits, rats and a pilot study in NHP. Additional batches are being produced for the pivotal NHP study and toxicity study (WP7). For the adjuvant CDA, the production processes were optimized and several batches of GMP-compliant CDA were produced (WP7).
A scientific advice meeting at the regulatory authority has already been conducted to address questions regarding the development strategy for GMP-compliant product and the intended non-clinical development program (WP11).
The potential demand for Traspain vaccine has been estimated by discrete choice experiments (DCEs) involving Chagas disease patients and suspected positive cases in Barcelona (a non-endemic area) and in the Chaco province in Argentina (a T. cruzi endemic area) (WP14). The results were published: Ramponi F, et al., Development of vaccines for Chagas disease (CRUZIVAX): stakeholders' preferences and potential impacts on healthcare. Gac Sanit. 2022. doi: 10.1016/j.gaceta.2022.102275). Data on the long-term use of health resources by Chagas disease patients were obtained by the Hospital Clinical of Barcelona and from various sources, mainly governmental, in Argentina. Important lower-bound estimates of the costs associated with the management of Chagas disease have been produced (WP15).
Efficacy experiments rendered excellent results because the two selected vaccine formulations were able to confer protection against a lethal challenge with a highly virulent T. cruzi strain. This prophylactic vaccine was also able to prevent chronic phase-associated damage (WP1). Furthermore, we are conducting additional experiments addressing the potential of the vaccine in a therapeutic setting (WP2).
A dose-finding pilot study was carried out in dogs to establish the framework for the main dog study. The results demonstrated that CDA in combination with Traspain elicits humoral and cellular responses when administered by parenteral or intranasal route. In the subsequent main study in dogs, intranasal vaccination with Traspain+CDA conferred protection against T. cruzi challenge. Vaccination induced a specific humoral immune response and an antigen-specific cellular immune response. After the challenge, vaccinated dogs showed normal physical examination and ECG readings and the clinicopathological parameters were within normal values (WP3).
In NHP, a preliminary vaccine immunogenicity study revealed induction of a humoral and cellular response in 100% of animals immunized intramuscularly and 50% of the animals immunized intranasally at a high dose. This highlighted the interest of pursuing both intramuscular and intranasal routes as options for the prophylactic vaccination studies in NHP, and the possibility of increasing vaccine response with higher vaccine dosages. A larger experiment is being conducted to test the immunogenicity and efficacy of the prophylactic vaccine (WP5).
For the safety assessment of the vaccine formulation, preliminary immunogenicity studies were conducted in rats and New Zealand White rabbits. The IgG titers confirmed the rabbit as a relevant species for the toxicity study. A bio-distribution study was carried out in mice after a single intranasal administration of CDA with and without Traspain. The analysis of samples is in progress (WP10).
The upstream and downstream processing for producing Traspain were developed. Traspain was produced for the preclinical studies in mice, dogs, rabbits, rats and a pilot study in NHP. Additional batches are being produced for the pivotal NHP study and toxicity study (WP7). For the adjuvant CDA, the production processes were optimized and several batches of GMP-compliant CDA were produced (WP7).
A scientific advice meeting at the regulatory authority has already been conducted to address questions regarding the development strategy for GMP-compliant product and the intended non-clinical development program (WP11).
The potential demand for Traspain vaccine has been estimated by discrete choice experiments (DCEs) involving Chagas disease patients and suspected positive cases in Barcelona (a non-endemic area) and in the Chaco province in Argentina (a T. cruzi endemic area) (WP14). The results were published: Ramponi F, et al., Development of vaccines for Chagas disease (CRUZIVAX): stakeholders' preferences and potential impacts on healthcare. Gac Sanit. 2022. doi: 10.1016/j.gaceta.2022.102275). Data on the long-term use of health resources by Chagas disease patients were obtained by the Hospital Clinical of Barcelona and from various sources, mainly governmental, in Argentina. Important lower-bound estimates of the costs associated with the management of Chagas disease have been produced (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.
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.