Accelerating the Development of a Therapeutic Vaccine for Human Chagas Disease

Rationale and Prospects

Eric Dumonteil; Maria Elena Bottazzi; Bin Zhan; Michael J Heffernan; Kathryn Jones; Jesus G Valenzuela; Shaden Kamhawi; Jaime Ortega; Samuel Ponce de Leon Rosales; Bruce Y Lee; Kristina M Bacon; Bernhard Fleischer; BT Slingsby; Miguel Betancourt Cravioto; Roberto Tapia-Conyer; Peter J Hotez

Disclosures

Expert Rev Vaccines. 2012;11(9):1043-1055.

Comparative Advantage of a Chagas Vaccine

An alternative approach for developing and testing new small molecular drug targets and candidates would be to develop and test a therapeutic vaccine, which could be administered as an immunotherapy either to individuals with chronic Chagas disease or those with indeterminate status who may go on to develop cardiomyopathy. The advantages of a therapeutic Chagas disease vaccine compared with benznidazole alone (the current major competing product in clinical use) could include the following:

Reductions in toxicities, thereby allowing its expanded use in indeterminate and determinate patients;
Higher efficacies at preventing cardiac complications;
Higher rates of seroreversion to T. cruzi antigens not contained in the vaccine;
Potential use in pregnancy to prevent congenital Chagas disease.

An effective therapeutic vaccine for human Chagas disease could prevent cardiac complications among the estimated 40,000 new cases of Chagas disease that occur in Latin America annually,^[22] avert over 600,000 DALYs annually that result from cardiomyopathy and gastrointestinal disease,^[1] and prevent 10,000 deaths or more annually (Box 1).^[22]

Three recent comprehensive reviews have summarized work on the development of a Chagas vaccine, with an emphasis on the development of a preventive vaccine.^[34–36] Here the authors summarize recent efforts by a product development partnership (DP) to begin the development of a new therapeutic vaccine, with an emphasis on its development in Mexico and its use for Latin America and elsewhere.

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Abstract
Disease Burden
Disease Progression
Current Gaps in Treatment
Comparative Advantage of a Chagas Vaccine
Global Access: Economics & Cost–Effectiveness
Target Product Profile
Proposed First-generation Therapeutic Chagas Disease Vaccine
Product Development of the Vaccine
Preclinical & Clinical Development of the Vaccine
Expert Commentary
Five-year View
References
Sidebar

Table 1. Chagas vaccine initiative: proposed target product profile.
Item	Desired target	Minimally acceptable target
Indication	A therapeutic vaccine to prevent the onset of Chagasic cardiomyopathy in patients with indeterminate Chagas disease (as determined by antibody seropositivity using a licensed diagnostic kit) or in determinate patients with early-stage evidence of clinical Chagas disease (as determined by antibody seropositivity, together with cardiac clinical manifestations; i.e., ECG or echocardiographic alterations)	A therapeutic vaccine to delay the onset of Chagasic cardiomyopathy in patients with indeterminate Chagas disease (as determined by antibody seropositivity using a licensed diagnostic kit) or in determinate patients with early-stage evidence of clinical Chagas disease (as determined by antibody seropositivity, together with cardiac clinical manifestations; i.e., ECG or echocardiographic alterations)
Target population	Children (>2 years) and adults	Adults >16 years
Route of administration	Intramuscular injection	Intramuscular injection
Product presentation	Single-dose vials. 1.0 ml volume of delivery	Single-dose vials. 0.5 ml volume of delivery
Dosage schedule	Maximum of two immunizations regardless of age, with the second injection given 1–2 months after the first immunization	Maximum of four immunizations according to a 0, 1–2 months, 4–12 months and 5-year schedule
Warnings and precautions/pregnancy and lactation	Mild-to-moderate local injection site reactions such as erythema, edema and pain, the character, frequency and severity of which is similar to licensed recombinant protein vaccines. Less than 0.001% risk of urticaria and other systemic allergic reactions. Incidence of SAEs no more than licensed comparator vaccines	Moderate local injection site reactions such as erythema, edema and pain. Less than 0.1% risk of urticaria. Temporary cardiac inflammation (carditis) as determined by ECG changes lasting no more than 2–3 weeks following administration of any one dose. Beyond the ECG changes, the incidence of SAEs no more than licensed comparator vaccines
Expected efficacy	80% efficacy at preventing the onset of cardiac complications	80% efficacy of delaying the onset of cardiac complications by ≥10 years
Coadministration	All doses may be coadministered with currently available trypanocidal drugs, as well as heart medicines	Essential heart medicines
Shelf-life	5 years	1 year
Storage	Refrigeration between 2 and 8°C. Cannot be frozen. Can be out of refrigeration (at temperatures up to 25°C) for up to 72 h	Refrigeration between 2 and 8°C. Cannot be frozen. Temperature monitor required
Product registration and WHO prequalification	US FDA, in addition to licensure by COFEPRIS, the Mexican National Regulatory Authority. WHO prequalification of manufacturing facility at Birmex (Mexico City, Mexico)	Licensure by COFEPRIS, the Mexican National Regulatory Authority
Target price	$46, the minimal cost of treating a patient with Chagas	$200, one-fifth of the expected cost of treatment per patient per year

SAE: Serious adverse event.

Box 1. The public health impact of a Chagas disease vaccine.
An effective vaccine for Chagas disease could prevent cardiac complications among the estimated 40,000 new cases of Chagas disease that occur in Latin America annually,²² avert over 600,000 DALYs annually that result from cardiomyopathy and gastrointestinal disease,¹ and prevent 10,000 deaths or more annually.²²
DALY: Disability-adjusted life-year

Box 2. Rationale for selection of Tc24 and TSA-1 antigens.
Ability to protect BALB/c and C57BL/6 mice as a therapeutic Trypanosoma cruzivaccine Ability to protect ICR mice as a therapeutic vaccine in chronic T. cruziinfection Protection evidenced by reduced parasitemia and reduced cardiac inflammation Protection demonstrated to be antigen-specific for Tc24 and TSA-1 Protection demonstrated to depend on CD8⁺T cells and production of IFN-γ Antigens accessible to T cells and antibodies against the surface and excretory/secretory products of T. cruzi

Box 3. Activities of the Chagas vaccine initiative.
1. Scale-up process development (10–20 l scale) and formulation of the two lead candidate protein antigens Development of a process for fermentation, purification and formulation of the recombinant antigens at high yield (>200 mg/l), purity (>98%), and binding to alum (>90%) 2. Confirmatory preclinical efficacy testing for material generated during process development and re-engineering, including testing of E6020, an experimental adjuvant, and development of biomarkers Confirmation of protective immunity; independent confirmatory testing in at least two sites; and qualification of biomarkers for clinical assessment during Phase I and beyond 3. Technology transfer to Mexico Transfer of batch production records for a scaled-up process at the 60–100 l scale for the cGMP manufacture of Tc24 and TSA-1 and the Chagas disease therapeutic vaccine 4. cGMP manufacture cGMP manufacture of >1 g each of recombinant Tc24 and TSA-1 at purity >98% and formulated on alum + E6020 with >90% protein binding, passing lot release and 1-year stability testing 5. Regulatory filing with US FDA and COFEPRIS Parallel filings to perform GLP toxicology and to obtain approval for future Phase I testing 6. Clinical capacity building and site preparation for clinical testing Personnel trained, sites evaluated and selected in preparation for future clinical testing year 5 and beyond 7. Mathematical modeling and cost–effectiveness Cost–effectiveness conferred
cGMP: Current good manufacturing practice; GLP: Good laboratory practice.

Box 4. Strengths of the partnership.
Sabin Vaccine Institute is a product development program with an 11-year successful track record of partnering with developing country manufacturers and transitioning discoveries to the clinic. In preclinical testing studies conducted at Autonomous University of Yacutan (Yacutan, Mexico), proof-of-concept of protective efficacy of the two antigens when combined. As a deliverable, the advancement in development of an urgently needed new medical intervention, a therapeutic vaccine for Chagas disease, one of the most important neglected tropical diseases in the Americas and a major maternal–child health threat. High level of scientific innovation building on almost a decade of preliminary data, published in peer-reviewed journals. Capacity building with key Mexican institutions including CINVESTAV and Birmex, the public sector vaccine manufacturers in Mexico. Economic models confirming the cost–effectiveness of a therapeutic vaccine.

Authors and Disclosures

Eric Dumonteil^‡
Laboratorio de Parasitología Centro De Investigaciones Regional, "Dr. Hideo Noguchi" Autonomous University of Yucatan (UADY), Merida, Mexico

Maria Elena Bottazzi^‡
Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Departments of Pediatrics (Section of Pediatric Tropical Medicine) and Molecular Virology & Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA

Bin Zhan
Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Department of Pediatrics (Section of Pediatric Tropical Medicine), National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA

Michael J Heffernan
Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Department of Pediatrics (Section of Pediatric Tropical Medicine), National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA

Kathryn Jones
Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Departments of Pediatrics (Section of Pediatric Tropical Medicine) and Molecular Virology & Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA

Jesus G Valenzuela
Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

Shaden Kamhawi
Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

Jaime Ortega
Departamento de Biotecnologéa y Bioingeniería, Centro de Investigacion y de Estudios Avanzados - Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City, Mexico

Samuel Ponce de Leon Rosales
Laboratorios de Biológicos y Reactivos de México (BIRMEX), Mexico City, Mexico

Bruce Y Lee
Public Health Computational and Operations Research (PHICOR), University of Pittsburgh, Pittsburgh PA, USA

Kristina M Bacon
Public Health Computational and Operations Research (PHICOR), University of Pittsburgh, Pittsburgh PA, USA

Bernhard Fleischer
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

BT Slingsby
Eisai Co., Ltd, Tokyo, Japan

Miguel Betancourt Cravioto
Instituto Carlos Slim de la Salud (ICSS), Mexico City, Mexico

Roberto Tapia-Conyer
Instituto Carlos Slim de la Salud (ICSS), Mexico City, Mexico

Peter J Hotez*^‡
Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Departments of Pediatrics (Section of Pediatric Tropical Medicine) and Molecular Virology & Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, USA

Financial & competing interests disclosure
Michael Heffernan is a co-inventor on three patent applications pertaining to the pH-sensitive microparticles discussed in this manuscript. Several of the authors are involved in various aspects of the development and possible future manufacture of a potential vaccine currently in development against Chagas disease. The Carlos Slim Institute of Health and the Southwest Electronic Energy Medical Research Institute are providing financial support for the Chagas disease vaccine initiative. Eisai Co., Ltd is providing access to the E6020 adjuvant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

*Author for correspondence
hotez@bcm.edu

^‡Authors contributed equally to this manuscript.