Economic value of a therapeutic Chagas vaccine for indeterminate and Chagasic cardiomyopathy patients

Bartsch, Sarah M.; Bottazzi, María Elena; Asti, Lindsey; Strych, Ulrich; Meymandi, Sheba; Falcón-Lezama, Jorge Abelardo; Randall, Samuel; Hotez, Peter J.; Lee, Bruce Y.

doi:10.1016/j.vaccine.2019.05.028

Cited by 12 publications

(11 citation statements)

References 43 publications

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“…Therapeutic vaccines for indeterminate and chronic Chagas disease not only would provide health benefits but also result in economic benefits ( 15 ). Hence, millions of people are waiting for a development of anti- T. cruzi vaccines for prophylactic and therapeutic purposes to stop Chagas disease progression.…”

Section: Discussionmentioning

confidence: 99%

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Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

et al. 2020

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Chagas disease caused by the protozoan parasite Trypanosoma cruzi is endemic in 21 Latin American countries and the southern United States and now is spreading into several other countries due to migration. Despite the efforts to control the vector throughout the Americas, currently, there are almost seven million infected people worldwide, causing ~10,000 deaths per year, and 70 million people at risk to acquire the infection. Chagas disease treatment is restricted only to two parasiticidal drugs, benznidazole and nifurtimox, which are effective during the acute and early infections but have not been found to be as effective in chronic infection. No prophylactic or therapeutic vaccine for human use has been communicated at this moment. Here, we evaluate in a mouse model a therapeutic DNA vaccine combining Cruzipain (Cz), a T. cruzi cysteine protease that proved to be protective in several settings, and Chagasin (Chg), which is the natural Cz inhibitor. The DNAs of both antigens, as well as a plasmid encoding GM-CSF as adjuvant, were orally administrated and delivered by an attenuated Salmonella strain to treat mice during the acute phase of T. cruzi infection. The bicomponent vaccine based on Salmonella carrying Cz and Chg (SChg+SCz) was able to improve the protection obtained by each antigen as monocomponent therapeutic vaccine and significantly increased the titers of antigen- and parasite-specific antibodies. More importantly, the bicomponent vaccine triggered a robust cellular response with interferon gamma (IFN-γ) secretion that rapidly reduced the parasitemia during the acute phase and decreased the tissue damage in the chronic stage of the infection, suggesting it could be an effective tool to ameliorate the pathology associated to Chagas disease.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, they have severe adverse effects, causing up to 40% of dropout of the treatment and resistance issues being described ( 12 , 13 ). In this context, safer and more effective drugs or therapeutic vaccines are urgently needed ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

et al. 2020

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“…The Latin American region bears most of the burden of Chagas disease, accounting for at least 206,000[ 2 ] to 662,000 DALYs lost[ 4 ]. A study investigating the economic value of a therapeutic Chagas vaccine found that when administering standard of care benznidazole (BZN) to 1000 indeterminate patients, 148 discontinued treatment and 219 progressed to chronic disease, resulting in 119 Chagas-related deaths and 2293 DALYs, costing $18.9 million in lifetime societal costs[ 5 ]. Population migration dynamics combined with the increased risk of mothers infecting their unborn children and the increased risk of infection from blood or solid‐organ donations, means that CD has become a global problem[ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Fixed vs adjusted-dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: A systematic review and meta-analysis

Ciapponi

Barreira²,

Perelli

et al. 2020

PLoS Negl Trop Dis

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Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T . cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T . cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T . cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite‐related outcomes and efficacy or patient‐related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I 2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.

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“…The limited drug efficacy, together with the toxicity and lack of biomarkers to evaluate treatment efficacy, lead to healthcare providers and governments to neglect patients with CD 17 . In addition, as yet there is no vaccine available for the prevention or treatment of CD, 18 we have proposed the development of a therapeutic vaccine to target patients in asymptomatic chronic infection 19,20 …”

Section: Introductionmentioning

confidence: 99%

“…17 In addition, as yet there is no vaccine available for the prevention or treatment of CD, 18 we have proposed the development of a therapeutic vaccine to target patients in asymptomatic chronic infection. 19,20 Immunity against T cruzi requires the activation of both cellular and humoural immune response. CD4+Th1 cells producing IFN-γ activate macrophages and CD8 cytotoxic cells.…”

mentioning

confidence: 99%

TLR4 agonist protects against Trypanosoma cruzi acute lethal infection by decreasing cardiac parasite burdens

Villanueva‐Lizama

Cruz-Chan

Versteeg

et al. 2020

Parasite Immunology

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E6020 is a synthetic agonist of Toll‐like receptor‐4 (TLR4). The purpose of this study was to evaluate the effect of different doses of E6020‐SE on Trypanosoma cruzi‐specific immune responses and its ability to confer protection against acute lethal infection in mice. Forty female BALB/c were infected with 500 trypomastigotes of T cruzi H1 strain, divided into four groups (n = 10) and treated at 7‐ and 14‐day post‐infection (dpi) with different doses of E6020‐SE or PBS (control). Survival was followed for 51 days, mice were euthanized and hearts were collected to evaluate parasite burden, inflammation and fibrosis. We found significantly higher survival and lower parasite burdens in mice injected with E6020‐SE at all doses compared to the control group. However, E6020‐SE treatment did not significantly reduce cardiac inflammation or fibrosis. On the other hand, E6020‐SE modulated Th1 and Th2 cytokines, decreasing IFN‐γ and IL‐4 in a dose‐dependent manner after stimulation with parasite antigens. We conclude that E6020‐SE alone increased survival by decreasing cardiac parasite burdens in BALB/c mice acutely infected with T cruzi but failed to prevent cardiac damage. Our results suggest that for optimal protection, a vaccine antigen is necessary to balance and orient a protective immune response.

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Economic value of a therapeutic Chagas vaccine for indeterminate and Chagasic cardiomyopathy patients

Cited by 12 publications

References 43 publications

Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi

Fixed vs adjusted-dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: A systematic review and meta-analysis

TLR4 agonist protects against Trypanosoma cruzi acute lethal infection by decreasing cardiac parasite burdens

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