Safety and immunogenicity of a recombinant vaccine against Trypanosoma cruzi in Rhesus macaques

Dumonteil, Eric; Herrera, Claudia; Tu, Weihong; Goff, Kelly; Fahlberg, Marissa; Haupt, Erin; Kaur, Amitinder; Marx, Preston A.; Ortega‐López, Jaime; Hotez, Peter J.; Bottazzi, María Elena

doi:10.1016/j.vaccine.2020.05.010

Cited by 24 publications

(29 citation statements)

References 34 publications

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“…The search for a vaccine against T. cruzi started in 1912 when it was observed that animals surviving acute infection became resistant to a second infection. [60] Since then, a variety of experimental vaccine candidates have been tested, involving live, killed, or attenuated parasites, recombinant T. cruzi proteins, peptides, and DNA [11,[61][62][63][64][65][66][67]. Both the acute and chronic stages of Chagas disease can be reflected in several experimental animal models, [68][69][70] most examples using the Colombian (TcI) and Y (TcII) strains of T. cruzi [71].…”

Section: Discussionmentioning

confidence: 99%

α-Gal immunization positively impacts Trypanosoma cruzi colonization of heart tissue in a mouse model

et al. 2021

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Chagas disease, caused by the parasite Trypanosoma cruzi, is considered endemic in more than 20 countries but lacks both an approved vaccine and limited treatment for its chronic stage. Chronic infection is most harmful to human health because of long-term parasitic infection of the heart. Here we show that immunization with a virus-like particle vaccine displaying a high density of the immunogenic α-Gal trisaccharide (Qβ-αGal) induced several beneficial effects concerning acute and chronic T. cruzi infection in α1,3-galactosyltransferase knockout mice. Approximately 60% of these animals were protected from initial infection with high parasite loads. Vaccinated animals also produced high anti-αGal IgG antibody titers, improved IFN-γ and IL-12 cytokine production, and controlled parasitemia in the acute phase at 8 days post-infection (dpi) for the Y strain and 22 dpi for the Colombian strain. In the chronic stage of infection (36 and 190 dpi, respectively), all of the vaccinated group survived, showing significantly decreased heart inflammation and clearance of amastigote nests from the heart tissue.

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Section: Discussionmentioning

confidence: 99%

α-Gal immunization positively impacts Trypanosoma cruzi colonization of heart tissue in a mouse model

et al. 2021

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“…Previous studies have demonstrated the ability of E6020 alone or formulated together with T cruzi recombinant antigens, including Tc24‐C4 and TSA‐1, in a squalene emulsion to decrease cardiac parasite burdens and increase survival of BALB/c mice with acute T cruzi infection 24,31,32 . Additional studies have confirmed the immunogenicity of T cruzi vaccines formulated with E6020 in Rhesus macaques 41 . However, little is known about the dose‐ranging effect of this TLR‐4 agonist and its ability to confer protection against cardiac damage.…”

Section: Introductionmentioning

confidence: 90%

“…24,31,32 Additional studies have confirmed the immunogenicity of T cruzi vaccines formulated with E6020 in Rhesus macaques. 41 However, little is known about the dose-ranging effect of this TLR-4 agonist and its ability to confer protection against cardiac damage. Such information would be useful in designing downstream vaccine and immunotherapy strategies.…”

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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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“…More recent studies have detected a recall cellular response by Tc24 and TSA1 vaccine antigens in Chagasic patients, indicating that they are processed during natural infection, supporting the potential use of these antigens in humans [ 92 ]. Furthermore, the first evaluation of this vaccine candidate in non-human primates indicated that it is safe, with no hepatic or renal alterations, and immunogenic, with humoral and cellular responses [ 93 ]. Thus, these encouraging results should spur additional studies to expand the work on murine models, and pave the way to clinical trials.…”

Section: Challenges and The Way Forwardmentioning

confidence: 99%

The Case for the Development of a Chagas Disease Vaccine: Why? How? When?

Dumonteil

Herrera

2021

TropicalMed

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Chagas disease is a major neglected tropical disease, transmitted predominantly by triatomine insect vectors, but also through congenital and oral routes. While endemic in the Americas, it has turned into a global disease. Because of the current drug treatment limitations, a vaccine would represent a major advancement for better control of the disease. Here, we review some of the rationale, advances, and challenges for the ongoing development of a vaccine against Chagas disease. Recent pre-clinical studies in murine models have further expanded (i) the range of vaccine platforms and formulations tested; (ii) our understanding of the immune correlates for protection; and (iii) the extent of vaccine effects on cardiac function, beyond survival and parasite burden. We further discuss outstanding issues and opportunities to move Chagas disease development forward in the near future.

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Safety and immunogenicity of a recombinant vaccine against Trypanosoma cruzi in Rhesus macaques

Cited by 24 publications

References 34 publications

α-Gal immunization positively impacts Trypanosoma cruzi colonization of heart tissue in a mouse model

α-Gal immunization positively impacts Trypanosoma cruzi colonization of heart tissue in a mouse model

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

The Case for the Development of a Chagas Disease Vaccine: Why? How? When?

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