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Review

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

by
Eric Dumonteil
* and
Claudia Herrera
Department of Tropical Medicine, Vector-Borne and Infectious Disease Research Center, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
*
Author to whom correspondence should be addressed.
Trop. Med. Infect. Dis. 2021, 6(1), 16; https://0-doi-org.brum.beds.ac.uk/10.3390/tropicalmed6010016
Submission received: 1 December 2020 / Revised: 6 January 2021 / Accepted: 19 January 2021 / Published: 26 January 2021
(This article belongs to the Special Issue Vaccines against Neglected Tropical Diseases)
Review Reports Versions Notes

Abstract

:
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.

1. Background

Chagas disease is a major neglected tropical disease, transmitted predominantly by triatomine insect vectors, but also through congenital and oral routes. It is endemic in the Americas, from southern Brazil and Chile to the US, but human migrations have turned it into a global disease with a significant number of cases in non-endemic regions such as Canada or Europe, among others [1,2]. There are at least 6 million cases in the Americas [3], but these estimates suffer from important uncertainties, as disease surveillance and reporting are highly heterogeneous among countries, and the disease burden could be higher. For example, recent estimates for Mexico, one of the most affected countries, range from less than 1 million [3] up to over 4 millions cases [4], and uncertainty is significant with potential publication bias [5].
Chagas disease control has so far relied on two main strategies—vector control and patient treatment. Vector control is mostly based on indoor spraying of residual insecticides to eliminate or at least reduce domestic triatomine populations inside dwellings, thereby reducing the incidence of new human cases. Despite some key achievements to control major vector species, and even eliminating transmission caused by Triatoma infestans and Rhodnius prolixus in some countries/regions [6,7], the continued presence of many other vector species able to transiently invade houses and maintain a low-level transmission implies a continued risk for human transmission and a challenge for effective vector control [8]. Therefore, there is growing recognition that a complete interruption of transmission to humans is not a feasible goal, and modeling suggests that vector control should be combined with other efforts to improve access to better care for patients in order to effectively reach the goals of the World Health Organization (WHO) 2020 London declaration, which call for a 100% certified interruption or control of Chagas disease [9].
The disease develops as an initial acute phase associated with a high parasitemia and non-specific signs of infection. Next, patients enter a chronic phase that is initially asymptomatic, with an apparent control of the parasitemia. However, 20−40% of patients will slowly develop clinical manifestations many years after the initial infection, the most common of which is chronic Chagasic cardiomyopathy (CCC). CCC is characterized by arrhythmias of increasing severity, leading to cardiac failure and death [1,10,11]. Other clinical manifestations include megaesophagus and megacolon, affecting about 10% of patients. The treatment of infected patients with trypanocidal drugs is being promoted to reduce morbidity and mortality associated with Chagas disease [10]. Benznidazole and nifurtimox are the two drugs of choice, and a 60-day treatment regimen is required for benznidazole, while a 60–90-day treatment regimen is required for nifurtimox. Such prolonged treatment courses present a logistic and economic burden in vulnerable populations where healthcare is limited. Both drugs are also associated with side effects that can be very severe, leading to frequent treatment interruptions [12,13]. Treatment is contraindicated in pregnancy and for patients with kidney or liver disease. Furthermore, treatment efficacy is questionable in the chronic stage of the disease, as it can reduce the blood parasite load but does not improve cardiac function [14,15,16]. Indeed, almost 20% of CCC patients will die within five years following their cardiac diagnosis, despite the efficacy of the benznidazole clearance of trypanosomes in the blood [15,16]. Thus, patient care is often only palliative, and significant mortality is observed [17,18,19].

2. The rationale for a Vaccine

Based on the above, new drugs and/or alternative strategies are still needed to improve the care of Chagasic patients, and a therapeutic vaccine would represent an attractive opportunity. An initial target product profile for such a therapeutic vaccine has been proposed [20]. It aims at preventing (desired target) or at least delaying (minimally acceptable target) the progression of CCC in patients with indeterminate Chagas disease (determined by antibody seropositivity), or in patients with early-stage evidence of clinical CCC (as determined by antibody seropositivity and cardiac clinical manifestations), to be used alone or in combination with drug therapy. An economic analysis of a therapeutic vaccine alone showed that it is highly cost-effective and frequently saves costs under a wide range of efficacy conditions by delaying CCC outcomes and side effects, and is also likely to provide a positive return on investment [21]. Furthermore, its combined use with current drugs could help bridging their toxicity gap, as it may allow for reducing drug doses and the associated severe side effects without compromising treatment efficacy. Indeed, modeling studies indicated that combining a therapeutic vaccine with a reduced dose drug treatment would result in more patients completing the treatment and would prevent more deaths than drug treatment alone [22]. Vaccines are economically dominant in a wide range of conditions, even when reducing the risk of disease progression as low as 5% [22]. Thus, it is expected that such a therapeutic vaccine would complement and help overcome the shortcomings of current vector control and drug treatments.
Furthermore, this initial indication may be expanded, as multiple additional uses of a vaccine have been proposed. Its potential use as a preventative vaccine is rather obvious and is supported by multiple pre-clinical studies (see below), although there are some concerns in terms of efficacy and cost-effectiveness that need to be considered. Nonetheless, alternative uses for a preventative vaccine may be for dogs, as these are considered to be a major domestic reservoir of the parasite, and they significantly increase the risk of human infection in many countries, as well as epidemiological conditions [23,24,25]. Thus, decreasing T. cruzi infection in dogs through vaccination may help reduce parasite domestic circulation. Another potential indication of a vaccine could be the prevention of congenital transmission [26]. Indeed, parasite transmission from an infected mother to her baby occurs in about 5% of pregnancies, and parasitemia is a key risk factor for the transmission of parasites [27,28]. Observational studies suggest that infected women treated at a young age do not transmit the parasite when pregnant later in life [29,30,31,32,33], which has led to the current recommendation of treating infected women of reproductive age [30,34]. Inducing a decrease in parasitemia with a therapeutic preconceptional vaccine in these women would thus be expected to reduce congenital transmission. Again, economic modeling confirmed that even a 25% efficacious vaccine would significantly reduce the number of congenital cases and would be cost-effective [35]. In addition, it may also provide an easy endpoint for the rapid clinical evaluation of vaccine efficacy, which could help accelerate vaccine development [26]. Thus, these additional indications for a Chagas disease vaccine further strengthen the rationale for its development.

3. Current Vaccine Platforms

An extensive variety of Chagas disease vaccine platforms have been tested in animal models over the years, ranging from live attenuated vaccines, DNA, recombinant virus or bacteria, and recombinant proteins, with a diverse range of formulations and adjuvants [36,37,38]. Initial studies served as a proof-of-concept to illustrate that controlling T. cruzi infection in mouse models is possible by inducing an immune response against parasite proteins. In the past few years, studies have further expanded (i) the range of platforms and formulations tested, (ii) our understanding of the immune correlates for protection, and (iii) the extent of vaccine effects beyond survival and parasite burden (Table 1). What emerges from these studies is that a substantial decrease in parasite burden (in the blood, cardiac, and skeletal muscle tissues) and improved survival can be achieved in mice through preventative vaccination with multiple vaccine platforms. A smaller number of studies have also shown a similar effect for the therapeutic administration of a vaccine in infected mice during the acute phase, as well as during the chronic phase. These results confirmed earlier proof-of-concept studies, but because of the diversity of methods and animal models, direct comparisons of immunogenicity and efficacy are not feasible. A notable new approach targets the immune response against an immunodominant α-Gal glycotope from T. cruzi mucin surface glycoproteins, which induce high antibody levels in Chagasic patients [39].
These studies have also confirmed the central role of IFNγ and the activation of CD4+ and CD8+ T cells in mediating parasite control, and a balanced Th1/Th2 response seems to provide a better outcome compared with a hyperpolarized response (Table 1). Additional specific subpopulations of immune cells are also emerging as complementary contributors that can mediate parasite elimination, including Th17 and NK cells, as well as trypanolytic/neutralizing antibodies [53,59,60,61,65]. While the confirmation of earlier results is encouraging, a major limitation of these approaches is that they remain limited in the breadth of the immune response assessed. Therefore, more integrative approaches from system immunology, such as those used for malaria, influenza, or yellow fever vaccines [70,71,72], may help reach a more comprehensive understanding of responses to vaccines and the correlates for protection against T. cruzi.
In terms of protection/prevention of tissue damage, several of these studies have shown that vaccination can reduce cardiac damage and dysfunction, in addition to parasite burden (Table 1). This is key because, as mentioned above, these are not necessarily correlated, as drug treatment administered during the chronic stage of the disease in humans can reduce the blood parasite burden, without improving cardiac function [14,15]. Delaying damage or improving cardiac function is indeed a central goal of vaccines. For example, an adenoviral vaccine expressing ASP-2 and TS [51], a DNA vaccine encoding TcG2 and TcG4 [40,41], or a recombinant Tc24 vaccine [48] can prevent the development of fibrosis when administered as therapeutic vaccines following infection. Similarly, the preventative vaccination with recombinant Mycobacterium bovis expressing trans-sialidase and cruzipain fragments [65], or with a DNA vaccine encoding cruzipain, Tc52, and Tc24 antigens [58], can prevent fibrosis and necrosis. A few studies have also shown improvements in cardiac function in response to vaccination, as assessed by electrocardiogram (EKG) [51,66,67]. It seems particularly remarkable that the therapeutic vaccination of mice with recombinant Adenovirus encoding ASP-2 and TS antigens during the chronic phase not only delayed the progression of cardiac damage and dysfunction, but even reversed these, as assessed by the extent of fibrosis and EKG alterations [51]. Thus, cardiac damage and CCC may be at least partially reversible, which provides strong support to further explore therapeutic vaccination against T. cruzi and its effects on cardiac function.

4. Challenges and the Way Forward

While the studies presented above are highly encouraging, some gaps in knowledge remain that need to be addressed. A first major limitation is that most studies have focused on assessing short term vaccine efficacy (acute phase), which is unlikely to be of relevant clinical use, and it is unclear how these results can translate into long term efficacy. A few studies of therapeutic vaccination administered during the chronic phase do support the conclusion that some of these vaccine formulations can control the parasite and prevent cardiac damage at this stage [48,51]. Similarly, preventative vaccination may provide long-term protection against infection [73]. Nonetheless, some vaccine effects may be transients, as observed following preventative vaccination with recombinant Adenovirus and MVA vectors encoding ASP-2 and TS, which decreased the parasite burden in the short term (acute phase), but not in the long term (chronic phase)[52]. In that respect, parasite tissue distribution remains a challenge, and studies using whole-body imaging in mice to detect fluorescent/bioluminescent parasites have been very valuable to address this point [52]. Thus, while measuring parasite burden in cardiac and skeletal muscle is key for vaccine efficacy, the assessment of additional tissues and longer follow-up times will be needed for a more reliable evaluation of vaccine efficacy.
Parasite diversity represents another rarely addressed issue, although the potential lack of heterologous protection following vaccination has been demonstrated [74]. Indeed, T. cruzi presents extensive parasite diversity that is of a comparable magnitude to that observed among Leishmania species [75,76]. Thus, antigenic variation can be a significant issue for vaccine development. Epitopes from vaccine antigen TSA-1 were found to be conserved among parasite DTUs [77]. Similarly, analysis of Tc24 diversity among multiple strains from all DTUs indicated a high conservation and a strong purifying selection, which may limit antigen diversity [78]. Thus, these antigens may be effective against a wide diversity of strains, although this remains to be investigated. Nonetheless, another issue is that a large proportion of Chagasic patients harbor multiple parasite strains. This has been evidenced by changes in parasite genotypes following drug treatment, as well as direct genotyping [79,80,81]. While it is unclear if this represents sequential or simultaneous infections, interactions among parasite strains are likely to occur, as suggested by some co-infection studies in mice [82,83,84]. Further modelling suggests that co-infections in humans may result, in part, from insufficient immunity [85]. Thus, vaccine efficacy may be affected by co-infections, but this will be challenging to evaluate in a laboratory setting, given the limitations imposed by extrapolating from a necessary limited number of strain combinations. Field studies of natural infections should help assess this point.
An additional challenge is that the large majority of vaccine studies described above focus on mouse models, and the extent to which the strong vaccine immunogenicity and efficacy observed can be extrapolated to humans remains unknown. Studies in dogs have shown promise in reducing the T. cruzi parasite burden [86,87,88,89,90], but their limited scope does not provide sufficient evidence supporting vaccine efficacy to delay or prevent cardiac dysfunction. Infectiousness of dogs may nonetheless be reduced by vaccination [91]. 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.
An additional aspect to be considered for developing a Chagas disease vaccine is the potential for scaling-up GMP production and regulatory issues of potential vaccine candidates and their further evaluation in clinical trials. So far, production processes for recombinant Tc24 and TSA-1 antigens are the only ones to undergo extensive process development and quality control. Specific mutations of cysteine residues were engineered in both antigens, to increase protein stability and yield, without compromising antigenicity, and scalable fermentation and purification steps have also been optimized and may be transferred for GMP production [45,46,94,95].
An overview of the current clinical development landscape for vaccines provides further insight on the potential of different platforms for further development (Table 2). Most vaccine platforms are amendable to large scale GMP production, although live attenuated and recombinant protein production may face variable hurdles, depending on specific organisms or antigens, respectively. In the case of T. cruzi, the large-scale production, storage, and distribution of a potential live attenuated vaccine would certainly be most challenging because of the multiple constraints of cultivating a eukaryotic parasite under GMP guidelines and consistently maintaining its viability. Additional regulatory limitations may be faced for clinical trials. While multiple vaccine platforms against infectious diseases are undergoing clinical development in Phase 1 studies, only live attenuated and recombinant protein vaccines are readily progressing to Phase 2 and Phase 3 studies (Table 2). An important concern of DNA vaccines for example is their limited immunogenicity in humans, although multiple strategies are being investigated to boost their efficacy [96]. On the other hand, Adenovirus and other viral-based vaccines may face safety issues, and pre-existing immune cross-reactivity against the virus vector may interfere with vaccination [97,98]. Based on these data, a Chagas disease vaccine based on recombinant proteins may represent the quickest path toward clinical trials, and Tc24 and TSA-1 antigens are well poised for such a development.
In conclusion, recent advances have confirmed the potential of vaccines against Chagas disease and have solved some of the key challenges. A remaining challenge is the political will and investment needed to move a vaccine into clinical development for a neglected tropical disease such as Chagas disease. Indeed, despite its large health burden [99], it remains one of the most neglected of the neglected diseases, and further steps will require bold decisions from multiple stakeholders and partners to move this vaccine candidate into clinical trials [100,101,102].

Author Contributions

Conceptualization, E.D. and C.H.; writing—original draft preparation, E.D.; writing—review and editing, E.D. and C.H..; funding acquisition, E.D. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by grant #187714 from the Carlos Slim Foundation via Baylor College of Medicine, grant #632083 from Tulane University School of Public Health and Tropical Medicine.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors have no conflict of interest.

References

  1. Rassi, A., Jr.; Rassi, A.; Marin-Neto, J.A. Chagas disease. Lancet 2010, 375, 1388–1402. [Google Scholar] [CrossRef]
  2. Schmunis, G.A.; Yadon, Z.E. Chagas disease: A Latin American health problem becoming a world health problem. Acta Trop. 2010, 115, 14–21. [Google Scholar] [CrossRef] [PubMed]
  3. WHO. Chagas disease in Latin America: An epidemiological update based on 2010 estimates. Wkly. Epidemiol. Rec. 2015, 90, 33–43. [Google Scholar]
  4. Arnal, A.; Waleckx, E.; Rico-Chavez, O.; Herrera, C.; Dumonteil, E. Estimating the current burden of Chagas disease in Mexico: A systematic review and meta-analysis of epidemiological surveys from 2006 to 2017. PLoS Negl. Trop. Dis. 2019, 13, e0006859. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Buekens, P.; Lopez-Cardenas, J.; Dumonteil, E.; Padilla-Raygoza, N. Including unpublished surveys in reviews on Chagas disease in Mexico. Publ. Health Rev. 2020, 41, 24. [Google Scholar] [CrossRef] [PubMed]
  6. Schofield, C.J.; Dias, J.C. The Southern Cone Initiative against Chagas disease. Adv. Parasitol. 1999, 42, 1–27. [Google Scholar] [PubMed]
  7. Cedillos, R.A.; Romero, J.E.; Sasagawa, E. Elimination of Rhodnius prolixus in El Salvador, Central America. Mem. Inst. Oswaldo Cruz 2012, 107, 1068–1069. [Google Scholar] [CrossRef] [Green Version]
  8. Waleckx, E.; Gourbière, S.; Dumonteil, E. Intrusive triatomines and the challenge of adapting vector control practices. Mem. Inst. Oswaldo Cruz 2015, 110, 324–338. [Google Scholar] [CrossRef] [Green Version]
  9. Lee, B.Y.; Bartsch, S.M.; Skrip, L.; Hertenstein, D.L.; Avelis, C.M.; Ndeffo-Mbah, M.; Tilchin, C.; Dumonteil, E.O.; Galvani, A. Are the London Declaration’s 2020 goals sufficient to control Chagas disease?: Modeling scenarios for the Yucatan Peninsula. PLoS Negl. Trop. Dis. 2018, 12, e0006337. [Google Scholar] [CrossRef] [Green Version]
  10. Nunes, M.C.P.; Beaton, A.; Acquatella, H.; Bern, C.; Bolger, A.F.; Echeverria, L.E.; Dutra, W.O.; Gascon, J.; Morillo, C.A.; Oliveira-Filho, J.; et al. Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association. Circulation 2018, 138, e169–e209. [Google Scholar] [CrossRef]
  11. Marin-Neto, J.A.; Cunha-Neto, E.; Maciel, B.C.; Simoes, M.V. Pathogenesis of chronic Chagas heart disease. Circulation 2007, 115, 1109–1123. [Google Scholar] [CrossRef] [PubMed]
  12. Forsyth, C.J.; Hernandez, S.; Olmedo, W.; Abuhamidah, A.; Traina, M.I.; Sanchez, D.R.; Soverow, J.; Meymandi, S.K. Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States. Clin. Infect. Dis. 2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Castro, J.A.; de Mecca, M.M.; Bartel, L.C. Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis). Hum. Exp. Toxicol. 2006, 25, 471–479. [Google Scholar] [CrossRef] [PubMed]
  14. Pecoul, B.; Batista, C.; Stobbaerts, E.; Ribeiro, I.; Vilasanjuan, R.; Gascon, J.; Pinazo, M.J.; Moriana, S.; Gold, S.; Pereiro, A.; et al. The BENEFIT Trial: Where Do We Go from Here? PLoS Negl. Trop. Dis. 2016, 10, e0004343. [Google Scholar] [CrossRef] [PubMed]
  15. Rassi, A., Jr.; Marin, J.A.N.; Rassi, A. Chronic Chagas cardiomyopathy: A review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial. Mem. Inst. Oswaldo Cruz 2017, 112, 224–235. [Google Scholar] [CrossRef] [PubMed]
  16. Morillo, C.A.; Marin-Neto, J.A.; Avezum, A.; Sosa-Estani, S.; Rassi, A., Jr.; Rosas, F.; Villena, E.; Quiroz, R.; Bonilla, R.; Britto, C.; et al. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. New Engl. J. Med. 2015, 373, 1295–1306. [Google Scholar] [CrossRef] [Green Version]
  17. Cucunuba, Z.M.; Okuwoga, O.; Basanez, M.G.; Nouvellet, P. Increased mortality attributed to Chagas disease: A systematic review and meta-analysis. Parasites Vectors 2016, 9, 42. [Google Scholar] [CrossRef] [Green Version]
  18. Nadruz, W., Jr.; Gioli-Pereira, L.; Bernardez-Pereira, S.; Marcondes-Braga, F.G.; Fernandes-Silva, M.M.; Silvestre, O.M.; Sposito, A.C.; Ribeiro, A.L.; Bacal, F.; Fernandes, F.; et al. Temporal trends in the contribution of Chagas cardiomyopathy to mortality among patients with heart failure. Heart 2018, 104, 1522–1528. [Google Scholar] [CrossRef]
  19. Rassi, A., Jr.; Rassi, A.; Rassi, S.G. Predictors of mortality in chronic Chagas disease: A systematic review of observational studies. Circulation 2007, 115, 1101–1108. [Google Scholar]
  20. Dumonteil, E.; Bottazzi, M.E.; Zhan, B.; Heffernan, M.J.; Jones, K.; Valenzuela, J.G.; Kamhawi, S.; Ortega, J.; Rosales, S.P.; Lee, B.Y.; et al. Accelerating the development of a therapeutic vaccine for human Chagas disease: Rationale and prospects. Expert Rev. Vaccines 2012, 11, 1043–1055. [Google Scholar] [CrossRef] [Green Version]
  21. Lee, B.Y.; Bacon, K.M.; Wateska, A.R.; Bottazzi, M.E.; Dumonteil, E.; Hotez, P.J. Modeling the Economic Value of a Chagas’ Disease Therapeutic Vaccine. Hum. Vaccines Immunother. 2012, 8, 1293–1301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Bartsch, S.M.; Bottazzi, M.E.; Asti, L.; Strych, U.; Meymandi, S.; Falcon-Lezama, J.A.; Randall, S.; Hotez, P.J.; Lee, B.Y. Economic value of a therapeutic Chagas vaccine for indeterminate and Chagasic cardiomyopathy patients. Vaccine 2019, 37, 3704–3714. [Google Scholar] [CrossRef] [PubMed]
  23. Mott, K.E.; Mota, E.A.; Sherlock, I.; Hoff, R.; Muniz, T.M.; Oliveira, T.S.; Draper, C.C. Trypanosoma cruzi infection in dogs and cats and household seroreactivity to T. cruzi in a rural community in northeast Brazil. Am. J. Trop. Med. Hyg. 1978, 27, 1123–1127. [Google Scholar] [CrossRef] [PubMed]
  24. Tenney, T.D.; Curtis-Robles, R.; Snowden, K.F.; Hamer, S.A. Shelter dogs as sentinels for Trypanosoma cruzi transmission across Texas. Emerg. Infect. Dis. 2014, 20, 1323–1326. [Google Scholar] [CrossRef]
  25. Gurtler, R.E.; Cecere, M.C.; Lauricella, M.A.; Cardinal, M.V.; Kitron, U.; Cohen, J.E. Domestic dogs and cats as sources of Trypanosoma cruzi infection in rural northwestern Argentina. Parasitology 2007, 134, 69–82. [Google Scholar] [CrossRef] [Green Version]
  26. Dumonteil, E.; Herrera, C.; Buekens, P. A therapeutic preconceptional vaccine against Chagas disease: A novel indication that could reduce congenital transmission and accelerate vaccine development. PLoS Negl. Trop. Dis. 2019, 13, e0006985. [Google Scholar] [CrossRef] [Green Version]
  27. Carlier, Y.; Sosa-Estani, S.; Luquetti, A.O.; Buekens, P. Congenital Chagas disease: An update. Mem. Inst. Oswaldo Cruz 2015, 110, 363–368. [Google Scholar] [CrossRef] [Green Version]
  28. Howard, E.J.; Xiong, X.; Carlier, Y.; Sosa-Estani, S.; Buekens, P. Frequency of the congenital transmission of Trypanosoma cruzi: A systematic review and meta-analysis. BJOG 2014, 121, 22–33. [Google Scholar] [CrossRef] [Green Version]
  29. Fabbro, D.L.; Danesi, E.; Olivera, V.; Codebo, M.O.; Denner, S.; Heredia, C.; Streiger, M.; Sosa-Estani, S. Trypanocide treatment of women infected with Trypanosoma cruzi and its effect on preventing congenital Chagas. PLoS Negl. Trop. Dis. 2014, 8, e3312. [Google Scholar] [CrossRef] [Green Version]
  30. Sosa-Estani, S.; Cura, E.; Velazquez, E.; Yampotis, C.; Segura, E.L. Etiological treatment of young women infected with Trypanosoma cruzi, and prevention of congenital transmission. Rev. Soc. Bras. Med. Trop. 2009, 42, 484–487. [Google Scholar] [CrossRef] [Green Version]
  31. Moscatelli, G.; Moroni, S.; Garcia-Bournissen, F.; Ballering, G.; Bisio, M.; Freilij, H.; Altcheh, J. Prevention of congenital Chagas through treatment of girls and women of childbearing age. Mem. Inst. Oswaldo Cruz 2015, 110, 507–509. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Murcia, L.; Simon, M.; Carrilero, B.; Roig, M.; Segovia, M. Treatment of Infected Women of Childbearing Age Prevents Congenital Trypanosoma cruzi Infection by Eliminating the Parasitemia Detected by PCR. J. Infect. Dis. 2017, 215, 1452–1458. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Alvarez, M.G.; Vigliano, C.; Lococo, B.; Bertocchi, G.; Viotti, R. Prevention of congenital Chagas disease by Benznidazole treatment in reproductive-age women. An observational study. Acta Trop. 2017, 174, 149–152. [Google Scholar] [CrossRef] [PubMed]
  34. Bern, C.; Montgomery, S.P.; Herwaldt, B.L.; Rassi, A., Jr.; Marin-Neto, J.A.; Dantas, R.O.; Maguire, J.H.; Acquatella, H.; Morillo, C.; Kirchhoff, L.V.; et al. Evaluation and treatment of chagas disease in the United States: A systematic review. JAMA 2007, 298, 2171–2181. [Google Scholar] [CrossRef] [Green Version]
  35. Bartsch, S.M.; Stokes-Cawley, O.J.; Buekens, P.; Asti, L.; Bottazzi, M.E.; Strych, U.; Wedlock, P.T.; Mitgang, E.A.; Meymandi, S.; Falcon-Lezama, J.A.; et al. The potential economic value of a therapeutic Chagas disease vaccine for pregnant women to prevent congenital transmission. Vaccine 2020, 38, 3261–3270. [Google Scholar] [CrossRef]
  36. Quijano-Hernandez, I.; Dumonteil, E. Advances and challenges towards a vaccine against Chagas disease. Hum. Vaccines 2011, 7, 1184–1191. [Google Scholar] [CrossRef] [Green Version]
  37. Beaumier, C.M.; Gillespie, P.M.; Strych, U.; Hayward, T.; Hotez, P.J.; Bottazzi, M.E. Status of vaccine research and development of vaccines for Chagas disease. Vaccine 2016, 34, 2996–3000. [Google Scholar] [CrossRef]
  38. Cazorla, S.I.; Frank, F.M.; Malchiodi, E.L. Vaccination approaches against Trypanosoma cruzi infection. Expert Rev. Vaccines 2009, 8, 921–935. [Google Scholar] [CrossRef]
  39. Portillo, S.; Zepeda, B.G.; Iniguez, E.; Olivas, J.J.; Karimi, N.H.; Moreira, O.C.; Marques, A.F.; Michael, K.; Maldonado, R.A.; Almeida, I.C. A prophylactic alpha-Gal-based glycovaccine effectively protects against murine acute Chagas disease. NPJ Vaccines 2019, 4, 13. [Google Scholar] [CrossRef]
  40. Lokugamage, N.; Choudhuri, S.; Davies, C.; Chowdhury, I.H.; Garg, N.J. Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of Trypanosoma cruzi Infection. Vaccines 2020, 8, 96. [Google Scholar] [CrossRef] [Green Version]
  41. Hegazy-Hassan, W.; Zepeda-Escobar, J.A.; Ochoa-Garcia, L.; Contreras-Ortiz, J.M.E.; Tenorio-Borroto, E.; Barbabosa-Pliego, A.; Aparicio-Burgos, J.E.; Oros-Pantoja, R.; Rivas-Santiago, B.; Diaz-Albiter, H.; et al. TcVac1 vaccine delivery by intradermal electroporation enhances vaccine induced immune protection against Trypanosoma cruzi infection in mice. Vaccine 2019, 37, 248–257. [Google Scholar] [CrossRef] [PubMed]
  42. Cerny, N.; Bivona, A.E.; Sanchez Alberti, A.; Trinitario, S.N.; Morales, C.; Cardoso Landaburu, A.; Cazorla, S.I.; Malchiodi, E.L. Cruzipain and Its Physiological Inhibitor, Chagasin, as a DNA-Based Therapeutic Vaccine Against Trypanosoma cruzi. Front. Immunol. 2020, 11, 565142. [Google Scholar] [CrossRef] [PubMed]
  43. Teh-Poot, C.; Tzec-Arjona, E.; Martinez-Vega, P.; Ramirez-Sierra, M.J.; Rosado-Vallado, M.; Dumonteil, E. From genome screening to creation of vaccine against Trypanosoma cruzi by use of immunoinformatics. J. Infect. Dis. 2015, 211, 258–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Biter, A.B.; Weltje, S.; Hudspeth, E.M.; Seid, C.A.; McAtee, C.P.; Chen, W.H.; Pollet, J.B.; Strych, U.; Hotez, P.J.; Bottazzi, M.E. Characterization and Stability of Trypanosoma cruzi 24-C4 (Tc24-C4), a Candidate Antigen for a Therapeutic Vaccine against Chagas Disease. J. Pharm. Sci. 2018, 107, 1468–1473. [Google Scholar] [CrossRef] [PubMed]
  45. de la Cruz, J.J.; Villanueva-Lizama, L.; Dzul-Huchim, V.; Ramírez-Sierra, M.J.; Martinez-Vega, P.; Rosado-Vallado, M.; Ortega-Lopez, J.; Flores-Pucheta, C.I.; Gillespie, P.; Zhan, B.; et al. Production of recombinant TSA-1 and evaluation of its potential for the immuno-therapeutic control of Trypanosoma cruzi infection in mice. Hum. Vaccines Immunother. 2019, 15, 210–219. [Google Scholar] [CrossRef] [Green Version]
  46. Martinez-Campos, V.; Martinez-Vega, P.; Ramirez-Sierra, M.J.; Rosado-Vallado, M.; Seid, C.A.; Hudspeth, E.M.; Wei, J.; Liu, Z.; Kwityn, C.; Hammond, M.; et al. Expression, purification, immunogenicity, and protective efficacy of a recombinant Tc24 antigen as a vaccine against Trypanosoma cruzi infection in mice. Vaccine 2015, 33, 4505–4512. [Google Scholar] [CrossRef]
  47. Barry, M.A.; Wang, Q.; Jones, K.M.; Heffernan, M.J.; Buhaya, M.H.; Beaumier, C.M.; Keegan, B.P.; Zhan, B.; Dumonteil, E.; Bottazzi, M.E.; et al. A therapeutic nanoparticle vaccine against Trypanosoma cruzi in a BALB/c mouse model of Chagas disease. Hum. Vaccines Immunother. 2016, 12, 976–987. [Google Scholar] [CrossRef] [Green Version]
  48. Barry, M.A.; Versteeg, L.; Wang, Q.; Pollet, J.; Zhan, B.; Gusovsky, F.; Bottazzi, M.E.; Hotez, P.J.; Jones, K.M. A therapeutic vaccine prototype induces protective immunity and reduces cardiac fibrosis in a mouse model of chronic Trypanosoma cruzi infection. PLoS Negl. Trop. Dis. 2019, 13, e0007413. [Google Scholar] [CrossRef]
  49. Jones, K.; Versteeg, L.; Damania, A.; Keegan, B.; Kendricks, A.; Pollet, J.; Cruz-Chan, J.V.; Gusovsky, F.; Hotez, P.J.; Bottazzi, M.E. Vaccine-Linked Chemotherapy Improves Benznidazole Efficacy for Acute Chagas Disease. Infect. Immun. 2018, 86. [Google Scholar] [CrossRef] [Green Version]
  50. Ribeiro, F.A.P.; Pontes, C.; Gazzinelli, R.T.; Romero, O.B.; Lazzarin, M.C.; Dos Santos, J.F.; de Oliveira, F.; Pisani, L.P.; de Vasconcelos, J.R.C.; Ribeiro, D.A. Therapeutic effects of vaccine derived from amastigote surface protein-2 (ASP-2) against Chagas disease in mouse liver. Cytokine 2019, 113, 285–290. [Google Scholar] [CrossRef]
  51. Pereira, I.R.; Vilar-Pereira, G.; Marques, V.; da Silva, A.A.; Caetano, B.; Moreira, O.C.; Machado, A.V.; Bruna-Romero, O.; Rodrigues, M.M.; Gazzinelli, R.T.; et al. A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy. PLoS Pathog. 2015, 11, e1004594. [Google Scholar] [CrossRef] [PubMed]
  52. Mann, G.S.; Francisco, A.F.; Jayawardhana, S.; Taylor, M.C.; Lewis, M.D.; Olmo, F.; de Freitas, E.O.; Leoratti, F.M.S.; Lopez-Camacho, C.; Reyes-Sandoval, A.; et al. Drug-cured experimental Trypanosoma cruzi infections confer long-lasting and cross-strain protection. PLoS Negl. Trop. Dis. 2020, 14, e0007717. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Williams, T.; Guerrero-Ros, I.; Ma, Y.; Matos Dos Santos, F.; Scherer, P.E.; Gordillo, R.; Horta, A.; Macian, F.; Weiss, L.M.; Huang, H. Induction of Effective Immunity against Trypanosoma cruzi. Infect. Immun. 2020, 88. [Google Scholar] [CrossRef] [PubMed]
  54. Ma, Y.; Weiss, L.M.; Huang, H. Inducible suicide vector systems for Trypanosoma cruzi. Microbes Infect. 2015, 17, 440–450. [Google Scholar] [CrossRef]
  55. Perez Brandan, C.; Mesias, A.C.; Parodi, C.; Cimino, R.O.; Perez Brandan, C.; Diosque, P.; Basombrio, M.A. Effects of IFN-gamma coding plasmid supplementation in the immune response and protection elicited by Trypanosoma cruzi attenuated parasites. BMC Infect. Dis. 2017, 17, 732. [Google Scholar] [CrossRef]
  56. Gupta, S.; Salgado-Jimenez, B.; Lokugamage, N.; Vazquez-Chagoyan, J.C.; Garg, N.J. TcG2/TcG4 DNA Vaccine Induces Th1 Immunity Against Acute Trypanosoma cruzi Infection: Adjuvant and Antigenic Effects of Heterologous T. rangeli Booster Immunization. Front. Immunol. 2019, 10, 1456. [Google Scholar] [CrossRef]
  57. Cerny, N.; Sanchez Alberti, A.; Bivona, A.E.; De Marzi, M.C.; Frank, F.M.; Cazorla, S.I.; Malchiodi, E.L. Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine against Trypanosoma cruzi infection. Hum. Vaccines Immunother. 2016, 12, 438–450. [Google Scholar] [CrossRef] [Green Version]
  58. Cazorla, S.I.; Matos, M.N.; Cerny, N.; Ramirez, C.; Alberti, A.S.; Bivona, A.E.; Morales, C.; Guzman, C.A.; Malchiodi, E.L. Oral multicomponent DNA vaccine delivered by attenuated Salmonella elicited immunoprotection against American trypanosomiasis. J. Infect. Dis. 2015, 211, 698–707. [Google Scholar] [CrossRef] [Green Version]
  59. Antonoglou, M.B.; Sanchez Alberti, A.; Redolfi, D.M.; Bivona, A.E.; Fernandez Lynch, M.J.; Noli Truant, S.; Sarratea, M.B.; Iannantuono Lopez, L.V.; Malchiodi, E.L.; Fernandez, M.M. Heterologous Chimeric Construct Comprising a Modified Bacterial Superantigen and a Cruzipain Domain Confers Protection Against Trypanosoma cruzi Infection. Front. Immunol. 2020, 11, 1279. [Google Scholar] [CrossRef]
  60. Sanchez Alberti, A.; Bivona, A.E.; Matos, M.N.; Cerny, N.; Schulze, K.; Weissmann, S.; Ebensen, T.; Gonzalez, G.; Morales, C.; Cardoso, A.C.; et al. Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi. Front. Immunol. 2020, 11, 128. [Google Scholar] [CrossRef] [Green Version]
  61. Matos, M.N.; Cazorla, S.I.; Schulze, K.; Ebensen, T.; Guzman, C.A.; Malchiodi, E.L. Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against Trypanosoma cruzi. PLoS Negl. Trop. Dis. 2017, 11, e0005300. [Google Scholar] [CrossRef] [PubMed]
  62. Arce-Fonseca, M.; González-Vázquez, M.C.; Rodríguez-Morales, O.; Graullera-Rivera, V.; Aranda-Fraustro, A.; Reyes, P.A.; Carabarin-Lima, A.; Rosales-Encina, J.L. Recombinant Enolase of Trypanosoma cruzi as a Novel Vaccine Candidate against Chagas Disease in a Mouse Model of Acute Infection. J. Immunol. Res. 2018, 2018, 8964085. [Google Scholar] [CrossRef] [Green Version]
  63. Prochetto, E.; Roldan, C.; Bontempi, I.A.; Bertona, D.; Peverengo, L.; Vicco, M.H.; Rodeles, L.M.; Perez, A.R.; Marcipar, I.S.; Cabrera, G. Trans-sialidase-based vaccine candidate protects against Trypanosoma cruzi infection, not only inducing an effector immune response but also affecting cells with regulatory/suppressor phenotype. Oncotarget 2017, 8, 58003–58020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Bontempi, I.A.; Vicco, M.H.; Cabrera, G.; Villar, S.R.; Gonzalez, F.B.; Roggero, E.A.; Ameloot, P.; Callewaert, N.; Perez, A.R.; Marcipar, I.S. Efficacy of a trans-sialidase-ISCOMATRIX subunit vaccine candidate to protect against experimental Chagas disease. Vaccine 2015, 33, 1274–1283. [Google Scholar] [CrossRef] [PubMed]
  65. Bontempi, I.; Leal, K.; Prochetto, E.; Díaz, G.; Cabrera, G.; Bortolotti, A.; Morbidoni, H.R.; Borsuk, S.; Dellagostin, O.; Marcipar, I. Recombinant Mycobacterium bovis BCG is a promising platform to develop vaccines against Trypansoma cruzi infection. Clin. Exp. Immunol. 2020, 201, 306–316. [Google Scholar] [CrossRef] [PubMed]
  66. Sanchez Alberti, A.; Bivona, A.E.; Cerny, N.; Schulze, K.; Weissmann, S.; Ebensen, T.; Morales, C.; Padilla, A.M.; Cazorla, S.I.; Tarleton, R.L.; et al. Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection. NPJ Vaccines 2017, 2, 9. [Google Scholar] [CrossRef] [PubMed]
  67. Bivona, A.E.; Sanchez Alberti, A.; Matos, M.N.; Cerny, N.; Cardoso, A.C.; Morales, C.; Gonzalez, G.; Cazorla, S.I.; Malchiodi, E.L. Trypanosoma cruzi 80 kDa prolyl oligopeptidase (Tc80) as a novel immunogen for Chagas disease vaccine. PLoS Negl. Trop. Dis. 2018, 12, e0006384. [Google Scholar] [CrossRef]
  68. Matos, M.N.; Sanchez Alberti, A.; Morales, C.; Cazorla, S.I.; Malchiodi, E.L. A prime-boost immunization with Tc52 N-terminal domain DNA and the recombinant protein expressed in Pichia pastoris protects against Trypanosoma cruzi infection. Vaccine 2016, 34, 3243–3251. [Google Scholar] [CrossRef]
  69. Gupta, S.; Garg, N.J. A Two-Component DNA-Prime/Protein-Boost Vaccination Strategy for Eliciting Long-Term, Protective T Cell Immunity against Trypanosoma cruzi. PLoS Pathog. 2015, 11, e1004828. [Google Scholar] [CrossRef] [Green Version]
  70. Kotliarov, Y.; Sparks, R.; Martins, A.J.; Mule, M.P.; Lu, Y.; Goswami, M.; Kardava, L.; Banchereau, R.; Pascual, V.; Biancotto, A.; et al. Broad immune activation underlies shared set point signatures for vaccine responsiveness in healthy individuals and disease activity in patients with lupus. Nat. Med. 2020, 26, 618–629. [Google Scholar] [CrossRef]
  71. Moncunill, G.; Scholzen, A.; Mpina, M.; Nhabomba, A.; Hounkpatin, A.B.; Osaba, L.; Valls, R.; Campo, J.J.; Sanz, H.; Jairoce, C.; et al. Antigen-stimulated PBMC transcriptional protective signatures for malaria immunization. Sci. Transl. Med. 2020, 12. [Google Scholar] [CrossRef] [PubMed]
  72. Hipc-Chi Signatures Project Team. Multicohort analysis reveals baseline transcriptional predictors of influenza vaccination responses. Sci. Immunol. 2017, 2. [Google Scholar] [CrossRef] [Green Version]
  73. Machado, A.V.; Cardoso, J.E.; Claser, C.; Rodrigues, M.M.; Gazzinelli, R.T.; Bruna-Romero, O. Long-term protective immunity induced against Trypanosoma cruzi infection after vaccination with recombinant adenoviruses encoding amastigote surface protein-2 and trans-sialidase. Hum. Gene 2006, 17, 898–908. [Google Scholar]
  74. Haolla, F.A.; Claser, C.; de Alencar, B.C.; Tzelepis, F.; de Vasconcelos, J.R.; de Oliveira, G.; Silverio, J.C.; Machado, A.V.; Lannes-Vieira, J.; Bruna-Romero, O.; et al. Strain-specific protective immunity following vaccination against experimental Trypanosoma cruzi infection. Vaccine 2009, 27, 5644–5653. [Google Scholar] [CrossRef] [PubMed]
  75. Flores-Ferrer, A.; Marcou, O.; Waleckx, E.; Dumonteil, E.; Gourbière, S. Evolutionary ecology of Chagas disease; what do we know and what do we need? Evol. Appl. 2017, 11, 470–487. [Google Scholar] [CrossRef]
  76. Zingales, B.; Andrade, S.G.; Briones, M.R.; Campbell, D.A.; Chiari, E.; Fernandes, O.; Guhl, F.; Lages-Silva, E.; Macedo, A.M.; Machado, C.R.; et al. A new consensus for Trypanosoma cruzi intraspecific nomenclature: Second revision meeting recommends TcI to TcVI. Mem. Inst. Oswaldo Cruz 2009, 104, 1051–1054. [Google Scholar] [CrossRef]
  77. Knight, J.M.; Zingales, B.; Bottazzi, M.E.; Hotez, P.; Zhan, B. Limited antigenic variation in the Trypanosoma cruzi candidate vaccine antigen TSA-1. Parasite Immunol. 2014, 36, 708–712. [Google Scholar] [CrossRef]
  78. Arnal, A.; Villanueva-Lizama, L.; Teh-Poot, C.; Herrera, C.; Dumonteil, E. Extent of polymorphism and selection pressure on the Trypanosoma cruzi vaccine candidate antigen Tc24. Evol. Appl. 2020, 13, 2663–2672. [Google Scholar] [CrossRef]
  79. Monje-Rumi, M.M.; Brandan, C.P.; Ragone, P.G.; Tomasini, N.; Lauthier, J.J.; Alberti D’Amato, A.M.; Cimino, R.O.; Orellana, V.; Basombrio, M.A.; Diosque, P. Trypanosoma cruzi diversity in the Gran Chaco: Mixed infections and differential host distribution of TcV and TcVI. Infect. Genet. Evol. 2015, 29, 53–59. [Google Scholar] [CrossRef]
  80. Martinez-Perez, A.; Poveda, C.; Ramirez, J.D.; Norman, F.; Girones, N.; Guhl, F.; Monge-Maillo, B.; Fresno, M.; Lopez-Velez, R. Prevalence of Trypanosoma cruzi’s Discrete Typing Units in a cohort of Latin American migrants in Spain. Acta Trop. 2016, 157, 145–150. [Google Scholar] [CrossRef]
  81. Villanueva-Lizama, L.; Teh-Poot, C.; Majeau, A.; Herrera, C.; Dumonteil, E. Molecular genotyping of Trypanosoma cruzi by next-generation sequencing of the mini-exon gene reveals infections with multiple parasite DTUs in Chagasic patients from Yucatan, Mexico. J. Inf. Dis. 2019, 219, 1980–1988. [Google Scholar] [CrossRef] [PubMed]
  82. Bustamante, J.M.; Rivarola, H.W.; Fernandez, A.R.; Enders, J.E.; Fretes, R.; Palma, J.A.; Paglini-Oliva, P.A. Trypanosoma cruzi reinfections in mice determine the severity of cardiac damage. Int. J. Parasitol. 2002, 32, 889–896. [Google Scholar] [CrossRef]
  83. Martins, H.R.; Toledo, M.J.; Veloso, V.M.; Carneiro, C.M.; Machado-Coelho, G.L.; Tafuri, W.L.; Bahia, M.T.; Valadares, H.M.; Macedo, A.M.; Lana, M. Trypanosoma cruzi: Impact of dual-clone infections on parasite biological properties in BALB/c mice. Exp. Parasitol. 2006, 112, 237–246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Ragone, P.G.; Perez Brandan, C.; Monje Rumi, M.; Tomasini, N.; Lauthier, J.J.; Cimino, R.O.; Uncos, A.; Ramos, F.; Alberti D’Amato, A.M.; Basombrio, M.A.; et al. Experimental evidence of biological interactions among different isolates of Trypanosoma cruzi from the Chaco Region. PLoS ONE 2015, 10, e0119866. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Tomasini, N.; Ragone, P.G.; Gourbiere, S.; Aparicio, J.P.; Diosque, P. Epidemiological modeling of Trypanosoma cruzi: Low stercorarian transmission and failure of host adaptive immunity explain the frequency of mixed infections in humans. PLoS Comput. Biol. 2017, 13, e1005532. [Google Scholar] [CrossRef] [Green Version]
  86. Aparicio-Burgos, J.E.; Ochoa-Garcia, L.; Zepeda-Escobar, J.A.; Gupta, S.; Dhiman, M.; Martinez, J.S.; de Oca-Jimenez, R.M.; Arreola, M.V.; Barbabosa-Pliego, A.; Vazquez-Chagoyan, J.C.; et al. Testing the efficacy of a multi-component DNA-prime/DNA-boost vaccine against Trypanosoma cruzi infection in dogs. PLoS Negl. Trop. Dis. 2011, 5, e1050. [Google Scholar] [CrossRef]
  87. Aparicio-Burgos, J.E.; Zepeda-Escobar, J.A.; de Oca-Jimenez, R.M.; Estrada-Franco, J.G.; Barbabosa-Pliego, A.; Ochoa-Garcia, L.; Alejandre-Aguilar, R.; Rivas, N.; Penuelas-Rivas, G.; Val-Arreola, M.; et al. Immune protection against Trypanosoma cruzi induced by TcVac4 in a canine model. PLoS Negl. Trop. Dis. 2015, 9, e0003625. [Google Scholar] [CrossRef]
  88. Quijano-Hernandez, I.A.; Castro-Barcena, A.; Vazquez-Chagoyan, J.C.; Bolio-Gonzalez, M.E.; Ortega-Lopez, J.; Dumonteil, E. Preventive and therapeutic DNA vaccination partially protect dogs against an infectious challenge with Trypanosoma cruzi. Vaccine 2013, 31, 2246–2252. [Google Scholar] [CrossRef]
  89. Arce-Fonseca, M.; Carbajal-Hernandez, A.C.; Lozano-Camacho, M.; Carrillo-Sanchez, S.D.C.; Roldan, F.J.; Aranda-Fraustro, A.; Rosales-Encina, J.L.; Rodriguez-Morales, O. DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi. J. Immunol. Res. 2020, 2020, 9794575. [Google Scholar] [CrossRef]
  90. Rodriguez-Morales, O.; Roldan, F.J.; Vargas-Barron, J.; Parra-Benitez, E.; Medina-Garcia, M.L.; Vergara-Bello, E.; Arce-Fonseca, M. Echocardiographic Findings in Canine Model of Chagas Disease Immunized with DNA Trypanosoma cruzi Genes. Animals 2020, 10, 648. [Google Scholar] [CrossRef] [Green Version]
  91. Basso, B.; Castro, I.; Introini, V.; Gil, P.; Truyens, C.; Moretti, E. Vaccination with Trypanosoma rangeli reduces the infectiousness of dogs experimentally infected with Trypanosoma cruzi. Vaccine 2007, 25, 3855–3858. [Google Scholar] [CrossRef] [PubMed]
  92. Villanueva-Lizama, L.; Cruz-Chan, J.V.; Cetina-Aguilar, A.C.; Herrera-Sanchez, L.F.; Rodriguez-Perez, J.M.; Rosado-Vallado, M.E.; Ramirez-Sierra, M.J.; Ortega-Lopez, J.; Jones, K.; Hotez, P.; et al. Trypanosoma cruzi vaccine candidate antigens Tc24 and TSA-1 recall memory immune response associated with HLA-A and –B supertypes in Chagasic chronic patients from Mexico. PLoS Negl. Trop. Dis. 2018, 12, e0006240. [Google Scholar] [CrossRef] [PubMed]
  93. Dumonteil, E.; Herrera, C.; Tu, W.; Goff, K.; Fahlberg, M.; Haupt, E.; Kaur, A.; Marx, P.A.; Ortega-Lopez, J.; Hotez, P.J.; et al. Safety and immunogenicity of a recombinant vaccine against Trypanosoma cruzi in Rhesus macaques. Vaccine 2020, 38, 4584–4591. [Google Scholar] [CrossRef] [PubMed]
  94. Seid, C.A.; Jones, K.M.; Pollet, J.; Keegan, B.; Hudspeth, E.; Hammond, M.; Wei, J.; McAtee, C.P.; Versteeg, L.; Gutierrez, A.; et al. Cysteine mutagenesis improves the production without abrogating antigenicity of a recombinant protein vaccine candidate for human chagas disease. Hum. Vaccines Immunother. 2017, 13, 621–633. [Google Scholar] [CrossRef] [Green Version]
  95. Gunter, S.M.; Jones, K.M.; Seid, C.A.; Essigmann, H.T.; Zhan, B.; Strych, U.; Bottazzi, M.E.; Hotez, P.J.; Brown, E.L. Mutations to Cysteine Residues in the Trypanosoma cruzi B-Cell Superantigen Tc24 Diminish Susceptibility to IgM-Mediated Hydrolysis. J. Parasitol. 2017, 103, 579–583. [Google Scholar] [CrossRef]
  96. Suschak, J.J.; Williams, J.A.; Schmaljohn, C.S. Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum. Vaccines Immunother. 2017, 13, 2837–2848. [Google Scholar] [CrossRef] [Green Version]
  97. Fougeroux, C.; Holst, P.J. Future Prospects for the Development of Cost-Effective Adenovirus Vaccines. Int. J. Mol. Sci. 2017, 18, 686. [Google Scholar] [CrossRef] [Green Version]
  98. Buchbinder, S.P.; McElrath, M.J.; Dieffenbach, C.; Corey, L. Use of adenovirus type-5 vectored vaccines: A cautionary tale. Lancet 2020, 396, e68–e69. [Google Scholar] [CrossRef]
  99. Lee, B.Y.; Bacon, K.M.; Bottazzi, M.E.; Hotez, P.J. Global economic burden of Chagas disease: A computational simulation model. Lancet Infect. Dis. 2013, 13, 342–348. [Google Scholar] [CrossRef] [Green Version]
  100. Cohen, J.; Dibner, M.S.; Wilson, A. Development of and access to products for neglected diseases. PLoS ONE 2010, 5, e10610. [Google Scholar] [CrossRef] [Green Version]
  101. Hotez, P.J.; Dumonteil, E.; Heffernan, M.J.; Bottazzi, M.E. Innovation for the ‘Bottom 100 million’: Eliminating neglected tropical diseases in the Americas. Adv. Exp. Med. Biol. 2013, 764, 1–12. [Google Scholar] [CrossRef] [PubMed]
  102. Chapman, N.; Doubell, A.; Barnsley, P.; Goldstein, M.; Oversteegen, L.; Chowdhary, V.; Rugarabamu, G.; Ong, M.; Borri, J.; Hynen, A.; et al. G-FINDER: Neglected Diseases Research and Development: Uneven Progress; Policy Cures Research: Sydney, Australia, 2019; p. 140. [Google Scholar]
Table
Table 1. Recent Chagas Disease Vaccine Platforms and Formulations.
Table 1. Recent Chagas Disease Vaccine Platforms and Formulations.
Antigens
and Use 		Adjuvants and Delivery Systems Immune Response Efficacy Against Parasite Efficacy Against Cardiac Damage and Dysfunction References
Therapeutic vaccines
DNATcG2+TcG4,
therapeutic during acute phase		Plasmids or nano plasmidsCD4+ and CD8+ producing IFNg, PRF, and GRZDecreased parasite burden in cardiac and skeletal muscleDecrease in fibrosis in heart and skeletal muscle, decrease in oxidative stress[40,41]
DNACruzipain and Chagasin plasmids with Salmonella carrier,
therapeutic during acute phase		GM-CSF expression plasmidIncreased IFNγ and antibodiesDecreased parasite burden in blood and heart, and increased survivalDecreased cardiac inflammation [42]
Peptides10 peptide epitopes mixture, therapeutic during acute phaseTLR4 agonist (MPLA)Increased IFNγDecreased cardiac parasite burden,
increased survival		N/A[43]
Recombinant proteinsTc24, TSA-1 and their optimized variants, therapeutic during acute phaseTLR4 agonists (E6020, MPLA, GLA), TLR9 agonist (CpG), nanoparticlesAntibodies, IFNγ, and CD4+ and CD8+ activationDecreased cardiac parasite burden,
increased survival		Decrease in cardiac inflammation and fibrosis[44,45,46,47]
Recombinant proteinsTc24, therapeutic during chronic phaseTLR4 agonists (E6020) High IFNγ and low IL4, and antibodiesDecreased parasitemiaDecrease in cardiac inflammation and fibrosis[48]
Recombinant proteinsTc24-C4, therapeutic combined with low dose BenznidazoleTLR4 agonist (E6020)Increased IFNγ, IL12, TNFa, IL2, IL4 and IL10, and CD4+ and CD8+ T cell activationDecreased parasitemia, increased survivalN/A[49]
Viral vectorsRecombinant Adenovirus expression ASP2, therapeutic during acute phase TNFa, iNOS, TLR4, and IL-10 expression in the liverIncreased survival, decreased parasite burden in liverN/A[50]
Viral vectorsRecombinant adenovirus expressing ASP2 and TS, therapeutic during chronic phase IFNγ and CD8+ T cellsIncreased survivalDecreased cardiac fibrosis and dysfunction [51]
Preventative vaccines
Live parasitesDrug-cured primary infection, preventative N/AN/ASustained decrease in parasite burden in all bodyN/A[52]
Live parasitesLive attenuated parasite (inducible expression of alpha-toxin, and cecropin A), preventativeN/AIFNγ, TNFa, CD4+ and CD8+ T cell activation, antibodies, and NK cellsNo detectable parasitesDecrease in cardiac inflammation[53,54]
Live parasitesLive attenuated parasite (TCC attenuated strain), preventative short term IFNγ expressing plasmidAntibodies and mixed Th1/Th2 responseDecreased parasitemia and increased survivalN/A[55]
DNATcG2+TcG4, preventative short termPlasmids alone or with Trypanosoma rangeli and/or Quil A as adjuvantsAntibodies, CD4+ and CD8+ producing IFNγ, TNFa, and PRFDecreased parasite burden in cardiac and skeletal muscle [56]
DNACruzipain plasmid,
preventative short term		GM-CSF plasmidAntibodies and DTHDecreased parasitemia, increased survivalDecreased cardiac tissue damage[57]
DNACruzipain, Tc52, Tc24 plasmids,
preventative short term		Salmonella enterica carrierTrypanolytic antibodies, DTH, IFNγ, IL12, and IL10Decreased parasitemia, increased survivalDecreased cardiac tissue inflammation, necrosis[58]
Recombinant proteinsCruzipain fused with staphylococcal superantigen, preventative short termTLR9 agonist (CpG)Neutralizing antibodies and DTHDecreased parasitemia and increased survivalN/A[59]
Recombinant proteinsRecombinant Traspain, Cruzipain and ASP-2 fusion protein, preventative short termc-di-AMP adjuvant (STING agonist)Neutralizing antibodies, CD4+ and CD8+ T cell activation, IFNγ, TNFa, IL2, and IL17Decreased parasitemia and increased survivalDecreased cardiac damage (CK, CK-MB), decreased necrosis and inflammation in the heart and skeletal muscle[60]
Recombinant proteinsRecombinant Tc52 fragment, preventative short term c-di-AMP adjuvant (STING agonist)Antibodies, CD4+ and CD8+ T cell activation, IFNγ, and IL17Decreased parasitemia and increased survivalN/A[61]
Recombinant proteinsTcTASV, preventative short termUnlipidated Outer Membrane Protein
19 of Brucella abortus (U-Omp19) as adjuvant		Trypanolytic antibodies, IFNγ, and IL17Decreased parasitemia and increased survivalN/A[59]
Recombinant proteinsEnolase, preventative short termFreund complete/incomplete adjuvantAntibodies, IFNγ, and IL2Decreased parasitemia and increased survivalDecreased cardiac and skeletal muscle inflammation [62]
Recombinant proteinsTrans-Sialidase fragment, Preventative short termISPA lipidic cages, ISCOMATRIX, or Freund adjuvantTrypanolytic antibodies, IFNγ, CD4+ and CD8+ T cell activation, Treg activationDecreased cardiac parasite burden,
increased survival		Decreased cardiac inflammation [63,64]
GlycotopeαGal glycotope, preventative short termTLR4 agonist (Liposomal-monophosphoryl lipid A)Trypanolytic antibodies, CD4+ and CD8+ T cell activationDecreased parasite burden in multiple tissues, increased survivalDecreased cardiac inflammation and necrosis[39]
Viral vectorsRecombinant Adenovirus and modified Vaccinia Ankara virus expressing ASP-2 and Trans-sialidase, preventative vaccinationPBS Decreased parasite burden during the acute phase in all body, but no impact on long-term burden during chronic phaseN/A[52]
Bacterial vectorsRecombinant Mycobacterium bovis (BCG) expressing trans-sialidase and cruzipain fragments, preventative short term Trypanolytic antibodies, and DTH, CD4+ expressing IFNγ, IL17, IL10, and CD8+Increased survivalDecreased cardiac inflammation and fibrosis[65]
Heterologous prime-boost combinationSalmonella enterica expressing Traspain and ASP-2TLR9 agonist (CpG)Increased IFNγ, IL17, low IL4, CD4+, and CD8+ T cell activationDecreased parasite burden in blood, heart and skeletal muscle, and increased survivalDecreased inflammation and improved EKG[66]
Heterologous prime-boost combinationRecombinant 80 kDa prolyl
oligopeptidase (Tc80) and plasmid DNA		TLR9 agonist (CpG)Increased IFNγ, IL2, TNFa, CD4+, and CD8+ T cell activationDecreased parasitemia, and increased survivalDecreased cardiac inflammation, damage (CK and CK-MB), improved EKG[67]
Heterologous prime-boost combinationRecombinant Tc52 and plasmid DNA with Salmonella carrier, preventative short termTLR9 agonist (CpG)Trypanoplytic antibodies, Increased IFNγ, IL10, CD4+, and CD8+ T cell activationDecreased parasitemia, and increased survivalDecreased cardiac inflammation[68]
Heterologous prime-boost combinationTcG1, TcG2, and TcG4 expression plasmids and recombinant proteins, preventative long termIL2 and GM-CSF plasmidsIncreased IFNγ, TNFa, CD4+ and CD8+ T cell activationN/AN/A[69]
PRF—perforin; GZN—granzyme; DTH—delated type hypersensitivity; TLR—Toll-like receptor; IL—interleukin; IFN—interferon; TNF—tumor necrosis factor; EKG—electrocardiogram; N/A—not applicable.
Table
Table 2. Production and Clinical Development of Vaccines against Infectious Diseases.
Table 2. Production and Clinical Development of Vaccines against Infectious Diseases.
Vaccine Type Ease of Production Clinical Development * Potential Issues
AttenuatedVariable140 Phase 1
71 Phase 2
43 Phase 3		Reversal of attenuation, storage, and distribution of a live vaccine
DNA++++207 Phase 1
61 Phase 2
0 Phase 3		Limited immunogenicity in humans
Adenovirus+++69 Phase 1
21 Phase 2
1 Phase 3		Risk of adverse effects and immunity to vector
Recombinant proteins++++ or variable195 Phase 1
76 Phase 2
55 Phase 3		Most widely accepted, safe and immunogenic
* Number of vaccine studies of the different phases registered in ClinicalTrials.gov, excluding COVID-19 vaccines (as of 30 October 2020).
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Dumonteil, E.; Herrera, C. The Case for the Development of a Chagas Disease Vaccine: Why? How? When? Trop. Med. Infect. Dis. 2021, 6, 16. https://0-doi-org.brum.beds.ac.uk/10.3390/tropicalmed6010016

AMA Style

Dumonteil E, Herrera C. The Case for the Development of a Chagas Disease Vaccine: Why? How? When? Tropical Medicine and Infectious Disease. 2021; 6(1):16. https://0-doi-org.brum.beds.ac.uk/10.3390/tropicalmed6010016

Chicago/Turabian Style

Dumonteil, Eric, and Claudia Herrera. 2021. "The Case for the Development of a Chagas Disease Vaccine: Why? How? When?" Tropical Medicine and Infectious Disease 6, no. 1: 16. https://0-doi-org.brum.beds.ac.uk/10.3390/tropicalmed6010016

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