New vaccine adjuvants: an important tool for immunotherapy of visceral leishmaniasis
DOI:
https://doi.org/10.34019/1982-8047.2018.v44.14123Keywords:
Recombinant proteins, Adjuvants, Vaccine, LeishmaniasisAbstract
Many of the vaccines in development are currently composed of individual antigenic proteins from parasites or a combination of several individual antigens that are produced as recombinant products obtained by molecular biology techniques. Among them, Leish-111f and its Leish-110f variation have gained prominence in protection against LV and LC and already have Phase II clinical trials in humans. The efficacy of a vaccine is optimized by the addition of immunological adjuvants. However, although adjuvants have been used for more than a century, until present date, only a few adjuvants are approved for use in humans, most intended to improve vaccine efficacy, the production of antigen-specific protective antibodies and an appropriate cell-immune response. The mechanisms of action of immunological adjuvants are diverse depending on their chemical and molecular nature being able to activate specific immune cells leading to improved innate and adaptive immune responses. Although the molecular mechanism of action of many adjuvants is still unknown, the discovery of Toll-like receptors (TLRs) has provided critical information on the immunostimulatory effect of numerous bacterial components involving interaction with TLR showing that these ligands improve both the quality as the amount of host adaptive immune responses when used in vaccine formulations. The potential of these TLR adjuvants in improving the design and results of many vaccines is in constantly evolution as new molecules agonists are discovered and tested in experimental models and clinical trials as well. In this review, a summary of recent progress in the development of second generation recombinant proteins and adjuvants of TLR is presented, being the main focus in TLR4 and its improvements.
Downloads
References
ABDIAN, N. et al. Evaluation of DNA/DNA and prime-boost vaccination using LPG3 against Leishmania major infection in susceptible BALB/c mice and its antigenic properties in human leishmaniasis. Experimental Parasitology, v. 127, n. 3, p. 627–636, 1 mar. 2011.
AKHOUNDI, M. et al. A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies. PLoS Neglected Tropical Diseases, v. 10, n. 3, p. 1–40, 3 mar. 2016.
ALVAR, J. et al. Leishmaniasis Worldwide and Global Estimates of Its Incidence. PLoS ONE, v. 7, n. 5, p. e35671, 31 maio 2012.
ALVAR, J. et al. Case study for a vaccine against leishmaniasis. Vaccine, v. 31, n. SUPPL2, p. B244–B249, 2013.
ALVING, C. R. et al. Adjuvants for human vaccines. Current Opinion in Immunology, v. 24, n. 3, p. 310–315, 1 jun. 2012.
ANDERSON, R. C. et al. Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations. Colloids and Surfaces B: Biointerfaces, v. 75, n. 1, p. 123–132, 2010.
ANTINORI, S.; SCHIFANELLA, L.; CORBELLINO, M. Leishmaniasis: New insights from an old and neglected disease. European Journal of Clinical Microbiology and Infectious Diseases, v. 31, n. 2, p. 109–118, 1 fev. 2012.
ARAÚJO, M. S. S. et al. Immunological changes in canine peripheral blood leukocytes triggered by immunization with first or second generation vaccines against canine visceral leishmaniasis. Veterinary Immunology and Immunopathology, v. 141, n. 1–2, p. 64–75, 15 maio 2011.
BALAÑA-FOUCE, R. et al. The pharmacology of leishmaniasis. General Pharmacology, v. 30, n. 4, p. 435–443, 1998.
BALDRIDGE, J. R.; CRANE, R. T. Monophosphoryl lipid A (MPL) formulations for the next generation of vaccines. Methods (San Diego, Calif.), v. 19, n. 1, p. 103–7, set. 1999.
BALDWIN, S. L. et al. Synthetic TLR4 agonists enhance functional antibodies and CD4+ T-cell responses against the Plasmodium falciparum GMZ2.6C multi-stage vaccine antigen. Vaccine, v. 34, n. 19, p. 2207–2215, 2016.
BETHONY, J. M. et al. Vaccines to combat the neglected tropical diseases. Immunological Reviews, v. 239, n. 1, p. 237–270, 2011.
BORGES, M. M. et al. Potent Stimulation of the Innate Immune System by a Leishmania brasiliensis Recombinant Protein. Infection and Immunity, v. 69, n. 9, p. 5270–5277, 1 set. 2001.
BORJA-CABRERA, G. P. et al. Long lasting protection against canine kala-azar using the FML-QuilA saponin vaccine in an endemic area of Brazil (São Gonçalo do Amarante, RN). Vaccine, v. 20, n. 27–28, p. 3277–84, 10 set. 2002.
BRITO, V. N. DE et al. Phlebotomine fauna, natural infection rate and feeding habits of Lutzomyia cruzi in Jaciara, state of Mato Grosso, Brazil. Memórias do Instituto Oswaldo Cruz, v. 109, n. 7, p. 899–904, nov. 2014.
CAMPOS-NETO, A. et al. Protection against Cutaneous Leishmaniasis Induced by Recombinant Antigens in Murine and Nonhuman Primate Models of the Human Disease. Infection and Immunity, v. 69, n. 6, p. 4103–4108, 1 jun. 2001.
CARTER, D. et al. A structure-function approach to optimizing TLR4 ligands for human vaccines. Clinical & Translational Immunology, v. 5, n. 11, p. e108, 2 nov. 2016.
CARVALHO, A. G. DE et al. High seroprevalence and peripheral spatial distribution of visceral leishmaniasis among domestic dogs in an emerging urban focus in Central Brazil: a cross-sectional study. Pathogens and Global Health, p. 1–8, 20 fev. 2018.
CHAKRAVARTY, J. et al. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine for use in the prevention of visceral leishmaniasis. Vaccine, v. 29, n. 19, p. 3531–3537, 2011.
CHAUHAN, P. et al. Redundant and regulatory roles for Toll-like receptors in Leishmania infection. Clinical & Experimental Immunology, v. 190, n. 2, p. 167–186, nov. 2017.
CHIN, J.; GIL, F. S. Skin delivery of a hybrid liposome/ISCOM vaccine implicates a role for adjuvants in rapid modulation of inflammatory cells involved in innate immunity before the enhancement of adaptive immune responses. Immunology and Cell Biology, v. 76, n. 3, p. 245–255, maio 1998.
COELHO, E. A. F. et al. Immune Responses Induced by the Leishmania (Leishmania) donovani A2 Antigen, but Not by the LACK Antigen, Are Protective against Experimental Leishmania (Leishmania) amazonensis Infection. Infection and Immunity, v. 71, n. 7, p. 3988–3994, 1 jul. 2003.
COLER, R. N. et al. Leish-111f, a Recombinant Polyprotein Vaccine That Protects against Visceral Leishmaniasis by Elicitation of CD4+ T Cells. Infection and Immunity, v. 75, n. 9, p. 4648–4654, 1 set. 2007.
COLER, R. N. et al. Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant. PLoS ONE, v. 6, n. 1, p. e16333, 26 jan. 2011.
COLER, R. N.; REED, S. G. Second-generation vaccines against leishmaniasis. Trends in parasitology, v. 21, n. 5, p. 244–9, maio 2005.
CONNELL, N. D. et al. Effective immunization against cutaneous leishmaniasis with recombinant bacille Calmette-Guérin expressing the Leishmania surface proteinase gp63. Proceedings of the National Academy of Sciences of the United States of America, v. 90, n. 24, p. 11473–7, 15 dez. 1993.
CUSCÓ, A. et al. Non-synonymous genetic variation in exonic regions of canine Toll-like receptors. Canine Genetics and Epidemiology, v. 1, n. 1, p. 11, 2014.
DE AMORIM, I. F. G. et al. Humoral immunological profile and parasitological statuses of Leishmune® vaccinated and visceral leishmaniasis infected dogs from an endemic area. Veterinary Parasitology, v. 173, n. 1–2, p. 55–63, 11 out. 2010.
DE MENDONÇA, L. Z. et al. Multicomponent LBSap vaccine displays immunological and parasitological profiles similar to those of Leish-Tec® and Leishmune® vaccines against visceral leishmaniasis. Parasites and Vectors, v. 9, n. 1, p. 1–12, 2016.
EVANS, J. T. et al. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert review of vaccines, v. 2, n. 2, p. 219–29, abr. 2003.
FERNANDES, A. P. et al. Protective immunity against challenge with Leishmania (Leishmania) chagasi in beagle dogs vaccinated with recombinant A2 protein. Vaccine, v. 26, n. 46, p. 5888–5895, 29 out. 2008.
FERNANDES, C. B. et al. Comparison of two commercial vaccines against visceral leishmaniasis in dogs from endemic areas: IgG, and subclasses, parasitism, and parasite transmission by xenodiagnosis. Vaccine, v. 32, n. 11, p. 1287–1295, 2014.
FERNANDES, W. DE S. et al. Sandfly fauna (Diptera: Psychodidae) in an urban area, Central-West of Brazil. Revista do Instituto de Medicina Tropical de Sao Paulo, v. 59, n. December 2016, p. 1–8, 2017.
FOX, C. B. et al. Current Status of Toll-Like Receptor 4 Ligand Vaccine Adjuvants. In: Immunopotentiators in Modern Vaccines. [s.l.] Elsevier, 2017. p. 105–127.
FUKATA, M.; VAMADEVAN, A. S.; ABREU, M. T. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Seminars in Immunology, v. 21, n. 4, p. 242–253, ago. 2009.
GHARBI, M. et al. Leishmaniosis (Leishmania infantum infection) in dogs. Revue Scientifique et Technique de l’OIE, v. 34, n. 2, p. 613–626, 2015.
GRADONI, L. et al. Failure of a multi-subunit recombinant leishmanial vaccine (MML) to protect dogs from Leishmania infantum infection and to prevent disease progression in infected animals. Vaccine, v. 23, n. 45, p. 5245–5251, 1 nov. 2005.
GRADONI, L. Canine Leishmania vaccines: Still a long way to go. Veterinary Parasitology, v. 208, n. 1–2, p. 94–100, 28 fev. 2015.
GUPTA, R. K.; SIBER, G. R. Adjuvants for human vaccines—current status, problems and future prospects. Vaccine, v. 13, n. 14, p. 1263–1276, 1 jan. 1995.
HANDMAN, E. et al. Passive transfer of Leishmania lipopolysaccharide confers parasite survival in macrophages. Journal of immunology (Baltimore, Md. : 1950), v. 137, n. 11, p. 3608–13, 1 dez. 1986.
HE, Q. et al. Calcium phosphate nanoparticle adjuvant. Clinical and diagnostic laboratory immunology, v. 7, n. 6, p. 899–903, nov. 2000.
HOSEIN, S.; BLAKE, D. P.; SOLANO-GALLEGO, L. Insights on adaptive and innate immunity in canine leishmaniosis. Parasitology, v. 144, n. 01, p. 95–115, 20 jan. 2017.
IRETON, G. C.; REED, S. G. Adjuvants containing natural and synthetic Toll-like receptor 4 ligands. Expert Review of Vaccines, v. 12, n. 7, p. 793–807, 9 jul. 2013.
JAIN, K.; JAIN, N. K. K. Vaccines for visceral leishmaniasis: A review. Journal of Immunological Methods, v. 422, p. 1–12, jul. 2015.
JARDIM, A. et al. The Leishmania donovani lipophosphoglycan T lymphocyte-reactive component is a tightly associated protein complex. Journal of immunology (Baltimore, Md. : 1950), v. 147, n. 10, p. 3538–44, 15 nov. 1991.
KAWAI, T.; AKIRA, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology, v. 11, n. 5, p. 373–384, 20 maio 2010.
KAYE, P. M.; AEBISCHER, T. Visceral leishmaniasis: immunology and prospects for a vaccine. Clinical Microbiology and Infection, v. 17, n. 10, p. 1462–1470, 1 out. 2011.
KAYE, P.; SCOTT, P. Leishmaniasis: complexity at the host–pathogen interface. Nature Reviews Microbiology, v. 9, n. 8, p. 604–615, 11 jul. 2011.
KOUTINAS, A. F.; KOUTINAS, C. K. Pathologic Mechanisms Underlying the Clinical Findings in Canine Leishmaniosis due to Leishmania infantum/chagasi. Veterinary Pathology, v. 51, n. 2, p. 527–538, 7 mar. 2014.
KUMAR, R.; ENGWERDA, C. Vaccines to prevent leishmaniasis. Clinical & Translational Immunology, v. 3, n. 3, p. e13, mar. 2014.
LAINSON, R.; RYAN, L.; SHAW, J. J. Infective stages of Leishmania in the sandfly vector and some observations on the mechanism of transmission. Memórias do Instituto Oswaldo Cruz, v. 82, n. 3, p. 421–424, set. 1987.
LIEW, F. Y.; O’DONNELL, C. A. Immunology of Leishmaniasis. Advances in Parasitology, v. 32, p. 161–259, 1 jan. 1993.
LLANOS-CUENTAS, A. et al. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine when used in combination with sodium stibogluconate for the treatment of mucosal leishmaniasis. Vaccine, v. 28, n. 46, p. 7427–7435, 28 out. 2010.
LOUSADA-DIETRICH, S. et al. A synthetic TLR4 agonist formulated in an emulsion enhances humoral and Type 1 cellular immune responses against GMZ2 - A GLURP-MSP3 fusion protein malaria vaccine candidate. Vaccine, v. 29, n. 17, p. 3284–3292, 2011.
MAROLI, M. et al. Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern. Medical and Veterinary Entomology, v. 27, n. 2, p. 123–147, jun. 2013.
MCGWIRE, B. S.; SATOSKAR, A. R. Leishmaniasis: clinical syndromes and treatment. QJM, v. 107, n. 1, p. 7–14, 1 jan. 2014.
MCMAHON-PRATT, D. et al. Recombinant vaccinia viruses expressing GP46/M-2 protect against Leishmania infection. Infection and immunity, v. 61, n. 8, p. 3351–9, ago. 1993.
MELBY, P. C. et al. Identification of vaccine candidates for experimental visceral leishmaniasis by immunization with sequential fractions of a cDNA expression library. Infection and immunity, v. 68, n. 10, p. 5595–602, out. 2000.
MINISTÉRIO DA SAÚDE. Leishmaniose visceral: o que é, causas, sintomas, tratamento, diagnóstico e prevenção. Disponível em: <http://portalms.saude.gov.br/saude-de-a-z/leishmaniose-visceral>. Acesso em: 8 maio. 2019.
MIRET, J. et al. Evaluation of an immunochemotherapeutic protocol constituted of N-methyl meglumine antimoniate (Glucantime®) and the recombinant Leish-110f®+MPL-SE® vaccine to treat canine visceral leishmaniasis. Vaccine, v. 26, n. 12, p. 1585–1594, 17 mar. 2008.
MIYAKE, K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Seminars in Immunology, v. 19, n. 1, p. 3–10, fev. 2007.
MIZEL, S. B.; BATES, J. T. Flagellin as an Adjuvant: Cellular Mechanisms and Potential. The Journal of Immunology, v. 185, n. 10, p. 5677–5682, 15 nov. 2010.
MOGENSEN, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clinical Microbiology Reviews, v. 22, n. 2, p. 240–273, 2009.
MORENO, J. et al. Immunization with H1, HASPB1 and MML Leishmania proteins in a vaccine trial against experimental canine leishmaniasis. Vaccine, v. 25, n. 29, p. 5290–5300, 20 jul. 2007.
MUKHERJEE, A. K. et al. Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: Role of TLR4 and TLR9. International Immunopharmacology, v. 12, n. 4, p. 565–572, 2012.
MURRAY, H. W. et al. Advances in leishmaniasis. The Lancet, v. 366, n. 9496, p. 1561–1577, 29 out. 2005.
NAGILL, R.; KAUR, S. Vaccine candidates for leishmaniasis: A review. International Immunopharmacology, v. 11, n. 10, p. 1464–1488, out. 2011.
NASCIMENTO, E. et al. A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine when used in combination with meglumine antimoniate for the treatment of cutaneous leishmaniasis. Vaccine, v. 28, n. 40, p. 6581–6587, 14 set. 2010.
NETEA, M. G. et al. Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system. Journal of Leukocyte Biology, v. 75, n. 5, p. 749–755, 2004.
ORGANIZACIÓN PANAMERICANA DE LA SALUD. Manual de procedimientos para vigilancia y control de las leishmaniasis en las Américas. Washington, D.C.: OPS; 2019.
OSPELT, C.; GAY, S. TLRs and chronic inflammation. The International Journal of Biochemistry & Cell Biology, v. 42, n. 4, p. 495–505, abr. 2010.
PAES, W. et al. Recombinant polymorphic membrane protein D in combination with a novel, second-generation lipid adjuvant protects against intra-vaginal Chlamydia trachomatis infection in mice. Vaccine, v. 34, n. 35, p. 4123–4131, 2016.
PALATNIK, C. B. et al. Inhibition of Leishmania donovani promastigote internalization into murine macrophages by chemically defined parasite glycoconjugate ligands. Infection and immunity, v. 57, n. 3, p. 754–63, mar. 1989.
PARK, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature, v. 458, n. 7242, p. 1191–1195, 2009.
PARRA, L. E. et al. Safety trial using the Leishmune® vaccine against canine visceral leishmaniasis in Brazil. Vaccine, v. 25, n. 12, p. 2180–2186, 8 mar. 2007.
PEREIRA-FONSECA, D. C. M. M. et al. Dog skin parasite load, TLR-2, IL-10 and TNF-α expression and infectiousness. Parasite Immunology, v. 39, n. 11, p. e12493, nov. 2017.
PICCININI, A. M.; MIDWOOD, K. S. DAMPening Inflammation by Modulating TLR Signalling. Mediators of Inflammation, v. 2010, p. 1–21, 2010.
PROBST, P. et al. ALeishmania protein that modulates interleukin (IL)-12, IL-10 and tumor necrosis factor-α production and expression of B7-1 in human monocyte-derived antigen-presenting cells. European Journal of Immunology, v. 27, n. 10, p. 2634–2642, out. 1997.
QURESHI, N. et al. Structure of the monophosphoryl lipid A moiety obtained from the lipopolysaccharide of Chlamydia trachomatis. The Journal of biological chemistry, v. 272, n. 16, p. 10594–600, 18 abr. 1997.
RACHAMIM, N.; JAFFE, C. L. Pure protein from Leishmania donovani protects mice against both cutaneous and visceral leishmaniasis. Journal of immunology (Baltimore, Md. : 1950), v. 150, n. 6, p. 2322–31, 15 mar. 1993.
RAFATI, S. et al. Identification of Leishmania major cysteine proteinases as targets of the immune response in humans. Molecular and biochemical parasitology, v. 113, n. 1, p. 35–43, mar. 2001.
RAMAN, V. S. et al. Adjuvants for Leishmania vaccines: From models to clinical application. Frontiers in Immunology, v. 3, n. JUN, p. 1–15, 2012.
RATH, S. et al. Antimoniais empregados no tratamento da leishmaniose: estado da arte. Química Nova, v. 26, n. 4, p. 550–555, ago. 2003.
READY, P. D. Biology of Phlebotomine Sand Flies as Vectors of Disease Agents. Annual Review of Entomology, v. 58, n. 1, p. 227–250, 7 jan. 2013.
REED, S. G. et al. New horizons in adjuvants for vaccine development. Trends in Immunology, v. 30, n. 1, p. 23–32, jan. 2009.
REED, S. G.; BADARO, R.; LLOYD, R. M. Identification of specific and cross-reactive antigens of Leishmania donovani chagasi by human infection sera. Journal of immunology (Baltimore, Md. : 1950), v. 138, n. 5, p. 1596–601, 1 mar. 1987.
REED, S. G.; ORR, M. T.; FOX, C. B. Key roles of adjuvants in modern vaccines. Nature Medicine, v. 19, n. 12, p. 1597–1608, 5 dez. 2013.
REGINA-SILVA, S. et al. Field randomized trial to evaluate the efficacy of the Leish-Tec ® vaccine against canine visceral leishmaniasis in an endemic area of Brazil. Vaccine, v. 34, n. 19, p. 2233–2239, 2016.
REZVAN, H.; MOAFI, M. An overview on Leishmania vaccines: A narrative review article. Veterinary Research Forum, v. 6, n. 1, p. 1–7, 2015.
RIBEIRO, R. R. et al. Canine Leishmaniasis: An Overview of the Current Status and Strategies for Control. BioMed Research International, v. 2018, n. Cl, p. 1–12, 2018.
RODRIGUES, V. et al. Regulation of immunity during visceral Leishmania infection. Parasites and Vectors, v. 9, n. 1, p. 1–13, 1 mar. 2016.
ROSS, R. FURTHER NOTES ON LEISHMAN’S BODIES. British medical journal, v. 2, n. 2239, p. 1401, 28 nov. 1903.
SAHA, P.; MUKHOPADHYAY, D.; CHATTERJEE, M. Immunomodulation by chemotherapeutic agents against Leishmaniasis. International Immunopharmacology, v. 11, n. 11, p. 1668–1679, nov. 2011.
SCHEIERMANN, J.; KLINMAN, D. M. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine, v. 32, n. 48, p. 6377–6389, 12 nov. 2014.
SCHIJNS, V. E. Immunological concepts of vaccine adjuvant activity. Current opinion in immunology, v. 12, n. 4, p. 456–63, ago. 2000.
SHIROTA, H.; KLINMAN, D. M. Recent progress concerning CpG DNA and its use as a vaccine adjuvant. Expert Review of Vaccines, v. 13, n. 2, p. 299–312, 26 fev. 2014.
SILVA, V. et al. A phase III trial of efficacy of the FML-vaccine against canine kala-azar in an endemic area of Brazil (São Gonçalo do Amaranto, RN). Vaccine, v. 19, n. 9–10, p. 1082–1092, 8 dez. 2000.
SINGH, N.; KUMAR, M.; SINGH, R. K. Leishmaniasis: current status of available drugs and new potential drug targets. Asian Pacific Journal of Tropical Medicine, v. 5, p. 485–497, 2012.
SKEIKY, Y. A. et al. A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12. The Journal of experimental medicine, v. 181, n. 4, p. 1527–37, 1 abr. 1995a.
SKEIKY, Y. A. et al. Immune responses of leishmaniasis patients to heat shock proteins of Leishmania species and humans. Infection and immunity, v. 63, n. 10, p. 4105–14, out. 1995b.
SKEIKY, Y. A. et al. LeIF: a recombinant Leishmania protein that induces an IL-12-mediated Th1 cytokine profile. Journal of immunology (Baltimore, Md. : 1950), v. 161, n. 11, p. 6171–9, 1 dez. 1998.
SKEIKY, Y. A. W. et al. Protective efficacy of a tandemly linked, multi-subunit recombinant leishmanial vaccine (Leish-111f) formulated in MPL adjuvant. Vaccine, v. 20, n. 27–28, p. 3292–303, 10 set. 2002.
STEINHAGEN, F. et al. TLR-based immune adjuvants. Vaccine, v. 29, n. 17, p. 3341–55, 12 abr. 2011.
TORRES-GUERRERO, E. et al. Leishmaniasis: a review. F1000Research, v. 6, n. May, p. 750, 2017.
TOUSSI, D. N.; MASSARI, P. Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands. Vaccines, v. 2, n. 2, p. 323–53, 25 abr. 2014.
TUON, F. F. et al. Toll-like receptors and leishmaniasis. Infection and Immunity, v. 76, n. 3, p. 866–872, 1 mar. 2008.
ULIANA, S. R. B.; TRINCONI, C. T.; COELHO, A. C. Chemotherapy of leishmaniasis: present challenges. Parasitology, p. 1–17, 2017.
VASILAKOS, J. P.; TOMAI, M. A. The use of Toll-like receptor 7/8 agonists as vaccine adjuvants. Expert Review of Vaccines, v. 12, n. 7, p. 809–819, 9 jul. 2013.
VEDVICK, T. et al. An Improved Manufacturing Process for a Recombinant Polyprotein Vaccine. Biopharm International, v. 21, 2 jan. 2008.
VÉLEZ, I. D. et al. Safety and immunogenicity of a defined vaccine for the prevention of cutaneous leishmaniasis. Vaccine, v. 28, n. 2, p. 329–337, 11 dez. 2009.
WEBB, J. R. et al. Molecular cloning of a novel protein antigen of Leishmania major that elicits a potent immune response in experimental murine leishmaniasis. Journal of immunology (Baltimore, Md. : 1950), v. 157, n. 11, p. 5034–41, 1 dez. 1996.
WEBB, J. R. et al. Human and murine immune responses to a novel Leishmania major recombinant protein encoded by members of a multicopy gene family. Infection and immunity, v. 66, n. 7, p. 3279–89, jul. 1998.
ZANIN, F. H. C. et al. Evaluation of immune responses and protection induced by A2 and nucleoside hydrolase (NH) DNA vaccines against Leishmania chagasi and Leishmania amazonensis experimental infections. 2007.
Downloads
Published
How to Cite
Issue
Section
License
Cessão de Primeira Publicação à HU Revista
Os autores mantém todos os direitos autorais sobre a publicação, sem restrições, e concedem à HU Revista o direito de primeira publicação, com o trabalho licenciado sob a Licença Creative Commons Attribution que permite o compartilhamento irrestrito do trabalho, com reconhecimento da autoria e crédito pela citação de publicação inicial nesta revista, referenciando inclusive seu DOI.
