In the past 25 years, the development of an effective malaria vaccine has become one of the biggest riddles in the biomedical sciences. Experimental data using animal infection models demonstrated that it is possible to induce protective immunity against different stages of malaria parasites. Nonetheless, the vast body of knowledge has generated disappointments when submitted to clinical conditions and presently a single antigen formulation has progressed to the point where it may be translated into a human vaccine. In parallel, new means to increase the protective effects of antigens in general have been pursued and depicted, such as the use of bacterial flagellins as carriers/adjuvants. Flagellins activate pathways in the innate immune system of both mice and humans. The recent report of the first Phase I clinical trial of a vaccine containing a Salmonella flagellin as carrier/adjuvant may fuel the use of these proteins in vaccine formulations. Herein, we review the studies on the use of recombinant flagellins as vaccine adjuvants with malarial antigens in the light of the current state of the art of malaria vaccine development. The available information indicates that bacterial flagellins should be seriously considered for malaria vaccine formulations to the development of effective human vaccines. 1. Whole Parasite Vaccines 1.1. Preerythrocytic Stages The seminal work using radiation-attenuated sporozoites has been reproduced in multiple experimental systems, demonstrating that attenuated infective forms of Plasmodium sp. administered by the endovenous route can provide solid vaccination status against any symptoms of malaria [1]. However, the use of radiation-attenuated, viable live sporozoites imposes a number of restrictions because if the radiation fails, then these parasites would cause the disease, thereby nullifying any protective effects. To definitively solve this problem, a number of genetically attenuated lines of parasites have been recently generated. These genetically attenuated parasites are now being pursued as possible antigenic sources for vaccine development for humans, and Phase I and II studies are about to begin [2–5]. 1.2. Erythrocytic Stages Likewise, genetically attenuated blood-stage forms of rodent malaria parasites have been successfully generated in the past few years and have been proposed as an antigen source for human vaccination trials [5–7]. To our knowledge, none of these parasite lines are being tested in Phase I or II trials. Although it is technically feasible to produce large amounts of genetically attenuated
References
[1]
R. S. Nussenzweig, J. Vanderberg, H. Most, and C. Orton, “Protective immunity produced by the injection of X-irradiated sporozoites of plasmodium berghei,” Nature, vol. 216, no. 5111, pp. 160–162, 1967.
[2]
A. K. Mueller, M. Labaied, S. Kappe, and K. Matuschewski, “Genetically modified Plasmodium parasites as a protective experimental malaria vaccine,” Nature, vol. 13, no. 7022, pp. 164–167, 2005.
[3]
M. R. Van Dijk, B. Douradinha, B. Franke-Fayard et al., “Genetically attenuated P36p-deficient malarial sporozouites induce protective immunity and apoptosis of infected liver cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 34, pp. 12194–12199, 2005.
[4]
K. M. VanBuskirk, M. T. O'Neill, P. De La Vega et al., “Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 13004–13009, 2009.
[5]
L. M. Ting, M. Gissot, A. Coppi, P. Sinnis, and K. Kim, “Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity,” Nature Medicine, vol. 14, no. 9, pp. 954–958, 2008.
[6]
A. S. I. Aly, M. J. Downie, C. B. Mamoun, and S. H. I. Kappe, “Subpatent infection with nucleoside transporter 1-deficient Plasmodium blood stage parasites confers sterile protection against lethal malaria in mice,” Cellular Microbiology, vol. 12, no. 7, pp. 930–938, 2010.
[7]
R. Spaccapelo, C. J. Janse, S. Caterbi et al., “Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria,” American Journal of Pathology, vol. 176, no. 1, pp. 205–217, 2010.
[8]
K. A. Kumar, G. I. Sano, S. Boscardin et al., “The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites,” Nature, vol. 444, no. 7121, pp. 937–940, 2006.
[9]
M. Mauduit, A. C. Grüner, R. Tewari et al., “A role for immune responses against non-CS components in the cross-species protection induced by immunization with irradiated malaria sporozoites,” PLoS ONE, vol. 4, no. 11, article e7717, 2009.
[10]
P. Romero, J. L. Maryanski, G. Corradin, R. S. Nussenzweig, V. Nussenzweig, and F. Zavala, “Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria,” Nature, vol. 341, no. 6240, pp. 323–326, 1989.
[11]
E. H. Nardin, D. A. Herrington, J. Davis et al., “Conserved repetitive epitope recognized by CD4 clones from a malaria-immunized volunteer,” Science, vol. 246, no. 4937, pp. 1603–1606, 1989.
[12]
L. Renia, M. S. Marussig, D. Grillot et al., “In vitro activity of CD4+ and CD8+ T lymphocytes from mice immunized with a synthetic malaria peptide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 18, pp. 7963–7967, 1991.
[13]
M. M. Rodrigues, A. S. Cordey, G. Arreaza et al., “CD8+ cytolytic T cell clones derived against the Plasmodium yoelii circumsporozoite protein protect against malaria,” International Immunology, vol. 3, no. 6, pp. 579–585, 1991.
[14]
A. Malik, J. E. Egan, R. A. Houghten, J. C. Sadoff, and S. L. Hoffman, “Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 8, pp. 3300–3304, 1991.
[15]
J. P. Tam, P. Clavijo, Y. A. Lu, V. Nussenzweig, R. Nussenzweig, and F. Zavala, “Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria,” Journal of Experimental Medicine, vol. 171, no. 1, pp. 299–306, 1990.
[16]
E. H. Nardin, G. A. Oliveira, J. M. Calvo-Calle, and R. S. Nussenzweig, “The use of multiple antigen peptides in the analysis and induction of protective immune responses against infectious diseases,” Advances in Immunology, vol. 60, pp. 105–149, 1995.
[17]
J. M. Calvo-Calle, G. A. Oliveira, C. O. Watta, J. Soverow, C. Parra-Lopez, and E. H. Nardin, “A linear peptide containing minimal T- and B-cell epitopes of Plasmodium falciparum circumsporozoite protein elicits protection against transgenic sporozoite challenge,” Infection and Immunity, vol. 74, no. 12, pp. 6929–6939, 2006.
[18]
O. Bru？a-Romero, G. González-Aseguinolaza, J. C. R. Hafalla, M. Tsuji, and R. S. Nussenzweig, “Complete, long-lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmodial antigen,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 20, pp. 11491–11496, 2001.
[19]
A. Reyes-Sandoval, T. Berthoud, N. Alder et al., “Prime-boost immunization with adenoviral and modified vaccinia virus Ankara vectors enhances the durability and polyfunctionality of protective malaria CD8+ T-cell responses,” Infection and Immunity, vol. 78, no. 1, pp. 145–153, 2010.
[20]
O. J. Ophorst, K. Rado？evi？, M. J. E. Havenga et al., “Immunogenicity and protection of a recombinant human adenovirus serotype 35-based malaria vaccine against Plasmodium yoelii in mice,” Infection and Immunity, vol. 74, no. 1, pp. 313–320, 2006.
[21]
T. Shiratsuchi, U. Rai, A. Krause, S. Worgall, and M. Tsuji, “Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice,” Journal of Clinical Investigation, vol. 120, no. 10, pp. 3688–3701, 2010.
[22]
S. Li, M. Rodrigues, D. Rodriguez et al., “Priming with recombinant influenza virus followed by administration of recombinant vaccinia virus induces CD8+ T-cell-mediated protective immunity against malaria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 11, pp. 5214–5218, 1993.
[23]
M. Rodrigues, S. Li, K. Murata et al., “Influenza and vaccinia viruses expressing malaria CD8+ T and B cell epitopes: comparison of their immunogenicity and capacity to induce protective immunity,” Journal of Immunology, vol. 153, no. 10, pp. 4636–4648, 1994.
[24]
M. Sedegah, T. R. Jones, M. Kaur et al., “Boosting with recombinant vaccinia increases immunogenicity and protective efficacy of malaria DNA vaccine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7648–7653, 1998.
[25]
J. Schneider, S. C. Gilbert, T. J. Blanchard et al., “Enhanced immunogenicity for CD8+ T cell induction and complete protective efficacy of malaria DNA vaccination by boosting with modified vaccinia virus Ankara,” Nature Medicine, vol. 4, no. 4, pp. 397–402, 1998.
[26]
D. P. Webster, S. Dunachie, J. M. Vuola et al., “Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 13, pp. 4836–4841, 2005.
[27]
S. J. Dunachie, M. Walther, J. E. Epstein et al., “A DNA prime-modified vaccinia virus Ankara boost vaccine encoding thrombospondin-related adhesion protein but not circumsporozoite protein partially protects healthy malaria-naive adults against Plasmodium falciparum sporozoite challenge,” Infection and Immunity, vol. 74, no. 10, pp. 5933–5942, 2006.
[28]
P. Bejon, E. Ogada, T. Mwangi et al., “Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya,” PLoS ONE, vol. 2, no. 8, article e707, 2007.
[29]
N. W. Schmidt, R. L. Podyminogin, N. S. Butler et al., “Memory CD8+ T cell responses exceeding a large but definable threshold provide long-term immunity to malaria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 37, pp. 14017–14022, 2008.
[30]
M. Rodrigues, R. S. Nussenzweig, P. Romero, and F. Zavala, “The in vivo cytotoxic activity of CD8+ T cell clones correlates with their levels of expression of adhesion molecules,” Journal of Experimental Medicine, vol. 175, no. 4, pp. 895–905, 1992.
[31]
J. Cohen, V. Nussenzweig, R. Nussenzweig, J. Vekemans, and A. Leach, “From the circumsporozoite protein to the RTS,S/AS candidate vaccine,” Human Vaccines, vol. 6, no. 1, pp. 90–96, 2010.
[32]
K. E. Kester, J. F. Cummings, O. Ofori-Anyinam et al., “Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection,” Journal of Infectious Diseases, vol. 200, no. 3, pp. 337–346, 2009.
[33]
P. Bejon, J. Lusingu, A. Olotu et al., “Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age,” New England Journal of Medicine, vol. 359, no. 24, pp. 2521–2532, 2008.
[34]
S. Abdulla, R. Oberholzer, O. Juma et al., “Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants,” New England Journal of Medicine, vol. 359, no. 24, pp. 2533–2544, 2008.
[35]
B. Gamain, J. D. Smith, N. K. Viebig, J. Gysin, and A. Scherf, “Pregnancy-associated malaria: parasite binding, natural immunity and vaccine development,” International Journal for Parasitology, vol. 37, no. 3-4, pp. 273–283, 2007.
[36]
J. Wipasa and E. M. Riley, “The immunological challenges of malaria vaccine development,” Expert Opinion on Biological Therapy, vol. 7, no. 12, pp. 1841–1852, 2007.
[37]
B. Genton and Z. H. Reed, “Asexual blood-stage malaria vaccine development: facing the challenges,” Current Opinion in Infectious Diseases, vol. 20, no. 5, pp. 467–475, 2007.
[38]
L. Hviid, “The role of Plasmodium falciparum variant surface antigens in protective immunity and vaccine development,” Human Vaccines, vol. 6, no. 1, pp. 84–89, 2010.
[39]
M. Dahlb？ck, M. A. Nielsen, and A. Salanti, “Can any lessons be learned from the ambiguous glycan binding of PfEMP1 domains?” Trends in Parasitology, vol. 26, no. 5, pp. 230–235, 2010.
[40]
P. Khunrae, M. Dahlb？ck, M. A. Nielsen et al., “Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies,” Journal of Molecular Biology, vol. 397, no. 3, pp. 826–834, 2010.
[41]
Z. H. Reed, M. Friede, and M. P. Kieny, “Malaria vaccine development: progress and challenges,” Current Molecular Medicine, vol. 6, no. 2, pp. 231–245, 2006.
[42]
S. S. Yazdani, P. Mukherjee, V. S. Chauhan, and C. E. Chitnis, “Immune responses to asexual blood-stages of malaria parasites,” Current Molecular Medicine, vol. 6, no. 2, pp. 187–203, 2006.
[43]
J. Langhorne, F. M. Ndungu, A. M. Sponaas, and K. Marsh, “Immunity to malaria: more questions than answers,” Nature Immunology, vol. 9, no. 7, pp. 725–732, 2008.
[44]
M. Kadekoppala and A. A. Holder, “Merozoite surface proteins of the malaria parasite: the MSP1 complex and the MSP7 family,” International Journal for Parasitology, vol. 40, no. 10, pp. 1155–1161, 2010.
[45]
E. J. Remarque, B. W. Faber, C. H. M. Kocken, and A. W. Thomas, “Apical membrane antigen 1: a malaria vaccine candidate in review,” Trends in Parasitology, vol. 24, no. 2, pp. 74–84, 2008.
[46]
C. E. Chitnis and A. Sharma, “Targeting the Plasmodium vivax Duffy-binding protein,” Trends in Parasitology, vol. 24, no. 1, pp. 29–34, 2008.
[47]
A. Brown and M. K. Higgins, “Carbohydrate binding molecules in malaria pathology,” Current Opinion in Structural Biology, vol. 20, no. 5, pp. 560–566, 2010.
[48]
J. J. Babon, W. D. Morgan, G. Kelly, J. F. Eccleston, J. Feeney, and A. A. Holder, “Structural studies on Plasmodium vivax merozoite surface protein-1,” Molecular and Biochemical Parasitology, vol. 153, no. 1, pp. 31–40, 2007.
[49]
R. A. O'Donnell, A. Saul, A. F. Cowman, and B. S. Crabb, “Functional conservation of the malaria vaccine antigen MSP-1 across distantly related Plasmodium species,” Nature Medicine, vol. 6, no. 1, pp. 91–95, 2000.
[50]
P. R. Sanders, L. M. Kats, D. R. Drew et al., “A set of glycosylphosphatidyl inositol-anchored membrane proteins of Plasmodium falciparum is refractory to genetic deletion,” Infection and Immunity, vol. 74, no. 7, pp. 4330–4338, 2006.
[51]
A. Combe, D. Giovannini, T. G. Carvalho et al., “Clonal conditional mutagenesis in malaria parasites,” Cell Host and Microbe, vol. 5, no. 4, pp. 386–396, 2009.
[52]
T. M. Daly and C. A. Long, “A recombinant 15-kilodalton carboxyl-terminal fragment of Plasmodium yoelii yoelii 17XL merozoite surface protein 1 induces a protective immune response in mice,” Infection and Immunity, vol. 61, no. 6, pp. 2462–2467, 1993.
[53]
T. M. Daly and C. A. Long, “Influence of adjuvants on protection induced by a recombinant fusion protein against malarial infection,” Infection and Immunity, vol. 64, no. 7, pp. 2602–2608, 1996.
[54]
B. Singh, M. Cabrera-Mora, J. Jiang, M. Galinski, and A. Moreno, “Genetic linkage of autologous T cell epitopes in a chimeric recombinant construct improves anti-parasite and anti-disease protective effect of a malaria vaccine candidate,” Vaccine, vol. 28, no. 14, pp. 2580–2592, 2010.
[55]
K. L. R. L. Perera, S. M. Handunnetti, I. Holm, S. Longacre, and K. Mendis, “Baculovirus merozoite surface protein 1 C-terminal recombinant antigens are highly protective in a natural primate model for human plasmodium vivax malaria,” Infection and Immunity, vol. 66, no. 4, pp. 1500–1506, 1998.
[56]
J. A. Lyon, E. Angov, M. P. Fay et al., “Protection induced by plasmodium falciparum MSP1 is strain-specific, antigen and adjuvant dependent, and correlates with antibody responses,” PLoS ONE, vol. 3, no. 7, article e2830, 2008.
[57]
B. R. Ogutu, O. J. Apollo, D. McKinney et al., “Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya,” PLoS ONE, vol. 4, no. 3, article e4708, 2009.
[58]
Z. H. Reed, M. P. Kieny, H. Engers et al., “Comparison of immunogenicity of five MSP1-based malaria vaccine candidate antigens in rabbits,” Vaccine, vol. 27, no. 10, pp. 1651–1660, 2009.
[59]
H. C. Ramos, M. Rumbo, and J. C. Sirard, “Bacterial flagellins: mediators of pathogenicity and host immune responses in mucosa,” Trends in Microbiology, vol. 12, no. 11, pp. 509–517, 2004.
[60]
F. Hayashi, K. D. Smith, A. Ozinsky et al., “The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5,” Nature, vol. 410, no. 6832, pp. 1099–1103, 2001.
[61]
K. D. Smith, E. Andersen-Nissen, F. Hayashi et al., “Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility,” Nature Immunology, vol. 4, no. 12, pp. 1247–1253, 2003.
[62]
T. K. Means, F. Hayashi, K. D. Smith, A. Aderem, and A. D. Luster, “The toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells,” Journal of Immunology, vol. 170, no. 10, pp. 5165–5175, 2003.
[63]
S. Arimilli, J. B. Johnson, K. M. Clark et al., “Engineered expression of the TLR5 ligand flagellin enhances paramyxovirus activation of human dendritic cell function,” Journal of Virology, vol. 82, no. 22, pp. 10975–10985, 2008.
[64]
A. Merlo, C. Calcaterra, S. Ménard, and A. Balsari, “Cross-talk between Toll-like receptors 5 and 9 on activation of human immune responses,” Journal of Leukocyte Biology, vol. 82, no. 3, pp. 509–518, 2007.
[65]
S. Agrawal, A. Agrawal, B. Doughty et al., “Cutting Edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos,” Journal of Immunology, vol. 171, no. 10, pp. 4984–4989, 2003.
[66]
A. Didierlaurent, I. Ferrero, L. A. Otten et al., “Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response,” Journal of Immunology, vol. 172, no. 11, pp. 6922–6930, 2004.
[67]
J. T. Bates, S. Uematsu, S. Akira, and S. B. Mizel, “Direct stimulation of tlr5+/+ CD11c+ cells is necessary for the adjuvant activity of flagellin,” Journal of Immunology, vol. 182, no. 12, pp. 7539–7547, 2009.
[68]
E. A. Miao, C. M. Alpuche-Aranda, M. Dors et al., “Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf,” Nature Immunology, vol. 7, no. 6, pp. 569–575, 2006.
[69]
K. L. Lightfield, J. Persson, S. W. Brubaker et al., “Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin,” Nature Immunology, vol. 9, no. 10, pp. 1171–1178, 2008.
[70]
D. S. Zamboni, K. S. Kobayashi, T. Kohlsdorf et al., “The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection,” Nature Immunology, vol. 7, no. 3, pp. 318–325, 2006.
[71]
M. Vinzing, J. Eitel, J. Lippmann et al., “NAIP and Ipaf control Legionella pneumophila replication in human cells,” Journal of Immunology, vol. 180, no. 10, pp. 6808–6815, 2008.
[72]
C. L. Buzzo, J. C. Campopiano, L. M. Massis et al., “A novel pathway for inducible nitric-oxide synthase activation through inflammasomes,” Journal of Biological Chemistry, vol. 285, no. 42, pp. 32087–32095, 2010.
[73]
K. R. Bortoluci and R. Medzhitov, “Control of infection by pyroptosis and autophagy: role of TLR and NLR,” Cellular and Molecular Life Sciences, vol. 67, no. 10, pp. 1643–1651, 2010.
[74]
S. M. C. Newton, C. O. Jacob, and B. A. D. Stocker, “Immune response to cholera toxin epitope inserted in Salmonella flagellin,” Science, vol. 244, no. 4900, pp. 70–72, 1989.
[75]
J. McEwen, R. Levi, R. J. Horwitz, and R. Arnon, “Synthetic recombinant vaccine expressing influenza haemagluttinin epitope in Salmonella flagellin leads to partial protection in mice,” Vaccine, vol. 10, no. 6, pp. 405–411, 1992.
[76]
M. G. Luna, M. M. Martins, S. M. C. Newton, S. O. P. Costa, D. F. Almeida, and L. C. S. Ferreira, “Cloning and expression of colonization factor antigen I (CFA/I) epitopes of enterotogenic Escherichia coli (ETEC) in Salmonella flagellin,” Research in Microbiology, vol. 148, no. 3, pp. 217–228, 1997.
[77]
S. B. Mizel and J. T. Bates, “Flagellin as an adjuvant: cellular mechanisms and potential,” Journal of Immunology, vol. 185, no. 10, pp. 5677–5682, 2010.
[78]
J. W. Huleatt, V. Nakaar, P. Desai et al., “Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin,” Vaccine, vol. 26, no. 2, pp. 201–214, 2008.
[79]
L. Song, V. Nakaar, U. Kavita et al., “Efficacious recombinant influenza vaccines produced by high yield bacterial expression: a solution to global pandemic and seasonal needs,” PLoS ONE, vol. 3, no. 5, article e2257, 2008.
[80]
J. J. Treanor, D. N. Taylor, L. Tussey et al., “Safety and immunogenicity of a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125) in healthy young adults,” Vaccine, vol. 28, no. 52, pp. 8268–8274, 2010.
[81]
M. B. Barbedo, R. Ricci, M. C. S. Jimenez et al., “Comparative recognition by human IgG antibodies of recombinant proteins representing three asexual erythrocytic stage vaccine candidates of Plasmodium vivax,” Memorias do Instituto Oswaldo Cruz, vol. 102, no. 3, pp. 335–339, 2007.
[82]
I. S. Soares, J. W. Barnwell, M. U. Ferreira et al., “A Plasmodium vivax vaccine candidate displays limited allele polymorphism, which does not restrict recognition by antibodies,” Molecular Medicine, vol. 5, no. 7, pp. 459–470, 1999.
[83]
M. H. C. Rodrigues, M. G. Cunha, R. L. D. Machado, O. C. Ferreira, M. M. Rodrigues, and I. S. Soares, “Serological detection of Plasmodium vivax malaria using recombinant proteins corresponding to the 19-kDa C-terminal region of the merozoite surface protein-1,” Malaria Journal, vol. 2, no. 1, pp. 1–7, 2003.
[84]
S. Dutta, D. C. Kaushal, L. A. Ware et al., “Merozoite surface protein 1 of Plasmodium vivax induces a protective response against Plasmodium cynomolgi challenge in rhesus monkeys,” Infection and Immunity, vol. 73, no. 9, pp. 5936–5944, 2005.
[85]
D. Y. Bargieri, D. S. Rosa, C. J. M. Braga et al., “New malaria vaccine candidates based on the Plasmodium vivax Merozoite Surface Protein-1 and the TLR-5 agonist Salmonella Typhimurium FliC flagellin,” Vaccine, vol. 26, no. 48, pp. 6132–6142, 2008.
[86]
D. Y. Bargieri, J. A. Leite, S. C. P. Lopes et al., “Immunogenic properties of a recombinant fusion protein containing the C-terminal 19 kDa of Plasmodium falciparum merozoite surface protein-1 and the innate immunity agonist FliC flagellin of Salmonella Typhimurium,” Vaccine, vol. 28, no. 16, pp. 2818–2826, 2010.
[87]
C. J. M. Braga, L. M. Massis, M. E. Sbrogio-Almeida et al., “CD8+ T cell adjuvant effects of Salmonella FliCd flagellin in live vaccine vectors or as purified protein,” Vaccine, vol. 28, no. 5, pp. 1373–1382, 2010.
[88]
O. Pino, M. Martin, and S. M. Michalek, “Cellular mechanisms of the adjuvant activity of the flagellin component FljB of Salmonella enterica serovar typhimurium to potentiate mucosal and systemic responses,” Infection and Immunity, vol. 73, no. 10, pp. 6763–6770, 2005.
[89]
S. K. Datta, V. Redecke, K. R. Prilliman et al., “A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells,” Journal of Immunology, vol. 170, no. 8, pp. 4102–4110, 2003.
[90]
I. Vicente-Suarez, J. Brayer, A. Villagra, F. Cheng, and E. M. Sotomayor, “TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses,” Immunology Letters, vol. 125, no. 2, pp. 114–118, 2009.
[91]
C. J. Sanders, L. Franchi, F. Yarovinsky et al., “Induction of adaptive immunity by flagellin does not require robust activation of innate immunity,” European Journal of Immunology, vol. 39, no. 2, pp. 359–371, 2009.
[92]
M. Vijay-Kumar, F. A. Carvalho, J. D. Aitken, N. H. Fifadara, and A. T. Gewirtz, “TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin,” European Journal of Immunology, vol. 40, no. 12, pp. 3528–3534, 2010.
