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Development of vaccines based on recombinant BCG: Tuberculosis, Pertussis, Pneumococcus and Schistosoma

Grant number: 17/24832-6
Support Opportunities:Research Projects - Thematic Grants
Duration: November 01, 2018 - October 31, 2024
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Luciana Cezar de Cerqueira Leite
Grantee:Luciana Cezar de Cerqueira Leite
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Pesquisadores principais:
Viviane Maimoni Gonçalves
Associated researchers:Alex Issamu Kanno ; Ana Carolina Ramos Moreno ; Celio Lopes Silva ; Dunia Del Carmen Rodriguez Soto ; Giovana Cappio Barazzone ; Helder Takashi Imoto Nakaya ; Ivan Pereira Nascimento ; Johnjoe McFadden ; Leonardo Paiva Farias ; Michelle Darrieux Sampaio Bertoncini ; Ricardo Carneiro Borra ; Richard Malley ; Robert Alan Wilson ; Sergio Costa Oliveira ; Sergio Verjovski Almeida
Associated scholarship(s):22/13917-9 - Investigation of the mechanisms of innate immune response activation induced by rBCG-LTAK63 and rBCG-S1PT vaccines: autophagy and inflammasome activation, BP.MS
23/03874-3 - Immunization with recombinant BCG expressing epitopes from SARS-CoV-2 spike and nuceloprotein protects against infection in hACE-2 murine model, BP.PD
22/15269-4 - Assessment of pH control and feeding of amino acid and carbon sources to optimize the onco-rBCG-pertussis immunotherapy production in 1 and 10 L bioreactors, BP.PD
+ associated scholarships 22/14764-1 - Immunotherapy based on recombinant Bacillus Calmette-Guérin (BCG) for the treatment of bladder cancer in a murine model, BP.IC
21/14376-9 - Optimization of SARS-CoV-2 antigen production in Expi293 cell culture aiming OMV-based vaccine generation, BP.MS
21/12711-5 - Recombinant BCG as a vaccine platform against COVID-19: construction of polyvalent vaccines for the most important SARS-CoV-2 variants, BP.PD
21/12120-7 - Development of a vaccine against the SARS-CoV-2 Coronavirus using the new antigen presenting system (MAPS - OMV), BP.PD
20/14443-5 - Conjugation of antigens to the surface of BCG vaccine: application of the avidin-biotin system, BP.MS
20/05589-6 - Immunological characterization of a recombinant BCG strain that simultaneously expresses mutant Pertussis toxin S1PT and adjuvant LTAK63 (rBCG-LTAK63-S1PT) for use as a bivalent vaccine to prevent Neonatal Pertussis and Tuberculosis, BP.DD
21/00145-5 - Development of a vaccine against the SARS-CoV-2 Coronavirus using the new antigen presenter system (MAPS - OMV), BP.TT
20/14758-6 - Development of a vaccine against the SARS-CoV-2 Coronavirus using the new Antigen Presenting System (MAPS - OMV), BP.PD
20/07547-9 - Development of a vaccine against Coronavirus SARS-CoV-2 using a new antigen presenting system, BP.PD
20/02049-0 - Strategies for monitoring and controlling the cultivation of recombinant BCG-pertussis, BP.MS
19/25728-3 - Evaluation of the role of POLIAMINAS PotD transporter in the formation of biofilm in vitro by Streptococcus pneumoniae, BP.IC
19/06454-0 - Evaluation of BCG expressing adjuvant LTAK63 in a humanized mouse model as a therapeutic vaccine for Tuberculosis, BP.PD
19/02305-0 - Investigation of immune response mechanisms effective of a BCG Vaccine Recombinant against Tuberculosis by Systems Biology, BP.PD - associated scholarships


Our studies have demonstrated the advantages of Mycobacterium bovis BCG as an antigen presenting system in the development of new vaccines. The project aims to expand the use of methods of heterologous gene expression in BCG developed in our laboratories with the aim of proposing new vaccines in the immunization against Pertussis, Tuberculosis, Pneumococcus and Schistosome, and to improve the immunotherapeutic treatment of Bladder Cancer. Some proposals are more advanced, such as the recombinant BCG (rBCG) vaccine against Neonatal Pertussis and the rBCG strain used for improved treatment against Bladder Cancer that are heading for clinical trials. The rBCG strain expressing an E. coli antigen as adjuvant, which was shown to induce greater protection against Tuberculosis, completed the proof of concept phase and it should be further characterized. The establishment of the CRISPR/Cas9 platform and the Systems Biology approach will boost these studies. We have extensive research on pneumococcal antigens under different forms of presentation. The association of this information with the advantages of rBCG has been shown to be a promising approach. Schistosoma functional genomics provided a number of genes / proteins that have been characterized as potential vaccine candidates, but require a more immunogenic presentation to the immune system. We will investigate new expression vectors in rBCG and a new strategy, MAPS (Multiple Antigen Presenting System), aiming to improve the induction of immune responses and protection. Immune responses induced by rBCG strains will be compared to other forms of antigen presentation in search for correlates of protection. The results of each of the subprojects are expected to generate effective immunobiologicals against major diseases in the public health context of the country to enable large-scale, low-cost production. (AU)

Articles published in Pesquisa para Inovação FAPESP about research grant:
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Scientific publications (32)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MARINHO, FABIO V.; FAHEL, JULIA S.; DE ARAUJO, ANA CAROLINA V. S. C.; DINIZ, LUNNA T. S.; GOMES, MARCO T. R.; RESENDE, DANILO P.; JUNQUEIRA-KIPNIS, ANA P.; OLIVEIRA, SERGIO C.. Guanylate binding proteins contained in the murine chromosome 3 are important to control mycobacterial infection. Journal of Leukocyte Biology, . (17/24832-6)
MARQUES-NETO, LAZARO M.; PIWOWARSKA, ZUZANNA; KANNO, I, ALEX; MORAES, LUANA; TRENTINI, MONALISA M.; RODRIGUEZ, DUNIA; SILVA, JOSE L. S. C.; LEITE, LUCIANA C. C.. Thirty years of recombinant BCG: new trends for a centenary vaccine. EXPERT REVIEW OF VACCINES, v. 20, n. 8, . (17/24832-6)
DE QUEIROZ, NINA MARI G. P.; MARINHO, FABIO V.; CHAGAS, MARCELO A.; LEITE, LUCIANA C. C.; HOMAN, E. JANE; DE MAGALHAES, MARIANA T. Q.; OLIVEIRA, SERGIO C.. Vaccines for COVID-19: perspectives from nucleic acid vaccines to BCG as delivery vector system. Microbes and Infection, v. 22, n. 10, p. 515-524, . (17/24832-6)
SANCHES, RODRIGO C. O.; SOUZA, CLAUDIA; OLIVEIRA, SERGIO C.. Schistosoma antigens as activators of inflammasome pathway: from an unexpected stimulus to an intriguing role. Microbes and Infection, v. 22, n. 10, p. 534-539, . (17/24832-6)
MAMBELLI, F. S.; FIGUEIREDO, B. C.; MORAIS, S. B.; ASSIS, N. R. G.; FONSECA, C. T.; OLIVEIRA, S. C.. Recombinant micro-exon gene 3 (MEG-3) antigens from Schistosoma mansoni failed to induce protection against infection but show potential for serological diagnosis. Acta Tropica, v. 204, . (17/24832-6)
LARISSA V NASCIMENTO; CARINA C SANTOS; LUCIANA CC LEITE; IVAN P NASCIMENTO. Characterisation of alternative expression vectors for recombinant Bacillus Calmette-Guérin as live bacterial delivery systems. Memórias do Instituto Oswaldo Cruz, v. 115, . (14/01271-0, 17/24832-6)
DE QUEIROZ, NINA M. G. P.; MARINHO, FABIO V.; DE ARAUJO, ANA CAROLINA V. S. C.; FAHEL, JULIA S.; OLIVEIRA, SERGIO C.. MyD88-dependent BCG immunotherapy reduces tumor and regulates tumor microenvironment in bladder cancer murine model. SCIENTIFIC REPORTS, v. 11, n. 1, . (17/24832-6)
ZANE, LUCIANO; KRASCHOWETZ, STEFANIE; TRENTINI, MONALISA MARTINS; ALVES, VITOR DOS SANTOS; ARAUJO, SERGIO CARNEIRO; GOULART, CIBELLY; LEITE, LUCIANA CEZAR DE CERQUEIRA; GONCALVES, VIVIANE MAIMONI. Peptide linker increased the stability of pneumococcal fusion protein vaccine candidate. FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY, v. 11, p. 18-pg., . (16/50413-8, 21/02930-1, 19/06454-0, 17/24832-6, 09/17030-4)
CONVERSO, T. R.; ASSONI, L.; ANDRE, G. O.; DARRIEUX, M.; LEITE, L. C. C.. The long search for a serotype independent pneumococcal vaccine. EXPERT REVIEW OF VACCINES, v. 19, n. 1, . (17/24832-6)
ELIZAGARAY, MAIA L.; GOMES, MARCO TULIO R.; GUIMARAES, ERIKA S.; RUMBO, MARTIN; HOZBOR, DANIELA F.; OLIVEIRA, SERGIO C.; MORENO, GRISELDA. Canonical and Non-canonical Inflammasome Activation by Outer Membrane Vesicles Derived FromBordetella pertussis. FRONTIERS IN IMMUNOLOGY, v. 11, . (17/24832-6)
MARQUES-NETO, LAZARO MOREIRA; TRENTINI, MONALISA MARTINS; KANNO, ALEX ISSAMU; RODRIGUEZ, DUNIA; LEITE, LUCIANA CEZAR DE CERQUEIRA. Recombinant BCG expressing the LTAK63 adjuvant increased memory T cells and induced long-lasting protection against Mycobacterium tuberculosis challenge in mice. FRONTIERS IN IMMUNOLOGY, v. 14, p. 11-pg., . (19/06454-0, 19/02305-0, 17/24832-6)
SANCHES, RODRIGO C. O.. The role of the adaptor molecule STING during Schistosoma mansoni infection. SCIENTIFIC REPORTS, v. 10, n. 1, . (17/24832-6)
SANTOS, B. P. O.; ALVES, E. S. F.; FERREIRA, C. S.; FERREIRA-SILVA, A.; GOES-NETO, A.; VERLY, R. M.; LIAO, L. M.; OLIVEIRA, S. C.; DE MAGALHAES, M. T. Q.. Schistocins: Novel antimicrobial peptides encrypted in the Schistosoma mansoni Kunitz Inhibitor SmKI-1. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1865, n. 11, . (17/24832-6)
MORAES, LUANA; TRENTINI, MONALISA MARTINS; FOUSTERIS, DIMITRIOS; ETO, SILAS FERNANDES; CHUDZINSKI-TAVASSI, ANA MARISA; DE CERQUEIRA LEITE, LUCIANA CEZAR; KANNO, ALEX ISSAMU. CRISPR/Cas9 Approach to Generate an Auxotrophic BCG Strain for Unmarked Expression of LTAK63 Adjuvant: A Tuberculosis Vaccine Candidate. FRONTIERS IN IMMUNOLOGY, v. 13, p. 10-pg., . (17/24832-6, 17/17218-0, 19/06454-0)
MARINHO, FABIO V.; FAHEL, JULIA S.; DE ARAUJO, ANA CAROLINA V. S. C.; DINIZ, LUNNA T. S.; GOMES, MARCO T. R.; RESENDE, DANILO P.; JUNQUEIRA-KIPNIS, ANA P.; OLIVEIRA, SERGIO C.. Guanylate binding proteins contained in the murine chromosome 3 are important to control mycobacterial infection. Journal of Leukocyte Biology, v. 108, n. 4, p. 13-pg., . (17/24832-6)
DOS SANTOS, TANILA WOOD; GONCALVES, PEDRO ALMEIDA; RODRIGUEZ, DUNIA; PEREIRA, JOSE AIRES; REAL MARTINEZ, CARLOS AUGUSTO; LEITE, LUCIANA C. C.; FERRAZ, LUCIO F. C.; CONVERSO, THIAGO ROJAS; DARRIEUX, MICHELLE. A fusion protein comprising pneumococcal surface protein A and a pneumolysin derivate confers protection in a murine model of pneumococcal pneumonia. PLoS One, v. 17, n. 12, p. 12-pg., . (14/01115-9, 17/24832-6)
ALEX I. KANNO; MAYRA M.F. BARBOSA; LUANA MORAES; LUCIANA C.C. LEITE. SARS-CoV-2 vaccine development and how Brazil is contributing. GENETICS AND MOLECULAR BIOLOGY, v. 44, n. 1, . (17/24832-6, 20/07547-9, 17/17218-0)
FARIAS, LEONARDO P.; VANCE, GILLIAN M.; COULSON, PATRICIA S.; VITORIANO-SOUZA, JULIANA; NETO, ALMIRO PIRES DA SILVA; WANGWIWATSIN, ARPORN; NEVES, LEANDRO XAVIER; CASTRO-BORGES, WILLIAM; MCNICHOLAS, STUART; WILSON, KEITH S.; et al. Epitope Mapping of Exposed Tegument and Alimentary Tract Proteins Identifies Putative Antigenic Targets of the Attenuated Schistosome Vaccine. FRONTIERS IN IMMUNOLOGY, v. 11, . (12/23124-4, 17/24832-6)
DOS SANTOS, CARINA CARVALHO; RODRIGUEZ, DUNIA; ISSAMU, ALEX KANNO; DE CERQUEIRA LEITE, LUCIANA CEZAR; NASCIMENTO, IVAN PEREIRA. Recombinant BCG expressing the LTAK63 adjuvant induces increased early and long-term immune responses against Mycobacteria. HUMAN VACCINES & IMMUNOTHERAPEUTICS, v. 16, n. 3, p. 673-683, . (17/24832-6, 14/01271-0)
TRENTINI, MONALISA MARTINS; KANNO, ALEX ISSAMU; RODRIGUEZ, DUNIA; MARQUES-NETO, LAZARO MOREIRA; ETO, SILAS FERNANDES; CHUDZINKI-TAVASSI, ANA MARISA; LEITE, LUCIANA CEZAR DE CERQUEIRA. Recombinant BCG expressing the LTAK63 adjuvant improves a short-term chemotherapy schedule in the control of tuberculosis in mice. FRONTIERS IN IMMUNOLOGY, v. 13, p. 12-pg., . (17/24832-6, 19/02305-0, 19/06454-0)
PAGLIARONE, ANA CAROLINA; CASTANEDA, EDWIN DAVID; PEDOTT SANTANA, JHONNE PEDRO; DE OLIVEIRA, CAIO ALMEIDA; ROBELDO, THAIANE ALCARDE; TEIXEIRA, FELIPE ROBERTI; BORRA, RICARDO CARNEIRO. Mitochondrial heat shock protein mortalin as potential target for therapies based on oxidative stress. Photodiagnosis and Photodynamic Therapy, v. 34, . (17/24832-6)
OLIVEIRA, F. M.; MARINHO, F. V.; OLIVEIRA, S. C.; RESENDE, D. P.; JUNQUEIRA-KIPNIS, A. P.; KIPNIS, A.. Mycobacterium abscessus subsp. massiliense expressing bacterioferritin have improved resistance to stressful conditions. Journal of Applied Microbiology, v. 128, n. 6, . (17/24832-6)
OLIVEIRA, SERGIO C.; DE MAGALHAES, MARIANA T. Q.; HOMAN, E. JANE. Immunoinformatic Analysis of SARS-CoV-2 Nucleocapsid Protein and Identification of COVID-19 Vaccine Targets. FRONTIERS IN IMMUNOLOGY, v. 11, . (17/24832-6)
MAMBELLI, FABIO; SANTOS, BRUNO P. O.; MORAIS, SUELLEN B.; GIMENEZ, ENRICO G. T.; ASTONI, DUANA C. DOS S.; BRAGA, AMANDA D.; FERREIRA, RAFAELA S.; AMARAL, FLAVIO A.; DE MAGALHAES, MARIANA T. Q.; C. OLIVEIRA, SERGIO. S. mansoni SmKI-1 Kunitz-domain: Leucine point mutation at P1 site generates enhanced neutrophil elastase inhibitory activity. PLoS Neglected Tropical Diseases, v. 15, n. 1, . (17/24832-6)
ROBELDO, THAIANE; RIBEIRO, LUCAS S.; MANRIQUE, LIDA; KUBO, ANDRESSA MAYUMI; LONGO, ELSON; CAMARGO, EMERSON RODRIGUES; BORRA, RICARDO CARNEIRO. Modified Titanium Dioxide as a Potential Visible-Light-Activated Photosensitizer for Bladder Cancer Treatment. ACS OMEGA, v. N/A, p. 12-pg., . (13/07296-2, 17/24832-6)
SANCHES, RODRIGO C. O.; SOUZA, CLAUDIA; MARINHO, FABIO VITARELLI; MAMBELLI, FABIO SILVA; MORAIS, SUELLEN B.; GUIMARAES, ERIKA S.; OLIVEIRA, SERGIO COSTA. NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection. FRONTIERS IN IMMUNOLOGY, v. 11, . (17/24832-6)
CONVERSO, THIAGO ROJAS; GOULART, CIBELLY; RODRIGUEZ, DUNIA; SOUZA GUERRA, MARIA EDUARDA; DARRIEUX, MICHELLE; LEITE, LUCIANA C. C.. Immune response induced in mice by a hybrid rPotD-PdT pneumococcal protein. PLoS One, v. 17, n. 8, p. 14-pg., . (12/04286-3, 17/24832-6, 19/23566-6)
RODRIGUEZ, DUNIA; GOULART, CIBELLY; PAGLIARONE, ANA C.; SILVA, ELIANE P.; CUNEGUNDES, PRISCILA S.; NASCIMENTO, IVAN P.; BORRA, RICARDO C.; DIAS, WALDELY O.; TAGLIABUE, ALDO; BORASCHI, DIANA; et al. In vitro Evidence of Human Immune Responsiveness Shows the Improved Potential of a Recombinant BCG Strain for Bladder Cancer Treatment. FRONTIERS IN IMMUNOLOGY, v. 10, . (17/24832-6)
KANNO, I, ALEX; BARBOSA, MAYRA M. F.; MORAES, LUANA; LEITE, LUCIANA C. C.. SARS-CoV-2 vaccine development and how Brazil is contributing. GENETICS AND MOLECULAR BIOLOGY, v. 44, n. 1, 1, . (17/17218-0, 17/24832-6, 20/07547-9)
DOS SANTOS, CARINA C.; WALBURG, KIMBERLEY, V; VAN VEEN, SUZANNE; WILSON, LOUIS G.; TRUFEN, CARLOS E. M.; NASCIMENTO, IVAN P.; OTTENHOFF, TOM H. M.; LEITE, LUCIANA C. C.; HAKS, MARIELLE C.. Recombinant BCG-LTAK63 Vaccine Candidate for Tuberculosis Induces an Inflammatory Profile in Human Macrophages. VACCINES, v. 10, n. 6, p. 14-pg., . (17/24832-6, 14/01271-0, 17/03332-5)
PEDOTT SANTANA, JHONNE PEDRO; MARCATO, PRISCYLA DANIELY; CHRYSOSTOMO MASSARO, TAIS NADER; GODOY, NAIANE LIMA; ANIBAL, FERNANDA DE FREITAS; BORRA, RICARDO CARNEIRO. Efficacy of instillation of MB49 cells and thermoreversible polymeric gel in urothelial bladder carcinoma immunization. LABORATORY ANIMAL RESEARCH, v. 38, n. 1, p. 12-pg., . (17/24832-6, 18/13465-5, 13/07296-2)

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