Evaluation of BCG expressing adjuvant LTAK63 in a humanized mouse model as a therapeutic vaccine for Tuberculosis

• Grant number: 19/06454-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2019
• End date: August 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Luciana Cezar de Cerqueira Leite
• Grantee: Monalisa Martins Trentini
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 17/24832-6 - Development of vaccines based on recombinant BCG: Tuberculosis, Pertussis, Pneumococcus and Schistosoma, AP.TEM

Abstract

One third of the human population is believed to be infected with Mycobacterium Tuberculosis (Mtb), the causative agent of Tuberculosis (TB). Despite enormous efforts, TB remains a major global health problem because of the millions of deaths associated with TB. Thus, several strategies are in development aiming at better diagnosis, as well as improved treatment and prevention for TB. The use of vaccines in the treatment of diseases aims at complementing the chemotherapy, reducing the time of antibiotic use. Due to the strong induction of inflammatory cells, BCG (Bacille Calmette-Guerin) has been widely used in the immunotherapy of some diseases, such as Bladder Cancer. BCG has also been considered effective for the treatment of Asthma, due to the high induction of IFN-³ and IL-2. However, recombinant BCG vaccines have not yet been investigated for the treatment of TB. In this sense, our research group has developed a recombinant BCG vaccine that expresses the adjuvant LTAK63 (rBCG-LTAK63) that was able to induce high Th1 and Th17 responses, in addition to high levels of TGF-² after challenge, culminating in elevated protection of mice challenged with Mtb. Therefore, this work aims to investigate rBCG-LTAK63 for the treatment of TB. The induction of immune responses will be characterized in the lungs of mice in models of active or reactivated latent TB infection, and the effectiveness in reducing infection will be investigated. In addition, both the immune response and the efficacy of the treatment using the rBCG-LTAK63 vaccine will be evaluated in a humanized mice model, mimicking the progression of infection and treatment that could occur in humans. (AU)

Scientific publications

(4)

(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)

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., 2022-08-31. (17/24832-6, 19/02305-0, 19/06454-0)

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., 2023-01-26. (16/50413-8, 21/02930-1, 19/06454-0, 17/24832-6, 09/17030-4)

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., 2023-07-13. (19/06454-0, 19/02305-0, 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., 2022-03-30. (17/24832-6, 17/17218-0, 19/06454-0)