Bacillus Calmette-Guérin Immunotherapy for Cancer.

Bacillus Calmette-Guérin (BCG), an attenuated vaccine from Mycobacterium bovis, was initially developed as an agent for vaccination against tuberculosis. BCG proved to be the first successful immunotherapy against established human bladder cancer and other neoplasms. The use of BCG has been shown to induce a long-lasting antitumor response over all other forms of treatment against intermediate, non-invasive muscle bladder cancer Several types of tumors may now be treated by releasing the immune response through the blockade of checkpoint inhibitory molecules, such as CTLA-4 and PD-1. In addition, Toll-Like Receptor (TLR) agonists and BCG are used to potentiate the immune response against tumors. Studies concerning TLR-ligands combined with BCG to treat melanoma have demonstrated efficacy in treating mice and patients This review addresses several interventions using BCG on neoplasms, such as Leukemia, Bladder Cancer, Lung Cancer, and Melanoma, describing treatments and antitumor responses promoted by this attenuated bacillus. Of essential importance, BCG is described recently to participate in an adequate microbiome, establishing an effective response during cell-target therapy when combined with anti-PD-1 antibody, which stimulates T cell responses against the melanoma. Finally, trained immunity is discussed, and reprogramming events to shape innate immune responses are addressed.

Oral delivery of BCG Moreau Rio de Janeiro gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination.

There is a need for an improved vaccine to better control human tuberculosis (TB), as the only currently available TB vaccine, bacillus Calmette-Guerin (BCG) delivered parenterally, offers variable levels of efficacy. Therefore, recombinant strains expressing additional antigens are being developed alongside alternative routes to parenteral delivery. There is strong evidence that BCG Moreau (RdJ) is a safe and effective vaccine in humans when given by the oral route. This study compared the efficacy of a single oral dose of wild type BCG Moreau Rio de Janeiro (RdJ), or a recombinant RdJ strain expressing Ag85B-ESAT6 fusion protein, formulated with and without lipid to enhance oral delivery, with subcutaneous BCG Danish 1331 and saline control groups in a guinea pig aerosol infection model of pulmonary tuberculosis. Protection was measured as survival at 30 weeks post-challenge and reduced bacterial load and histopathology in lungs and spleen. Results showed that a single oral dose of BCG Moreau (RdJ) or recombinant BCG Moreau (RdJ)-Ag85B-ESAT6, formulated with or without lipid, gave protection equivalent to subcutaneously delivered BCG Danish in the 30 weeks post-challenge survival study. The orally delivered vaccines gave reduced pathology scores in the lungs (three of the four formulations) and spleens (all four formulations) compared to subcutaneously delivered BCG Danish. The oral wild type BCG Moreau (RdJ) in lipid and the unformulated oral wild type BCG Moreau (RdJ) vaccine also gave statistically lower bacterial loads in the lungs and spleens, respectively, compared to subcutaneously delivered BCG Danish. This study provides further evidence to show that lipid formulation does not impair vaccine efficacy and may enhance the delivery and stability of oral vaccines intended for use in countries with poor health infrastructure. Oral delivery also avoids needles (and associated cross-infection risks) and immunisation without the need for specially trained medical professional staff.

The dolabellane diterpene Dolabelladienetriol is a typical noncompetitive inhibitor of HIV-1 reverse transcriptase enzyme.

We recently described that a dollabelane diterpene isolated from the marine algae Dictyota pfaffii (Dolabelladienetriol) inhibits the human immunodeficiency virus type 1 (HIV-1) enzyme reverse transcriptase (RT), and HIV-1 replication in primary cells. Based on these findings, we investigated additional antiretroviral properties of Dolabelladienetriol. Here, we describe that Dolabelladienetriol blocked the synthesis and integration of HIV-1 provirus and completely abrogated viral replication in primary cells. Also, studies of kinetic mode of action revealed that the Dolabelladienetriol is a nonnucleoside RT inhibitor (NNRTI), acting as a noncompetitive inhibitor, with a K(i) value equal to 7.2 microM. To assess whether Dolabelladienetriol could potentiate the anti-HIV-1 effects of other HIV-1 inhibitors, HIV-1-infected cells were treated with Dolabelladienetriol at its EC(50) dose plus sub-optimal concentrations of classical antiretrovirals. Dolabelladienetriol provided an additive effect with the nucleoside RT inhibitor AZT, and a synergistic effect with the protease inhibitor atazanavir sulphate. There was no increment of the anti-HIV-1 effect resulting from the combination between Dolabelladienetriol and the NNRTI nevirapine. Using a large panel of HIV-1 isolates harboring NNRTI resistance mutations, we found no cross-resistance between Dolabelladienetriol and clinical available NNRTIs. Thus, Dolabelladienetriol is an NNRTI, with potent activity against HIV-1 isolates carrying common NNRTI-associated resistance mutations. Dolabelladienetriol may be considered as a potential new agent for anti-HIV-1 therapy.

Inhibition of HIV-1 replication in human primary cells by a dolabellane diterpene isolated from the marine algae Dictyota pfaffii.

We describe in this paper that the dolabellane diterpene 8,10,18-trihydroxy-2,6-dolabelladiene (3), isolated from the marine algae Dictyota pfaffii, inhibits the HIV-1 infection in human primary cells and tumor cell lines. We initially observed that compound 3 inhibited the activity of a purified HIV-1 enzyme reverse transcriptase (RT) in a dose-dependent manner, with an IC (50) value of 16.5 +/- 4.3 microM. Next, we found that compound 3 inhibited HIV-1 infection by an R5-tropic isolate in peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner with an EC (50) value of 8.4 +/- 2.8 microM. The replication of HIV-1 isolates presenting distinct tropism for chemokine receptors was also inhibited, as analyzed in PBMCs or U87 cells infected with R5-, X4- or R5X4-tropic isolates. Likewise, compound 3 blocked HIV-1 infection in macrophages by R5 and R5X4 viruses in a dose-dependent manner with EC (50) values of 1.7 +/- 0.6 microM and 1.85 +/- 0.75 microM, respectively. Compound 3 sustained antiretroviral activity even when added to HIV-1-infected Sup-T1 cells at 12 h after infection, suggesting that, as well as inhibiting HIV-1 RT, it also blocks HIV-1 replication at a post transcriptional step. Our results support further investigations on compound 3 pharmacokinetics and we propose that this diterpene could be considered as a potential compound for HIV-1 therapy.

BCG Moreau Rio de Janeiro: an oral vaccine against tuberculosis--review.

The vaccine Bacillus of Calmette Guérin (BCG) was originally developed in France as an oral vaccine against tuberculosis. The oral use of this vaccine was replaced by the parenteral route in almost all countries after the Lubeck disaster. In contrast, Brazil retained the oral delivery of the vaccine until the mid-seventies when it was replaced by the intradermal route. This change in route of delivery was mainly secondary to pressure by medical practitioners based on the poor responses of oral immunized subjects to purified protein derivative (PPD) skin tests. Even after the change of route of delivery, Ataulpho de Paiva Foundation continued making the oral vaccine. Currently, BCG Moreau has been described as one of the most immunogenic and with fewer side effects than other BCGs. The genomics, proteomics and vaccine trials for oral BCG Moreau Rio de Janeiro are currently under investigation. In this review, we intend to describe the history of BCG Moreau Rio de Janeiro in Brazil.

BCG Moreau Rio de Janeiro: an oral vaccine against tuberculosis - review

The vaccine Bacillus of Calmette Guérin (BCG) was originally developed in France as an oral vaccine against tuberculosis. The oral use of this vaccine was replaced by the parenteral route in almost all countries after the Lubeck disaster. In contrast, Brazil retained the oral delivery of the vaccine until the mid-seventies when it was replaced by the intradermal route. This change in route of delivery was mainly secondary to pressure by medical practitioners based on the poor responses of oral immunized subjects to purified protein derivative (PPD) skin tests. Even after the change of route of delivery, Ataulpho de Paiva Foundation continued making the oral vaccine. Currently, BCG Moreau has been described as one of the most immunogenic and with fewer side effects than other BCGs. The genomics, proteomics and vaccine trials for oral BCG Moreau Rio de Janeiro are currently under investigation. In this review, we intend to describe the history of BCG Moreau Rio de Janeiro in Brazil.

Investigação dos aspectos nutricionais em homens abrigados em uma instituição filantrópica envolvida em surto de tuberculose

Em exames médicos de rotina realizados em um centro de integração social que abriga, em regime de internato, cerca de 160 homens, ex-moradores de rua, na faixa etária de 20 a 74 anos foram detectados sinais e sintomas de tuberculose pulmonar em alguns comunitários, sendo confirmado o diagnóstico em cinco deles. Foram investigados os aspectos nutricionais e os fatores de risco que poderiam estar associados ao surto infeccioso. Realizamos avaliações dietéticas, antropométricas e laboratoriais em todos os indivíduos. Na análise dietética verificou-se que esta é superestimada com relação ao valor energético e deficitária na oferta dos micronutrientes associados à imunocompetência. Quando avaliamos os compartimentos corporais observamos que grande parte da população estudada (47%) encontrava-se com a reserva gordurosa acima dos valores de normalidade e a massa protéica somática com valores abaixo do normal. Ao compararmos o grupo de tuberculosos com os não doentes somente os valores para hemoglobina foram significativos, sendo inferiores nos indivíduos doentes. Esta alteração pode estar associada a parasitoses intestinais, já que a ingestão de ferro foi similar em todos os indivíduos investigados. Ancilostomíase, amebíase, giardíase e ascaridíase estavam presentes em 40% da amostra de albergados investigada. A correlação entre os achados da avaliação antropométrica e dietética nos sugere que fatores envolvidos com a qualidade da dieta, tal qual o teor de alguns micronutrientes, possam estar envolvidos com o maior risco para o desenvolvimento de tuberculose

Diagnostic detection of human immunodeficiency virus type 1 antibodies in urine: a brazilian study.

We evaluated, for the first time in Latin America, the performance of a commercial enzyme immunoassay (EIA) (Calypte Biomedical Corporation, Berkeley, Calif.) that detects human immunodeficiency virus type 1 (HIV-1)-specific antibodies in urine in comparison to standard serological assays (two commercial EIAs and a commercial Western blot [WB] assay). Paired serum and urine specimens were collected from two different groups of Brazilian patients: 225 drug users with unknown HIV status who attended drug treatment centers in Rio de Janeiro, Brazil, and 135 subjects with known HIV status. Patients showing positive results in the serum EIAs and/or in the urine EIA were serologically confirmed by WB assay. For 135 individuals with known HIV status, the urine EIA showed 100% sensitivity (74 positive samples) and 95.1% specificity (58 of 61 negative specimens). For 225 drug users, the test showed 100% sensitivity (2 positive samples) and 98.7% specificity (220 of 223 negative samples) compared to WB-confirmed serological EIA results. Thus, in a total of 360 samples, the urine EIA correctly identified all 76 HIV-positive samples and 278 of 284 negative samples (100% sensitivity and 97.9% specificity). Detailed analysis of the urine EIA results indicates that an increase of the recommended cutoff value might raise the specificity of the assay without affecting its sensitivity. Our results suggest that the HIV-1 urine EIA is a good screening test suitable for developing countries like Brazil. However, as for all other HIV screening tests on the market, it is not specific enough to be used as a one-step test and therefore requires confirmation.

Immunization of persons with HIV infection and other secondary immunodeficiencies

Patients with secondary immunodeficiencies are at a high risk of infection. Currently some of these infections are preventable through specific immunization. Prevention of these diseases can diminish morbidity and mortality amongst these patients. In this review we describe the use of vaccines in persons with secondary immunodeficiencies.