Immunogenicity of COVID-19 adsorbed inactivated vaccine (CoronaVac) and additional doses of mRNA BNT162b2 vaccine in immunocompromised adults compared with immunocompetent persons.

Inactivated COVID-19 vaccines data in immunocompromised individuals are scarce. This trial assessed the immunogenicity of two CoronaVac doses and additional BNT162b2 mRNA vaccine doses in immunocompromised (IC) and immunocompetent (H) individuals. Adults with solid organ transplant (SOT), hematopoietic stem cell transplant, cancer, inborn immunity errors or rheumatic diseases were included in the IC group. Immunocompetent adults were used as control group for comparison. Participants received two CoronaVac doses within a 28-day interval. IC received two additional BNT162b2 doses and H received a third BNT162b2 dose (booster). Blood samples were collected at baseline, 28 days after each dose, pre-booster and at the trial end. We used three serological tests to detect antibodies to SARS-CoV-2 nucleocapsid (N), trimeric spike (S), and receptor binding domain (RBD). Outcomes included seroconversion rates (SCR), geometric mean titers (GMT) and GMT ratio (GMTR). A total of 241 IC and 100 H adults participated in the study. After two CoronaVac doses, IC had lower SCR than H: anti-N, 33.3% vs 79%; anti-S, 33.8% vs 86%, and anti-RBD, 48.5% vs 85%, respectively. IC also showed lower GMT than H: anti-N, 2.3 vs 15.1; anti-S, 58.8 vs 213.2 BAU/mL; and anti-RBD, 22.4 vs 168.0 U/mL, respectively. After the 3rd and 4th BNT162b2 doses, IC had significant anti-S and anti-RBD seroconversion, but still lower than H after the 3rd dose. After boosting, GMT increased in IC, but remained lower than in the H group. CoronaVac two-dose schedule immunogenicity was lower in IC than in H. BNT162b2 heterologous booster enhanced immune response in both groups.

Assessment of biomarkers and clinical parameters as predictors of survival in patients with chagasic heart failure.

BACKGROUND: Chagas disease, endemic in Latin America and spreading globally due to emigration, has a significant health burden, particularly in relation to chagasic heart failure (HF). Chagasic cardiomyopathy (CCM) is characterized by chronic inflammatory myocardial disease. This study aimed to identify inflammatory parameters and biomarkers that could aid in the management of patients with chagasic HF. METHODS AND FINDINGS: A cohort study was conducted at a tertiary cardiology single-center over a mean follow-up period of 2.4 years. The study included patients with HF secondary to CCM enrolled between October 2013 and July 2017. Various clinical parameters, echocardiography findings, parasitemia status, brain natriuretic peptide (BNP) and troponin T (TnT) levels, and inflammatory biomarkers (IL-6, IL-10, IL-12p70, IL-17A, adiponectin, and IFN-γ) were assessed. The study encompassed a cohort of 103 patients, with a median age of 53 years and 70% being male. The left ventricular ejection fraction (LVEF) was 28%, with 40% of patients classified as NYHA II functional class. The median BNP level was 291 pg/ml. The observed mortality rate during the study period was 38.8%. Predictors of lower survival were identified as elevated levels of BNP, TnT, reduced LVEF, and increased adiponectin (thresholds: BNP > 309 pg/ml, TnT > 27.5 ng/ml, LVEF < 25.5%, adiponectin > 38 µg/mL). Notably, there was no evidence indicating a relationship between parasitemia and the inflammatory parameters with lower survival in these patients, including INF-γ, IL-6, IL-10, IL12-(p70), and IL17a. CONCLUSION: Despite the presence of a chronic inflammatory process, the evaluated inflammatory biomarkers in this cohort were not predictive of survival in patients with chagasic HF with reduced ejection fraction (HFrEF). However, reduced LVEF, elevated BNP, adiponectin levels, and troponin T were identified as predictors of lower survival in these patients.

Monocyte-Derived Dendritic Cells Can Revert In Vitro Antigen-Specific Cellular Anergy in Active Human Paracoccidioidomycosis.

We investigated the in vitro effects of two Paracoccidioides brasiliensis antigens on monocyte-derived dendritic cells (moDCs) from patients with paracoccidioidomycosis (PCM). MoDCs from patients with active or treated PCM and non-PCM subjects were generated, stimulated with TNF-α, and P. brasiliensis antigens, 43 kDa glycoprotein (gp43) and cell-free antigen (CFA), and analyzed by flow cytometry and enzyme-linked immunosorbent assays (ELISA). Our data revealed that patients with PCM had a high frequency of HLA-DR+ cells, but the treated group had more CD86+ cells with increased IL-12p40. Patients with active PCM had more CD80+ moDCs, and as a novel finding, large amounts of chemokine (C-C motif) ligand 18 (CCL18) in the supernatants from their in vitro moDC cultures. Both gp43- and CFA-stimulated moDCs from the patients with PCM successfully reverted the in vitro antigen-specific anergy, inducing a proliferative response. However, CFA-stimulated moDCs led to higher lymphoproliferation, with increased IFN-γ and TNF-α in the cells from the patients with active PCM compared with gp43. These original results combined with constant IL-10 and increased IL-12p40 levels suggest that a more complex antigen, such as CFA, may be a better inducer of the protective Th1 immune response than purified gp43 is, and a suitable target for future studies on anti-P. brasiliensis dendritic cell (DC)-based vaccines.

A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease.

Background: Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy. Methods: Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR. Results: Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24-0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07-0.97, P = 0.044; and OR = 0.35, 95% CI 0.14-0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class ≥ 2 (OR = 0.21, 95% CI 0.06-0.68, P = 0.009; and OR = 0.48, 95% CI 0.24-0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05-0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23-0.96, P = 0.039), NYHA class ≥ 2 (OR = 0.15, 95% CI 0.06-0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00-0.25, P = 0.001). Digestive involvement was negatively associated with NYHA ≥ 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09-0.47, P < 0.001; and OR = 0.24, 95% CI 0.09-0.62, P = 0.004, respectively). Conclusions: Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.

Polymorphism in the Promoter Region of the IL18 Gene and the Association With Severity on Paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is an important endemic, systemic disease in Latin America caused by Paracoccidioides spp. This mycosis has been associated with high morbidity and sequels, and its clinical manifestations depend on the virulence of the infecting strain, the degree and type of immune response, infected tissues, and intrinsic characteristics of the host. The T helper(Th)1 and Th17/Th22 cells are related to resistance and control of infection, and a Th2/Th9 response is associated with disease susceptibility. In this study, we focused on interleukin(IL)-12p35 (IL12A), IL-18 (IL18), and IFN-γ receptor 1 (IFNGR1) genetic polymorphisms because their respective roles have been described in human PCM. Real-time PCR was employed to analyze IL12A-504 G/T (rs2243115), IL18-607 C/A (rs1946518), and IFNGR1-611 A/G (rs1327474) single nucleotide polymorphisms (SNP). One hundred forty-nine patients with the acute form (AF), multifocal chronic (MC), or unifocal chronic (UC) forms of PCM and 110 non-PCM individuals as a control group were included. In the unconditional logistic regression analysis adjusted by ethnicity and sex, we observed a high risk of the IL18-607 A-allele for both AF [p = 0.015; OR = 3.10 (95% CI: 1.24-7.77)] and MC groups [p = 0.023; OR = 2.61 (95% CI: 1.14-5.96)] when compared with UC. The IL18-607 A-allele associated risk for the AF and MC groups as well as the protective role of the C-allele in UC are possibly linked to higher levels of IL-18 at different periods of the course of the disease. Therefore, a novel role of IL18-607 C/A SNP is shown in the present study, highlighting its importance in the outcome of PCM.

Avaliação dos efeitos de antígenos de Paracoccidioides brasiliensis em células dendríticas derivadas de monócitos de pacientes com paracoccidioidomicose: expressão de moléculas de superfície, linfoproliferação e secreção de citocinas / Evaluation of Paracoccidioides brasiliensis antigens effects on monocyte-derived dendritic cells from patients with paracoccidioidomycosis: expression of surface molecules, lymphoproliferation and secretion of cytokines

INTRODUÇÃO: A paracoccidioidomicose (PCM) induz uma resposta imune tipo Th1 relacionada à proteção, com imunodepressão antígeno-específica transitória. As células dendríticas (DCs) são as mais potentes apresentadoras de antígeno, porém, pouco se sabe sobre seu papel na PCM humana e sobre os efeitos do fungo em suas funções. OBJETIVO: Investigar os efeitos in vitro de antígenos de Paracoccidioides brasiliensis (P. brasiliensis) sobre as DCs derivadas de monócitos de pacientes com PCM. MÉTODOS: Foram incluídos 27 pacientes com PCM ativa (PA; com diagnóstico micológico, histopatológico ou títulos de anticorpos anti-P. brasiliensis >= 32) e 31 pacientes com PCM tratada (PT; anticorpos anti-P. brasiliensis com títulos <= 4, em duas coletas num período de 6 meses, e doença comprovada no passado pelos mesmos critérios de pacientes com PCM ativa), e de 39 indivíduos sadios (CO; não sensibilizados a antígenos de P. brasiliensis e sem anticorpos a tais antígenos fúngicos) foram geradas a partir de monócitos do sangue periférico, tratados com IL-4 e GM-CSF. As DC diferenciadas não-tratadas (nDC) ou tratadas com TNF-alfa (DC+TNF) foram estimuladas com os antígenos de P. brasiliensis: glicoproteína de 43 kDa (gp43) a 2 e 5 ug/mL (Gp2 e Gp5), e antígeno solúvel a 15 ug/mL (CFA). As moléculas de superfície CD11c, CD1a, HLA-DR, CD86, CD80 e DC-SIGN das DCs foram analisadas por citometria de fluxo e as citocinas IL-10, IL-12p40, IL-1beta e CCL18 foram dosadas nos sobrenadantes das culturas por ELISA. As DCs foram então co-cultivadas com linfócitos autólogos, medindo-se a linfoproliferação por incorporação de timidina triciada e dosando-se por ELISA os níveis de citocinas IL-10, IL-4, IFN-y e TNF-alfa foram dosadas nos sobrenadantes dessas culturas. RESULTADOS: As DCs de PA e PT apresentaram expressão de CD11c e CD1a similar à observada nas DCs de CO. No grupo PT, Gp5 induziu maior expressão de HLA-DR em comparação ao grupo PA, e o CFA aumentou o percentual de DCs CD86+. As...

INTRODUCTION: Paracoccidioidomycosis (PCM) induces a Th1 immune response associated with protection, with a transitory antigen-specific immunodepression. Dendritic cells (DCs) are the most potent antigen presenting cells, but little is known about their role on human PCM and the effects of fungal antigens on their functions. OBJECTIVE: To investigate the in vitro effects of Paracoccidioides brasiliensis (P. brasiliensis) antigens on monocyte-derived DCs from patients with PCM. METHODS: Twenty-seven patients with active PCM (PA; with mycological or histopathological diagnosis or antibody titles anti-P. brasiliensis >= 32) and 31 treated PCM (PT; antibody titles <= 4 on two samples within six months, and proved disease in the past by the same criteria of active PCM) and from 39 non-PCM subjects (CO; non-sensitized to P. brasiliensis antigens and without anti-fungal antigens antibodies) were included in this study and DCs were generated from peripheral blood monocytes with IL-4 and GM-CSF. Differentiated DCs were treated with TNF-alfa (DC+TNF) or left untreated (nDC) and then stimulated with P. brasiliensis antigens: 43 kDa glycoprotein (gp43) at 2 and 5 ug/mL (Gp2 and Gp5), and the cell-free antigen at 15 ug/mL (CFA). Surface molecules CD11c, CD1a, HLA-DR, CD85, CD80 and DC-SIGN were analyzed by flow cytometry and the cytokines IL-10, IL-12p40, IL-1beta and CCL18 were assayed by ELISA. DCs were cocultured with autologous lymphocytes: lymphoproliferation was measured by the incorporation of tritiated thymidine and the cytokines IL-10, IL-4, IFN-y and TNF-alfa were also assayed by ELISA. RESULTS: DCs from PA and PT groups showed similar expression of CD11c and CD1a to those of CO group. On the PT group, Gp5 induced higher expression of HLA-DR when compared to PA and CFA increased the percentage of CD86+ DCs. When stimulated with CFA, TNF-alfa -treated DCs from the PT group secreted large amounts of IL-12p40. This antigen also induced strong proliferation of...

Paracoccidioidomycosis: eco-epidemiology, taxonomy and clinical and therapeutic issues.

Acquired by inhalation of the thermal dimorphic fungi Paracoccidioides spp. conidia, paracoccidioidomycosis ranges from symptomatic to severe and potentially fatal disseminated disease. The main focus of this review is to highlight clinical aspects of paracoccidioidomycosis and, its pathogens' diversity ecology and particularities. In addition, we present strategies for therapy, including DNA vaccines and nanostructured drugs. Molecular and morphological data supported the split of the Paracoccidioides genus into two species, Paracoccidioides brasiliensis and Paracoccidioides lutzii. An acute form of the disease affects approximately 5% of cases and involves the phagocytic mononuclear system, resulting in progressive lymphadenopathy. The chronic form affects adult men and frequently involves lungs, skin and mucous membranes, lymph nodes, and adrenal glands. The clinical manifestations depend on the ability of the host to control the fungal multiplication and dissemination. The long survival time of the fungus in the host tissues allows it to evade immune responses; therefore, successful treatment often requires long-time therapy. The consensus for treatment must consider the severity of the disease and includes sulfone derivatives, amphotericin B and azoles. Novel strategies for therapy, based on DNA vaccines and nanostructured drugs are also presented and discussed in this review.