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BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).
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Vacinas contra Dengue , Vírus da Dengue , Dengue , Vacinas Atenuadas , Adulto , Criança , Pré-Escolar , Humanos , Anticorpos Antivirais , Dengue/prevenção & controle , Vacinas contra Dengue/efeitos adversos , Vacinas contra Dengue/uso terapêutico , Vírus da Dengue/imunologia , Método Duplo-Cego , Vacinação , Vacinas , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/uso terapêutico , Brasil , Eficácia de Vacinas , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , SeguimentosRESUMO
Skin ulcers of cutaneous leishmaniasis (CL) are characterized by a localized inflammatory response mediated by innate and adaptive immune cells, including dendritic cells (DC) and natural killer (NK) cells. Bidirectional interactions between DCs and NK cells contribute to tailor leishmaniasis outcome. Despite advances in the Leishmania biology field in recent decades, the mechanisms involved in DC/NK-mediated control of Leishmania sp. pathogenesis as well as the cellular and molecular players involved in such interaction remain unclear. The present study sought to investigate canonical pathways associated with CL arising from Leishmania braziliensis infection. Initially, two publicly available microarray datasets of skin biopsies from active CL lesions were analyzed, and five pathways were identified using differentially expressed genes. The "Crosstalk between DCs and NK cells" pathway was notable due to a high number of modulated genes. The molecules significantly involved in this pathway were identified, and our findings were validated in newly obtained CL biopsies. We found increased expression of TLR4, TNFRSF1B, IL-15, IL-6, CD40, CCR7, TNF and IFNG, confirming the analysis of publicly available datasets. These findings reveal the "crosstalk between DCs and NK cells" as a potential pathway to be further explored in the pathogenesis of CL, especially the expression of CCR7, which is correlated with lesion development.
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Visceral leishmaniasis is an opportunistic disease in HIV-1 infected individuals, unrecognized as a determining factor for AIDS diagnosis. The growing geographical overlap of HIV-1 and Leishmania infections is an emerging challenge worldwide, as co-infection increases morbidity and mortality for both infections. Here, we determined the prevalence of people living with HIV (PWH) with a previous or ongoing infection by Leishmania infantum and investigated the virological and immunological factors associated with co-infection. We adopted a two-stage cross-sectional cohort (CSC) design (CSC-I, n = 5,346 and CSC-II, n = 317) of treatment-naïve HIV-1-infected individuals in Bahia, Brazil. In CSC-I, samples collected between 1998 and 2013 were used for serological screening for leishmaniasis by an in-house Enzyme-Linked Immunosorbent Assay (ELISA) with SLA (Soluble Leishmania infantum Antigen), resulting in a prevalence of previous or ongoing infection of 16.27%. Next, 317 PWH were prospectively recruited from July 2014 to December 2015 with the collection of sociodemographic and clinical data. Serological validation by two different immunoassays confirmed a prevalence of 15.46 and 8.20% by anti-SLA, and anti-HSP70 serology, respectively, whereas 4.73% were double-positive (DP). Stratification of these 317 individuals in DP and double-negative (DN) revealed a significant reduction of CD4+ counts and CD4+/CD8+ ratios and a tendency of increased viral load in the DP group, as compared to DN. No statistical differences in HIV-1 subtype distribution were observed between the two groups. However, we found a significant increase of CXCL10 (p = 0.0076) and a tendency of increased CXCL9 (p = 0.061) in individuals with DP serology, demonstrating intensified immune activation in this group. These findings were corroborated at the transcriptome level in independent Leishmania- and HIV-1-infected cohorts (Swiss HIV Cohort and Piaui Northeast Brazil Cohort), indicating that CXCL10 transcripts are shared by the IFN-dominated immune activation gene signatures of both pathogens and positively correlated to viral load in untreated PWH. This study demonstrated a high prevalence of PWH with L. infantum seropositivity in Bahia, Brazil, linked to IFN-mediated immune activation and a significant decrease in CD4+ levels. Our results highlight the urgent need to increase awareness and define public health strategies for the management and prevention of HIV-1 and L. infantum co-infection.
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The Americas, particularly Brazil, were greatly impacted by the widespread Zika virus (ZIKV) outbreak in 2015 and 2016. Efforts were made to implement genomic surveillance of ZIKV as part of the public health responses. The accuracy of spatiotemporal reconstructions of the epidemic spread relies on the unbiased sampling of the transmission process. In the early stages of the outbreak, we recruited patients exhibiting clinical symptoms of arbovirus-like infection from Salvador and Campo Formoso, Bahia, in Northeast Brazil. Between May 2015 and June 2016, we identified 21 cases of acute ZIKV infection and subsequently recovered 14 near full-length sequences using the amplicon tiling multiplex approach with nanopore sequencing. We performed a time-calibrated discrete phylogeographic analysis to trace the spread and migration history of the ZIKV. Our phylogenetic analysis supports a consistent relationship between ZIKV migration from Northeast to Southeast Brazil and its subsequent dissemination beyond Brazil. Additionally, our analysis provides insights into the migration of ZIKV from Brazil to Haiti and the role Brazil played in the spread of ZIKV to other countries, such as Singapore, the USA, and the Dominican Republic. The data generated by this study enhances our understanding of ZIKV dynamics and supports the existing knowledge, which can aid in future surveillance efforts against the virus.
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Infecção por Zika virus , Zika virus , Humanos , Zika virus/genética , Brasil/epidemiologia , Filogenia , América/epidemiologiaRESUMO
Background: There is limited data on the prevalence and risk factors for long COVID and few prospective studies with appropriate control groups and adequate sample sizes. We performed a prospective study to determine the prevalence and risk factors for long COVID. Methods: We recruited individuals aged ≥15 years who were clinically suspected of having an acute SARS-CoV-2 infection from September 2020 to April 2021. We collected nasopharyngeal swabs three to five days following symptom onset for analysing using reverse transcriptase polymerase chain reaction (RT-PCR). We also collected clinical and sociodemographic characteristics from both SARS-CoV-2 positive and negative participants using structured questionnaires. We followed-up the participants via telephone interview to assess early outcomes and persistent symptoms. For COVID-19 cases, 5D-3L EuroQol questionnaire was used to assess the impact of symptoms on quality of life. Results: We followed 814 participants (412 COVID-19 positive and 402 COVID-19 negative persons). Most (n = 741/814) had mild symptoms. Both groups had similar sociodemographic and clinical characteristics, except for the hospitalization rate (15.8% in the COVID-19 positive vs 1.5% in the COVID-19 negative group). One month after disease onset, 122/412 (29.6%) individuals in the COVID-19 positive (long COVID) and 24 (6%) in the COVID-19 negative group reported residual symptoms. In the long COVID group, fatigue, olfactory disorder, and myalgia were the most frequent symptoms in the acute phase. Compared to recovered individuals, older age and having more than five symptoms during the acute phase were risk factors for long COVID. Quality of life was evaluated in 102 out of 122 cases of long COVID, with 57 (55.9%) reporting an impact in at least one dimension of the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) questionnaire. Conclusions: In this prospective study consisting predominantly of individuals with mild disease, the persistence of symptoms after an acute respiratory illness was associated with a diagnosis of COVID-19. Polysymptomatic acute disease and older age were risk factors for long COVID.
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COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Síndrome de COVID-19 Pós-Aguda , Estudos Prospectivos , Estudos de Coortes , Qualidade de Vida , Prevalência , Grupos Controle , Fatores de RiscoRESUMO
The draft genome of the parasite Leishmania braziliensis strain BA788, which was isolated from a patient from Bahia state, Brazil, was sequenced using Illumina paired-end technology. The assembled genome is 33.5 Mb long and contains 7,603 genes. This genome will contribute to studies aimed at understanding the pathogenesis caused by this parasite strain.
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Aims: Pre-existing conditions, such as age, hypertension, obesity, and diabetes, constitute known risk factors for severe COVID-19. However, the impact of prediabetes mellitus (PDM) on COVID-19 severity is less clear. This study aimed to evaluate the influence of PDM in the acute and long-term phases of COVID-19. Materials and methods: We compared inflammatory mediators, laboratory and clinical parameters and symptoms in COVID-19 patients with prediabetes (PDM) and without diabetes (NDM) during the acute phase of infection and at three months post-hospitalization. Results: Patients with PDM had longer hospital stays and required intensive care unit admission more frequently than NDM. Upon hospitalization, PDM patients exhibited higher serum levels of interleukin 6 (IL-6), which is related to reduced partial pressure of oxygen (PaO2) in arterial blood, oxygen saturation (SpO2) and increased COVID-19 severity. However, at three months after discharge, those with PDM did not exhibit significant alterations in laboratory parameters or residual symptoms; however, PDM was observed to influence the profile of reported symptoms. Conclusions: PDM seems to be associated with increased risk of severe COVID-19, as well as higher serum levels of IL-6, which may constitute a potential biomarker of severe COVID-19 risk in affected patients. Furthermore, while PDM correlated with more severe acute-phase COVID-19, no long-term worsening of sequelae was observed.
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COVID-19 , Diabetes Mellitus , Interleucina-6/biossíntese , Estado Pré-Diabético , COVID-19/complicações , Hospitalização , Humanos , Estado Pré-Diabético/complicaçõesRESUMO
Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19), the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. We aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of patients with and without diabetes hospitalized for COVID-19. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of the SARS-CoV-2 main receptor system (ACE2/TMPRSS2), and for the main molecule of the leukotriene B4 (LTB4) pathway (ALOX5). We found that diabetes activates the LTB4 pathway and that during COVID-19 it increases ACE2/TMPRSS2 as well as ALOX5 expression. Diabetes was also associated with COVID-19-related disorders, such as reduced oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen (FiO2) and arterial partial pressure of oxygen/FiO2 levels, and increased disease duration. In addition, the expressions of ACE2 and ALOX5 are positively correlated, with increased expression in patients with diabetes and COVID-19 requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB4 is significantly increased in individuals with diabetes. In addition, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB4 and IL-6 systemic levels, as well as ACE2/ALOX5 blood expression, could be early markers of severe COVID-19 in individuals with diabetes.
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Enzima de Conversão de Angiotensina 2/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , COVID-19/patologia , Diabetes Mellitus/patologia , Leucotrieno B4/metabolismo , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Araquidonato 5-Lipoxigenase/genética , COVID-19/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Leucotrieno B4/genética , Fatores de Risco , Transdução de SinaisRESUMO
BACKGROUND: The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. METHODS: A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. RESULTS: The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P = .003 vs Sbv), and 75.6% in the M + GM group (P = .004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P = .0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. CONCLUSIONS: Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. CLINICAL TRIALS REGISTRATION: NCT03023111.