151 research outputs found
FLUORESCENT LABELLING OF WILD TYPE PLASMODIUM SPECIES WITHIN THE MOSQUITO HOST: A NOVEL METHOD TO TARGET SPOROZOITES
Experience and Challenges from Clinical Trials with Malaria Vaccines in Africa.
Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available.African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need.However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained
A comparison of two Fendrix hepatitis B vaccination schedules in patients with inflammatory bowel disease
Systemic immunosuppressive therapy (IS) renders patients with inflammatory bowel disease (IBD) vulnerable to fulminant hepatitis B virus (HBV) infection. Seroprotection against HBV through a full vaccination scheme is preferably obtained before IS is initiated, but often conflicts with the clinical need to initiate therapy rapidly. Consequently, the vast majority of patients will use IS during booster vaccinations. In this retrospective cohort study, we examined the serological response after a modified vaccination schedule which includes an initial double dose of Fendrix in patients with IBD and compared the results with the serological responses of patients with IBD who received the standard schedule. Seroprotection rates were 86.2 % and 88.9 % in the modified and standard schedule groups respectively. One-third of patients obtained seroprotection after only one double dose vaccine. A double dose may be considered in patients with IBD at high short-term risk of HBV infection when a rapid protective response is warranted. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Immunogenetics and cellular immunology of bacterial infectious disease
First-in-human administration of a live-attenuated RSV vaccine lacking the G-protein assessing safety, tolerability, shedding and immunogenicity: a randomized controlled trial
Background: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVDG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVDG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVDG vaccine protected against replication of wildtype RSV, without inducing enhanced disease.Methods: We performed a first-in-human trial with primary objective to evaluate safety and shedding of RSV Delta G (6.5 log(10) CCID50) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log(2), received a single dose of either vaccine or placebo (n = 48, ratio 3:1). In addition to safety and tolerability, nasal viral load, and systemic and humoral immune responses were assessed at selected time points until 4 weeks after immunization.Results: Intranasal administration of RSV Delta G was well tolerated with no findings of clinical concern. No infectious virus was detected in nasal wash samples. Similar to other live-attenuated RSV vaccines, neutralizing antibody response following inoculation was limited in seropositive adults.Conclusions: A single dose of 6.5 log(10) CCID50 of RSV Delta G was safe and well-tolerated in seropositive healthy adults. RSV Delta G was sufficiently attenuated but there were no signs of induction of antibodies. Safety and immunogenicity can now be explored in children and eventually in seronegative infants. (C) 2020 The Author(s). Published by Elsevier Ltd.Host-parasite interactio
Limited efficacy of repeated praziquantel treatment in Schistosoma mansoni infections as revealed by highly accurate diagnostics, PCR and UCP-LF CAA (RePST trial)
BACKGROUND: Most studies assessing praziquantel (PZQ) efficacy have used relatively insensitive diagnostic methods, thereby overestimating cure rate (CR) and intensity reduction rate (IRR). To determine accurately PZQ efficacy, we employed more sensitive DNA and circulating antigen detection methods. METHODOLOGY: A sub-analysis was performed based on a previously published trial conducted in children from Cote d'Ivoire with a confirmed Schistosoma mansoni infection, who were randomly assigned to a standard (single dose of PZQ) or intense treatment group (4 repeated doses of PZQ at 2-week intervals). CR and IRR were estimated based on PCR detecting DNA in a single stool sample and the up-converting particle lateral flow (UCP-LF) test detecting circulating anodic antigen (CAA) in a single urine sample, and compared with traditional Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA). PRINCIPAL FINDINGS: Individuals positive by all diagnostic methods (i.e., KK, POC-CCA, PCR, and UCP-LF CAA) at baseline were included in the statistical analysis (n = 125). PCR showed a CR of 45% (95% confidence interval (CI) 32-59%) in the standard and 78% (95% CI 66-87%) in the intense treatment group, which is lower compared to the KK results (64%, 95% CI 52-75%) and 88%, 95% CI 78-93%). UCP-LF CAA showed a significantly lower CR in both groups, 16% (95% CI 11-24%) and 18% (95% CI 12-26%), even lower than observed by POC-CCA (31%, 95% CI 17-35% and 36%, 95% CI 26-47%). A substantial reduction in DNA and CAA-levels was observed after the first treatment, with no further decrease after additional treatment and no significant difference in IRR between treatment groups. CONCLUSION/SIGNIFICANCE: The efficacy of (repeated) PZQ treatment was overestimated when using egg-based diagnostics. Quantitative worm-based diagnostics revealed that active Schistosoma infections are still present despite multiple treatments. These results stress the need for using accurate diagnostic tools to monitor different PZQ treatment strategies, in particular when moving toward elimination of schistosomiasis. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT02868385
Specificity of the point-of-care urine strip test for schistosoma circulating cathodic antigen (POC-CCA) tested in non-endemic pregnant women and young children
ABSTRACTThe point-of-care urine based strip test for the detection of circulating cathodic antigen (POC-CCA) in schistosome infections is a frequently used tool for diagnosis and mapping of Schistosoma mansoni in school-aged children. Because of its ease of use, the test is increasingly applied to adults and preschool-aged children (PSAC), but its performance has not been specifically evaluated in these target groups. Recent observations have raised concerns about possible reduced specificity, in particular in pregnant women (PW) and PSAC. We thus explored specificity of the POC-CCA urine strip test (Rapid Medical Diagnostics, Pretoria, South Africa) in a non-endemic, nonexposed population of 47 healthy nonpregnant adults (NPAs), 52 PW, and 58 PSAC. A total of 157 urines were tested with POC-CCA, of which five (10.6%) NPAs, 17 (32.7%) PW, and 27 (46.5%) PSAC were positive. The highest scores were found in the youngest babies, with an infant of 9 months being the oldest positive case. On measuring pH, it appeared that all POC-CCA strongly positive urines were acidic (pH range 5–5.5), whereas addition of pH-neutral buffer to a subsample reversed the false positivity. We conclude that the POC-CCA test has reduced specificity in PW and infants younger than 9 months, but that the false positivity might be eliminated by modifications in the buffers used in the test.Cancer Signaling networks and Molecular Therapeutic
Longevity and Composition of Cellular Immune Responses Following Experimental Plasmodium falciparum Malaria Infection in Humans
Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO+ CD62L- effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ+IL-2+) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field
Toward a Surrogate Marker of Malaria Exposure: Modeling Longitudinal Antibody Measurements under Outbreak Conditions
Background: Biomarkers of exposure to Plasmodium falciparum would be a useful tool for the assessment of malaria burden and analysis of intervention and epidemiological studies. Antibodies to pre-erythrocytic antigens represent potential surrogates of exposure. Methods and Findings: In an outbreak cohort of U.S. Marines deployed to Liberia, we modeled pre- and post-deployment IgG against P. falciparum sporozoites by immunofluorescence antibody test, and both IgG and IgM against the P. falciparum circumsporozoite protein by enzyme-linked immunosorbant assay. Modeling seroconversion thresholds by a fixed ratio, linear regression or nonlinear regression produced sensitivity for identification of exposed U.S. Marines between 58-70% and specificities between 87-97%, compared with malaria-naïve U.S. volunteers. Exposure was predicted in 30-45% of the cohort. Conclusion: Each of the three models tested has merits in different studies, but further development and validation in endemic populations is required. Overall, these models provide support for an antibody-based surrogate marker of exposure to malaria
No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials
Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients
Connective Tissue Growth Factor Overexpression in Cardiomyocytes Promotes Cardiac Hypertrophy and Protection against Pressure Overload
Connective tissue growth factor (CTGF) is a secreted protein that is strongly induced in human and experimental heart failure. CTGF is said to be profibrotic; however, the precise function of CTGF is unclear. We generated transgenic mice and rats with cardiomyocyte-specific CTGF overexpression (CTGF-TG). To investigate CTGF as a fibrosis inducer, we performed morphological and gene expression analyses of CTGF-TG mice and rat hearts under basal conditions and after stimulation with angiotensin II (Ang II) or isoproterenol, respectively. Surprisingly, cardiac tissues of both models did not show increased fibrosis or enhanced gene expression of fibrotic markers. In contrast to controls, Ang II treated CTGF-TG mice displayed preserved cardiac function. However, CTGF-TG mice developed age-dependent cardiac dysfunction at the age of 7 months. CTGF related heart failure was associated with Akt and JNK activation, but not with the induction of natriuretic peptides. Furthermore, cardiomyocytes from CTGF-TG mice showed unaffected cellular contractility and an increased Ca2+ reuptake from sarcoplasmatic reticulum. In an ischemia/reperfusion model CTGF-TG hearts did not differ from controls
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