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Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries.

BackgroundInducible costimulator (ICOS) receptor belongs to the CD28/CTLA immunoglobulin super family, whose expression is restricted to T cells and is weakly expressed on resting TH17, follicular helper T cells, and regulatory T cells, but is highly induced on CD4+ and CD8+ T cells on activation by T-cell receptors. ICOS stimulation downstream effects include activation of conventional CD4+cells and cytotoxic CD8+cells, resulting in a durable antitumor response in preclinical models.MethodsAs part of a larger first-in-human study (GSK Study 204691), this study focused on 2 cohorts of 25 and 67 participants enrolled in a dose escalation and pharmacokinetic/pharmacodynamic (PK/PD) analysis of the ICOS agonist feladilimab (GSK3359609) as monotherapy. For these cohorts, the objectives were to determine the safety, tolerability, maximum tolerated dose (MTD) or maximum administered dose of feladilimab. Additional objectives included determining the recommended dose of feladilimab for further exploration, characterizing the PK properties, and immunogenicity.ResultsFeladilimab was examined over a range of 4 logs from 0.001 mg/kg to 10 mg/kg, and no MTD was established. Adverse events were manageable and consistent with those observed with other immunomodulatory treatments; fatigue, fever, and anemia were the most common events. PK showed a peak value 1 hour following infusion. Accumulation ratio ranged from 1.4 to 2.5 and was generally consistent with expected patterns of accumulation for a monoclonal antibody, and the drug showed linear dose proportionality. ICOS receptor occupancy was maximal at doses>0.1 mg/kg. Based on the collected data, doses of 0.3 and 1.0 mg/kg were selected for further exploration.ConclusionsThis study showed the feasibility of a modified Toxicity Proportion Interval design and PK/PD analysis to determine a recommended dose for a compound without a dose-limiting toxicity and a tolerable and manageable safety profile.

There is a well-known knowledge gap regarding the efficacy and safety of medicines in children of all ages and children are often treated with medicines off-label. Children are thus deprived of treatment based on the same quality of information that guides treatment in adults. The knowledge gap regarding efficacy and safety of medicines in children has been acknowledged by authorities and is reflected in legislation both in North America and in the European Union. Recent reports on the effects of legislation indicates that paediatric clinical trials remain a challenge.Paediatric clinical trials are needed in the entire developmental age spectrum and are especially needed in certain therapy areas. Paediatric clinical trials have special features compared with trials in adults, and these need to be taken into account. These special features include scientific issues related to small samples and heterogeneity, the consent/assent procedure, the need for age-appropriate study information, specific outcomes and safety issues related to development and maturation. Competence in paediatric clinical trials is required in both designing, planning, co-ordinating and organising paediatric clinical trials, as well as research infrastructure and networks to increase power and disseminate information and expert advice. Strengthening of paediatric clinical research is essential to facilitate generating the data that will let children enjoy new medical advances in a similar manner as adults.

Background Replicate experiments are often difficult to find in evolutionary biology, as this field is inherently an historical science. However, viruses, bacteria and phages provide opportunities to study evolution in both natural and experimental contexts, due to their accelerated rates of evolution and short generation times. Here we investigate HIV-1 evolution by using a natural model represented by monozygotic twins infected synchronically at birth with an HIV-1 population from a shared blood transfusion source. We explore the evolutionary processes and population dynamics that shape viral diversity of HIV in these monozygotic twins. Results Despite the identical host genetic backdrop of monozygotic twins and the identical source and timing of the HIV-1 inoculation, the resulting HIV populations differed in genetic diversity, growth rate, recombination rate, and selection pressure between the two infected twins. Conclusions Our study shows that the outcome of evolution is strikingly different between these two \"replicates\" of viral evolution. Given the identical starting points at infection, our results support the impact of random epigenetic selection in early infection dynamics. Our data also emphasize the need for a better understanding of the impact of host-virus interactions in viral evolution.

Children have the right to treatment based on the same quality of information that guides treatment in adults. Without the proper evaluation of medicinal products and devices in paediatric clinical trials that are designed to meet the rigorous standards of the competent authorities, children are discriminated from advances in medicine. There are regulatory, scientific and ethical incentives to address the knowledge gap regarding efficacy and safety of medicines in the paediatric population. High-quality clinical trials involving children of all ages can generate data that will ultimately close the knowledge gaps and support decision making.For clinical trials that enrol children, the needs are specialised and often resource intensive. Prerequisites for successful paediatric clinical trials are personnel with training in both paediatrics and neonatology and expertise in clinical trials in these populations. Moreover, national and international networks for efficient collaboration, dissemination of information, and sharing of resources and expertise are also needed, together with competent, efficient and high-quality local infrastructure with effective processes. Monitoring and oversight bodies with the relevant competence, including expertise in paediatrics, is also an important prerequisite for paediatric clinical trials. Compromise in any of these components will compromise the downstream results.This paper discusses the structures and competences needed in order to perform effective, high-quality paediatric clinical trials with the ultimate goal of better medicines and treatments for children. We propose a model of examining the process as a series of components that each has to be optimised, then all the components are actively optimised to function together as an ecosystem, and the resulting ecosystem functions well with the general research system and the healthcare delivery system.

Immunization in pregnancy provides a promising contribution to globally reducing neonatal and under-five childhood mortality and morbidity. Thorough assessment of benefits and risks for the primarily healthy pregnant women and their unborn babies is required. The GAIA project was formed in response to the call of the World Health Organization for a globally concerted approach to actively monitor the safety of vaccines and immunization in pregnancy programs. GAIA aims to improve the quality of outcome data from clinical vaccine trials in pregnant women with a specific focus on the needs and requirements for safety monitoring in LMIC. In the first year of the project, a large and functional network of experts was created. The first outputs include a guidance document for clinical trials of immunization in pregnancy, a basic data collection guide, ten case definitions of key obstetric and neonatal health outcomes, an ontology of key terms and a map of pertinent disease codes. The GAIA Network is designed as an open and growing forum for professionals sharing the GAIA vision and aim. Based on the initial achievements, tools and services are developed to support investigators and strengthen immunization in pregnancy programs with specific focus on LMIC.

To summarise contemporary approaches to evaluating medicines in children, emphasizing topics that are often misunderstood by one or more stakeholder groups. A narrative review that integrates the literature with experience in multiple settings. Children and young people need specific approaches to research about drugs because of growth and development. Specific approaches include practicalities such as the volume, frequency and technique of blood samples, and recruitment, including consent by proxy decision-makers and assent by children/young people. The design of drug development programmes includes working with children/young people from an early stage and minimising the burden of research through careful design while optimizing the contribution of extant, high quality information (including extrapolation).Regulators, academics, the pharmaceutical industry and other communities are well-placed to support pediatric drug development. Regulatory challenges include legislation that drives the extension to children of medicines used in adults (rather than a focus on the needs of children) and diversity between jurisdictions. Academics can improve the impact of their work by ensuring that data can be used in drug development programmes after they have answered a well-defined study question. Pharmaceutical companies, and public research funders can promote good return on the investment made in research (including the investment made by children/young people) by supporting data management to allow data reuse. a greater understanding of pediatric issues is relevant to diverse research communities that work to advance pharmacotherapy.

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.