Summary Background Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine ...contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations. Methods We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18–45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov , number NCT01224639. Findings We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group. Interpretation Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted. Funding Takeda Vaccines.
Executive function, an umbrella term used to describe the goal-directed regulation of thoughts, actions, and emotions, is an important dimension implicated in neurodiversity and established malleable ...predictor of multiple adult outcomes. Neurodevelopmental differences have been linked to both executive function strengths and weaknesses, but evidence for associations between specific profiles of executive function and specific neurodevelopmental conditions is mixed. In this exploratory study, we adopt an unsupervised machine learning approach (self-organising maps), combined with k-means clustering to identify data-driven profiles of executive function in a transdiagnostic sample of 566 neurodivergent children aged 8–18 years old. We include measures designed to capture two distinct aspects of executive function: performance-based tasks designed to tap the state-like efficiency of cognitive skills under optimal conditions, and behaviour ratings suited to capturing the trait-like application of cognitive control in everyday contexts. Three profiles of executive function were identified: one had consistent difficulties across both types of assessments, while the other two had inconsistent profiles of predominantly rating- or predominantly task-based difficulties. Girls and children without a formal diagnosis were more likely to have an inconsistent profile of primarily task-based difficulties. Children with these different profiles had differences in academic achievement and mental health outcomes and could further be differentiated from a comparison group of children on both shared and profile-unique patterns of neural white matter organisation. Importantly, children's executive function profiles were not directly related to diagnostic categories or to dimensions of neurodiversity associated with specific diagnoses (e.g., hyperactivity, inattention, social communication). These findings support the idea that the two types of executive function assessments provide non-redundant information related to children's neurodevelopmental differences and that they should not be used interchangeably. The findings advance our understanding of executive function profiles and their relationship to behavioural outcomes and neural variation in neurodivergent populations.
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