RÉSUMÉ
BACKGROUND: T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. METHODS: We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18-46years and 24 subjects aged 50years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18months. FINDINGS: Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1. In a mixed regression model, T-cell responses over 18months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP+M1. INTERPRETATION: A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP+M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. FUNDING SOURCE: Medical Research Council UK, NIHR BMRC Oxford.
RÉSUMÉ
The involvement of the human cerebellum in working memory has been well established in the last decade. However, the cerebro-cerebellar network for visual working memory is not as well defined. Our previous fMRI study showed superior and inferior cerebellar activations during a block design visual working memory task, but specific cerebellar contributions to cognitive processes in encoding, maintenance and retrieval have not yet been established. The current study examined cerebellar contributions to each of the components of visual working memory and presence of cerebellar hemispheric laterality was investigated. 40 young adults performed a Sternberg visual working memory task during fMRI scanning using a parametric paradigm. The contrast between high and low memory load during each phase was examined. We found that the most prominent activation was observed in vermal lobule VIIIb and bilateral lobule VI during encoding. Using a quantitative laterality index, we found that left-lateralized activation of lobule VIIIa was present in the encoding phase. In the maintenance phase, there was bilateral lobule VI and right-lateralized lobule VIIb activity. Changes in activation in right lobule VIIIa were present during the retrieval phase. The current results provide evidence that superior and inferior cerebellum contributes to visual working memory, with a tendency for left-lateralized activations in the inferior cerebellum during encoding and right-lateralized lobule VIIb activations during maintenance. The results of the study are in agreement with Baddeley's multi-component working memory model, but also suggest that stored visual representations are additionally supported by maintenance mechanisms that may employ verbal coding.