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Fletcher, P.

Publications and source records attributed to Fletcher, P..

12 recordsLinked to original sources

A Single-Dose Bundibugyo Virus Vaccine Protects Macaques Within 3 Days

Bundibugyo virus (BDBV), a member of the orthoebolaviruses in the Filoviridae family, causes severe hemorrhagic disease with high case-fatality rates. Currently, there are no medical countermeasures approved for human use hampering the response to the large ongoing outbreak in the Democratic Republic of the Congo and Uganda. While vesicular stomatitis virus (VSV)-based vaccines have demonstrated fast-acting prophylactic single-dose efficacy against multiple filoviruses, it has yet to be defined for VSV-BDBV. Here, we evaluated the rapid protection by a single-dose vaccination of VSV-BDBV in nonhuman primates (NHPs). Vaccination elicited rapid innate and early adaptive immune responses and conferred complete protection from clinical disease against BDBV challenge within 3 days. Vaccinated NHPs exhibited minimal clinical signs, limited systemic inflammation, and no infectious virus was isolated from the blood at any time. Protection correlated with neutralizing antibodies and Fc effector functionality of the humoral immune response. These findings establish VSV-BDBV as a fast-acting vaccine candidate suitable for outbreak response and highlight immune mechanisms underlying rapid protection.

microbiology↗

Delusions Emerge from Generative Model Reorganisation rather than Faulty Inference: Insights from Hybrid Predictive Coding

Predictive coding has influenced many conceptual accounts of delusions, the bizarre and distressing beliefs that accompany a range of neuropsychiatric conditions. However, these explanations remain incomplete and have rarely been tested directly using formal modelling. Here, we present a formal account of delusional beliefs based on hybrid predictive coding, which sheds light on the computational mechanisms underpinning the core features of delusions: thematic recurrence and imperviousness to contradictory evidence. In simulation experiments, we demonstrate that a combination of contextually inadequate initialisation of beliefs and excessive certainty (a hallmark of psychosis), triggers a reorganisation of the generative model relating observed events to hidden causes. This reorganisation enables the maintenance of delusional beliefs that are thematically stable, internally consistent with external inputs, and impervious to contradictory evidence, all without an increase in prediction error. Overall, our results suggest that delusions may arise not from faulty inference, as previously argued, but as an adaptive consequence of generative models learned under atypical conditions. These findings provide mechanistic insights into the computations underpinning delusions and have important implications for a novel therapeutic strategy in terms of re-training generative models.

neuroscience↗

Single-dose VSV-Sudan virus vaccine protects from lethal Sudan virus infection within one week: a challenge study in macaques

BackgroundThe Sudan virus (SUDV) outbreaks in recent years including the ongoing outbreak in Uganda created a public health emergency beyond the Eastern Africa region. Currently, there are licensed countermeasures for Ebola virus (EBOV); however, there are no licensed vaccines or therapeutics against SUDV. MethodsWe developed a vesicular stomatitis virus (VSV)-based vaccine expressing the SUDV glycoprotein. Cynomolgus macaques were vaccinated intramuscularly with a single dose of VSV-SUDV either one month or one week prior to SUDV challenge. A third group was vaccinated with a single dose of VSV-EBOV one month prior to SUDV challenge to assess its cross-protective potential, and a control group received an unrelated VSV-based vaccine. ResultsAll vaccinated nonhuman primates (NHPs) developed antigen-specific IgG within 2 weeks of vaccination, including cross-reactive responses. After challenge with a lethal dose of SUDV, all VSV-SUDV-vaccinated NHPs were uniformly protected from disease. In contrast, the VSV-EBOV-vaccinated and control NHPs succumbed to disease between day 5 and 7 after challenge presenting with classical signs of Sudan virus disease associated with high titer viremia, high viral organ load, dysregulated cytokine profiles and typical pathological changes. The humoral immune response in the NHPs vaccinated with VSV-SUDV one month before challenge resulted in a profound and sustained antibody response with a diverse functionality profile which was not observed to the same extend in NHPs vaccinated one week before challenge. InterpretationWe demonstrated that a single dose of VSV-SUDV protected NHPs from lethal SUDV infection within one week. The fast-acting nature makes VSV-SUDV an ideal countermeasure for ring vaccination during outbreaks of Sudan virus disease. In contrast, VSV-EBOV provided no relevant protection against SUDV infection in NHPs highlighting the need for species-specific filovirus vaccines.

microbiology↗

A bivalent Adenovirus-Vectored Vaccine induces a measurable humoral response, but does not protect cynomolgus macaques against a lethal challenge with Sudan virus

The most recent Sudan virus (SUDV) outbreak in Uganda was first detected in September 2022 and resulted in 164 laboratory-confirmed cases and 77 deaths. Currently, there are no approved vaccines or therapeutics against SUDV. In the current study, we investigated the protective efficacy of ChAdOx1-biEBOV in cynomolgus macaques using a prime or a prime-boost regimen. ChAdOx1-biEBOV is a replication-deficient simian adenovirus vector encoding SUDV and Ebola virus (EBOV) glycoproteins (GPs) at the E1 and E4 loci, respectively. Intramuscular vaccination induced SUDV and EBOV GP-specific IgG responses and neutralizing antibodies. Upon challenge with SUDV, vaccinated animals, regardless of vaccination scheme, showed signs of disease like those observed in control animals, and no difference in survival outcomes were measured among all three groups. Viral load in blood samples and in tissue samples obtained after necropsy were not significantly different between groups. Overall, this study highlights the importance of evaluating vaccines in multiple animal models, including nonhuman primates, and demonstrates the importance of understanding protective efficacy in both animal models and human hosts.

microbiology↗

VSV-based vaccine provides species-specific protection against Sudan virus challenge in macaques

The ongoing Sudan virus (SUDV) outbreak in Uganda highlights the need for rapid response capabilities against emerging viruses with high public health impact. While such countermeasures have been established for Ebola virus (EBOV), they unfortunately do not exist for SUDV or any other human-pathogenic filovirus. Here, we describe the generation and characterization of the vesicular stomatitis virus (VSV)-based vaccine VSV-SUDV and demonstrate the protective efficacy following a single-dose vaccination against lethal SUDV infection in nonhuman primates (NHPs). As we repurposed NHPs from a successful VSV-EBOV vaccine efficacy study, we further demonstrate that VSV-SUDV can be used effectively in individuals previously vaccinated against EBOV. While the NHPs developed cross-reactive humoral responses to SUDV after VSV-EBOV vaccination and EBOV challenge, cross-protection was limited emphasizing the need for the development of specific countermeasures for each human-pathogenic ebolavirus. Additionally, our data provides evidence that while previous VSV-EBOV immunity is boosted after VSV-SUDV vaccination, it has only limited impact on the immunogenicity and protective efficacy of VSV-SUDV vaccination important for frontline outbreak workers.

microbiology↗

Rapid protection of nonhuman primates against Marburg virus disease using a single low-dose VSV-based vaccine

Marburg virus (MARV) is the causative agent of Marburg virus disease (MVD) which has a case fatality rate up to ~90% in humans. Recently, there were cases reported in Guinea and Ghana highlighting this virus as a high-consequence pathogen potentially threatening global public health. There are no licensed treatments or vaccines available today. We used a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV-Angola glycoprotein (VSV-MARV) as the viral antigen. Previously, a single dose of 1x107 plaque-forming units (PFU) administered 7 days before challenge resulted in uniform protection from disease in cynomolgus macaques. Here, we sought to lower the vaccination dose to allow for more doses per vial in an emergency outbreak situation. We administered 1x105 or 1x103 PFU 14 days before challenge and achieved uniform protection in both groups. When we administered 1x103 PFU 7 days before challenge, vaccination resulted in uniform protection with no detectable viremia. Antigen-specific IgG responses were induced by both vaccine concentrations and were sustained until the study endpoint. Neutralizing antibody responses and antibody-dependent cellular phagocytosis were observed with both vaccination doses and timelines. The cellular response after vaccination was characterized by early induction of NK cell activation. Additionally, antigen-specific memory T cell subsets were detected in all vaccination cohorts indicating that while the primary protective mechanism of VSV-MARV is the humoral response, a functional cellular response is also induced. Overall, this data highlights VSV-MARV as a viable and fast-acting MARV vaccine candidate suitable for deployment in emergency outbreak situations and supports its clinical development. One Sentence SummaryA single low dose of VSV-MARV administered 14 or 7 days before challenge protects NHPs uniformly from lethal disease.

immunology↗

Pathogenic and transcriptomic differences of emerging SARS-CoV-2 variants in the Syrian golden hamster model

Following the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid spread throughout the world, new viral variants of concern (VOC) have emerged. There is a critical need to understand the impact of the emerging variants on host response and disease dynamics to facilitate the development of vaccines and therapeutics. Syrian golden hamsters are the leading small animal model that recapitulates key aspects of severe coronavirus disease 2019 (COVID-19). In this study, we show that intranasal inoculation of SARS-CoV-2 into hamsters with the ancestral virus (nCoV-WA1-2020) or VOC first identified in the United Kingdom (B.1.1.7) and South Africa (B.1.351) led to similar gross and histopathologic pulmonary lesions. Although differences in viral genomic copy numbers were noted in the lungs and oral swabs of challenged animals, infectious titers in the lungs were comparable. Antibody neutralization capacities varied, dependent on the original challenge virus and cross-variant protective capacity. Transcriptional profiling indicated significant induction of antiviral pathways in response to all three challenges with a more robust inflammatory signature in response to B.1.1.7. Furthermore, no additional mutations in the spike protein were detected at peak disease. In conclusion, the emerging VOC showed distinct humoral responses and transcriptional profiles in the hamster model compared to the ancestral virus.

microbiology↗

Low-level, prediction-based sensory and motor processesare unimpaired in Autism

A new promising account of human brain function suggests that sensory cortices try to optimise information processing via predictions that are based on prior experiences. The brain is thus likened to a probabilistic prediction machine. There has been a growing - though inconsistent - literature to suggest that features of autism spectrum conditions (ASCs) are associated with a deficit in modelling the world through such prediction-based inference. However empirical evidence for differences in low-level sensorimotor predictions in autism is still lacking. One approach to examining predictive processing in the sensorimotor domain is in the context of self-generated (predictable) as opposed to externally-generated (less predictable) effects. We employed two complementary tasks - force-matching and intentional binding - which examine self-versus externally-generated action effects in terms of sensory attenuation and attentional binding respectively in adults with and without autism. The results show that autism was associated with normal levels of sensory attenuation of internally-generated force and with unaltered temporal attraction of voluntary actions and their outcomes. Thus, our results do not support a general deficit in predictive processing in autism.

neuroscience↗

Reinforcement learning as an intermediate phenotype in psychosis? Deficits sensitive to illness stage but not associated with polygenic risk of schizophrenia in the general population

BackgroundSchizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning. MethodsWe administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls (n= 29, F|M=0.81), At Risk Mental State for psychosis (ARMS, n= 23, F|M=0.35) and FEP (First-episode psychosis, n= 26, F|M=0.18). Study 2 included healthy adolescents (n= 735, F|M= 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated. ResultsPatients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology. ConclusionsReinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy individuals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis.

neuroscience↗

Precision-weighting of superior frontal cortex unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of cortical unsigned prediction error (i.e., surprise) signals plays a key role in learning and decision-making, to be controlled by dopamine, and to contribute to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation and in patients with early psychosis. Behavioural computational modelling indicated that precision-weighting of unsigned prediction errors benefits learning in health, and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors relative to their precision in bilateral superior frontal gyri and dorsal anterior cingulate, which was perturbed by dopaminergic modulation, impaired in psychosis, and associated with task performance and schizotypy. We conclude that precision-weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

neuroscience↗

Influence of prior beliefs on perception in early psychosis: effects of illness stage and hierarchical level of belief

Alterations in the balance between prior expectations and sensory evidence may account for faulty perceptions and inferences leading to psychosis. However, uncertainties remain about the nature of altered prior expectations and the degree to which they vary with the emergence of psychosis. We explored how expectations arising at two different levels - cognitive and perceptual - influenced processing of sensory information and whether relative influences of higher and lower level priors differed across people with prodromal symptoms and those with psychotic illness. In two complementary auditory perception experiments, 91 participants (30 with first episode psychosis, 29 at clinical risk for psychosis, and 32 controls) were required to decipher a phoneme within ambiguous auditory input. Expectations were generated in two ways: an accompanying visual input of lip movements observed during auditory presentation, or through written presentation of a phoneme provided prior to auditory presentation. We determined how these different types of information shaped auditory perceptual experience, how this was altered across the prodromal and established phases of psychosis, and how this relates to cingulate glutamate levels assessed by magnetic resonance spectroscopy. The psychosis group relied more on high level cognitive priors compared to both healthy controls and those at clinical risk for psychosis, and more on low level perceptual priors than the clinical risk group. The risk group were marginally less reliant on low level perceptual priors than controls. The results are consistent with previous theory that influences of prior expectations in psychosis in perception differ according to level of prior and illness phase.\n\nGeneral scientific summaryWhat we perceive and believe on any given moment will allow us to form expectations about what we will experience in the next. In psychosis, it is believed that the influence of these so-called perceptual and cognitive prior expectations on perception is altered, thereby giving rise to the symptoms seen in psychosis. However, research thus far has found mixed evidence, some suggesting an increase in the influence of priors and some finding a decrease. Here we test the hypothesis that perceptual and cognitive priors are differentially affected in individuals at-risk for psychosis and individuals with a first episode of psychosis, thereby partially explaining the mixed findings in the literature. We indeed found evidence in favour of this hypothesis, finding weaker perceptual priors in individuals at-risk, but stronger cognitive priors in individuals with first episode psychosis.

neuroscience↗

Pleiotropic effects drive correlation between body mass index and cortical myelination

BackgroundEpidemiological studies have reported significant associations between obesity and neurocognitive decline. Understanding these associations will require deeper analyses of how body mass index (BMI) and brain structure are related. Here we explore the extent to which shared genetic factors (pleiotropy) govern the association between BMI and cortical myelination.\n\nMethodsStatistical models of bivariate heritability were applied to structural MR image data from a cohort of monozyogotic and dizygotic twins. Estimates of phenotypic and genetic correlation between BMI and cortical myelination were derived. A co-twin control design based on monozygotic twins was used to test the hypothesis of a causal relationship between BMI and myelination. The variation in the genetic correlation across the cortex was compared with the average statistical enrichment of genes associated with obesity derived from data from the Allen brain atlas.\n\nResultsStatistically significant phenotypic and genetic correlation between BMI and cortical myelination was observed across the cortex. Taking the heritability of each trait into account, approximately 80% of the phenotypic correlation between the traits was accounted for by shared genetic factors.\n\nIntra-pair differences between traits in monozygotic twins failed to support a causal relationship. Moreover, variation in genetic correlation across the cortex was significantly associated with the statistical enrichment of genes related to obesity.\n\nConclusionsThese results support the hypothesis that pleiotropic effects drive the association between BMI and cortical myelination. This observation may help to explain the co-occurrence of obesity in neurocognitive decline and mental health disorders characterized by changes in myelination and oligodendrocyte function.

neuroscience↗