Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression.

Oncolytic viruses (OVs) promote the anti-tumor immune response as their replication, and the subsequent lysis of tumor cells, triggers the activation of immune-sensing pathways. Arming OVs by expressing transgenes with the potential to promote immune cell recruitment and activation is an attractive strategy to enhance OVs' therapeutic benefit. For picornaviruses, a family of OVs with clinical experience, the expression of a transgene is limited by multiple factors: genome physical packaging limits, high rates of recombination, and viral-mediated inhibition of transgene secretion. Here, we evaluated strategies for arming Seneca Valley virus (SVV) with relevant immunomodulatory transgenes. Specificially in the contex of arming SVV, we evaluated transgene maximum size and stabiltity, transgene secretion, and the impact of transgene inclusion on viral fitness. We find that SVV is not capable of expressing secreted payloads and has a transgene packaging capacity of ∼10% of viral genome size. To enable transgene expression, we developed SVV replicons with greater transgene size capacity and secretion capabilities. SVV replicons can be packaged in trans by virus in co-infected cells to express immunomodulatory transgenes in surrounding cells, thus providing a means to enhance the potential of this therapeutic to augment the anti-tumor immune response.

Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer.

The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promotes immune cell infiltration, remodeling of the tumor microenvironment, and enhances the activity of anti-PD-1 checkpoint inhibitor. In mouse and non-human primates, Synthetic-SVV is well tolerated reaching exposure well above the requirement for anti-tumor activity. Altogether, the Synthetic RNA virus platform provides an approach that enables repeat intravenous administration of viral immunotherapy.

Carbapenemase-producing organism (CPO) colonisation at a district general hospital: universal screening may help reduce transmission.

OBJECTIVE: Assess the potential of hospital-wide routine screening by determining the prevalence and incidence of carbapenemase-producing organisms (CPOs) isolated from rectal screens at Barnet and Chase Farm Hospitals. METHODS: 3,553 samples were collected between 01/12/2018 and 31/08/2019: from adult critical care wards (universal screening - admission, discharge and weekly), from medical wards with risk-factor based screening according to the prevailing Public Health England (PHE) carbapenemase-producing Enterobacteriaceae (CPE) screening guidelines, or on an ad hoc basis. Prevalence was defined as previously documented positive CPO colonisation, or new positive status, as a proportion of all eligible samples. Incidence was defined as all newly positive patients per 1,000 patient-days. RESULTS: Overall CPO prevalence was 2.1% (95% CI: 1.61-2.58%). Inpatient prevalence was significantly higher at 2.6% vs outpatient at 0.5% (p < 0.001). Incidence was 0.44 per 1,000 patient-days (95% CI: 0.33-0.57), with a rate ratio between Barnet and Chase Farm of 4.9 (p = 0.013). Incidence was highest where universal screening strategy was applied (3.9 per 1000 patient-days, 95% CI: 2.4-5.91). This was 2.5 times higher than risk-factor based screening (p = 0.005) and 23.5 times that of wards without routine surveillance implemented (p < 0.001). CONCLUSION: Surveillance remains a cornerstone in controlling CPO transmission. Our local incidence, lacking hospital-wide screening, significantly exceeded the reported UK average. Universal screening could help to uncover the true prevalence and incidence of CPO, thereby providing the necessary information to properly control transmission, reducing nosocomial outbreaks and ultimately reducing the overall cost to healthcare.

Epidemiology and control measures of an OXA-48-producing Enterobacteriaceae hospital outbreak.

Carbapenemase-producing Enterobacteriaceae (CPE) are a significant challenge to healthcare and infection prevention and control teams. In the UK, OXA-48-like carbapenemases are frequently reported. We describe an outbreak of OXA-48-like producing Enterobacteriaceae and the control measures that proved effective in containing further spread. AIM: To describe epidemiologic and laboratory features of outbreak and highlight key control interventions. FINDINGS: Following the introduction of an increased sensitivity CPE screening protocol, OXA-48-like CPE were identified in screening and clinical samples from 96 patients across five hospital wards between November 2017 and July 2018. Klebsiella pneumoniae and Enterobacter cloacae were the most frequently isolated organisms, although a range of OXA-48-like positive organisms were identified. The outbreak was contained utilising certain key interventions, including the modification of laboratory screening processes, engagement of hospital senior management, clear and frequent communication and a strong 'ward presence' by the infection prevention and control team (IPCT). CONCLUSION: Our report describes how a change in laboratory CPE screening process unmasked a CPE outbreak. The range of bacterial species harbouring the OXA-48-like mechanism suggested plasmid-mediated transfer of resistance. The timely implementation of interventions using a clinical, 'ward-based' approach to infection prevention and control highlights the importance of behavioural change in infection control interventions and enabled the termination of a large outbreak without recourse to environmental sampling, major remedial construction work or extensive molecular strain or plasmid typing.

Tonic-clonic seizures in a postpartum patient: case report.

Eclamptic seizures are a known complication of pregnancy; less well publicized is the patient with late postpartum eclampsia. Late postpartum eclamptic seizures are convulsions that occur more then 48 hours after delivery. Because 40% of patients who have late postpartum eclampsia do not experience preeclampsia, clinical awareness is essential for early treatment and care.