ABSTRACT
Protection against SARS-CoV-2 and SARS-related zoonotic coronaviruses with pandemic potential is urgently needed. To evaluate immunization strategies, we made nanoparticles displaying the receptor-binding domain (RBD) of only SARS-CoV-2 (homotypic nanoparticles) or co-displaying the SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive antibody binding and neutralization responses, confirming increased immunogenicity from multimerization. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2-RBD-nanoparticles or antibodies from COVID-19 convalescent human plasmas. Moreover, sera from mosaic-RBD-immunized mice neutralized heterologous pseudotyped coronaviruses equivalently or better after priming than sera from homotypic SARS-CoV-2-RBD-nanoparticle immunizations, demonstrating no loss of immunogenicity against any particular RBD resulting from co-display. Thus, a single immunization with mosaic-RBD-nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses.
Subject(s)
COVID-19ABSTRACT
ObjectiveTo systematically describe CNS and PNS complications in hospitalized COVID-19 patients. MethodsWe conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission, at discharge and at 3-month follow-up. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. ResultsFrom April-September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom were referred to ICU for respiratory failure. Evaluation revealed a higher frequency of CNS/PNS symptoms in ICU patients compared to non-ICU patients. The most common CNS complication was encephalopathy (n=22, 36.1%), which was severe in 13 patients (GCS[≤]12), including 8 with akinetic mutism. Length of ICU admission was an independent predictor of encephalopathy (OR=1.23). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR=1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were classified as para/post-infectious. The remainder included cases secondary to critical illness or other causes (n=34) or without sufficient investigations (n=4). Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. ConclusionsCNS/PNS complications were common in hospitalized COVID-19 patients, particularly in ICU patients, and often attributable to critical illness. In cases with COVID-19 as the primary cause for neurological disease, there were no signs of viral neurotropism, but laboratory changes suggested autoimmune-mediated mechanisms.
Subject(s)
COVID-19ABSTRACT
Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of Imatinib in multiple models. Our results indicated that Imatinib and another TKI, the Masitinib, exhibit an antiviral activity in VeroE6 cells. However, Imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, Imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of Imatinib and similar TKIs as antivirals in the treatment of Covid-19.
Subject(s)
COVID-19 , Hematologic NeoplasmsABSTRACT
The evolutionary mechanisms by which SARS-CoV-2 viruses adapt to mammalian hosts and, potentially, escape human immunity depend on the ways genetic variation is generated and selected within and between individual hosts. Using domestic cats as a model, we show that SARS-CoV-2 consensus sequences remain largely unchanged over time within hosts, but dynamic sub-consensus diversity reveals processes of genetic drift and weak purifying selection. Transmission bottlenecks in this system appear narrow, with new infections being founded by fewer than ten viruses. We identify a notable variant at amino acid position 655 in Spike (H655Y) which arises rapidly in index cats and becomes fixed following transmission in two of three pairs, suggesting this site may be under positive selection in feline hosts. We speculate that narrow transmission bottlenecks and the lack of pervasive positive selection combine to constrain the pace of ongoing SARS-CoV-2 adaptive evolution in mammalian hosts.