Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network (preprint)

ABSTRACT The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus-host interactions. We developed a network-based algorithm that expands the SARS-CoV-2-host protein interaction network and identifies host targets that modulate viral infection. To disrupt the SARS-CoV-2 interactome, we systematically probed for potent compounds that selectively target the identified host proteins with high expression in cells relevant to COVID-19. We experimentally tested seven chemical inhibitors of the identified host proteins for modulation of SARS-CoV-2 infection in human cells that express ACE2 and TMPRSS2. Inhibition of the epigenetic regulators bromodomain-containing protein 4 (BRD4) and histone deacetylase 2 (HDAC2), along with ubiquitin specific peptidase (USP10), enhanced SARS-CoV-2 infection. Such proviral effect was observed upon treatment with compounds JQ1, vorinostat, romidepsin, and spautin-1, when measured by cytopathic effect and validated by viral RNA assays, suggesting that HDAC2, BRD4 and USP10 host proteins have antiviral functions. Mycophenolic acid and merimepodib, two inhibitors of inosine monophosphate dehydrogenase (IMPDH 1 and IMPDH 2), showed modest antiviral effects with no toxicity in mock-infected control cells. The network-based approach enables systematic identification of host-targets that selectively modulate the SARS-CoV-2 interactome, as well as reveal novel chemical tools to probe virus-host interactions that regulate virus infection. Synopsis Viruses exploit host machinery and therefore it is important to understand the virus-host dependencies to gain better insight of the key regulators of viral infection. Using a context-specific SARS-COV-2 PPI network, a computational framework was developed to identify host modulators of viral infection. Chromatin modifying host proteins HDAC2 and BRD4, along with deubiquitinating enzyme USP10, act as antiviral proteins. IMPDH inhibitors mycophenolic acid and merimipodib showed modest antiviral response to SARS-COV-2 infection, and no toxic effects. Cell context specificity is a critical factor when identifying selective modulators of viral infection and potential antiviral therapeutics. Topology-based network models cannot distinguish between host-proteins, the inhibition of which leads to either virus suppressive or enhancing effects.

Safety and immunogenicity of a SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in healthy adults: interim findings from a phase 2, randomised, dose-finding, multi-centre study (preprint)

Background This study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM. Methods This Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18-59/[≥]60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5{micro}g, 10{micro}g or 15{micro}g of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (Nabs) against the D614G variant are presented (primary objectives). Findings Of 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received [≥]1 injections (5{micro}g, n=240; 10{micro}g, n=239; 15{micro}g, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 na ive participants at D36, 96'9%, 97.0% and 97'6% of participants had [≥]4-fold-rise in NAb titres from baseline in the 5{micro}g-, 10{micro}g- and 15{micro}g-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5{micro}g-, 10{micro}g- and 15{micro}g-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-na ive adults after one injection were higher than titres after two injections in na ive adults. Interpretation Two injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 na ive and non-na ive adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.