Viroclinics Biosciences (Netherlands)

IntroductionIn severe COVID-19, direct-acting antiviral drugs were not effective in hyperinflammatory stages and steroid treatment may weaken host immunity. The MEK inhibitor zapnometinib, as a host-targeting drug, has demonstrated promising efficacy against severe acute viral infections. Proof-of-concept for the innovative approach was presented in a clinical Phase 2 trial with hospitalized COVID-19 patients.MethodsThe antiviral and immunomodulatory potential of zapnometinib was investigated in samples obtained from COVID-19 patients enrolled in a Phase 2 clinical trial (RESPIRE), as well as in a SARS-CoV-2 Syrian hamster model, an acute lung injury mouse model, and in cell culture. The antiviral activity of zapnometinib was assessed using viral load reduction assays and RT-qPCR. Cytokines and chemokines were analyzed via ELISA and RT-qPCR. Alterations in T and B cells from COVID-19 patients were analyzed using flow cytometry. Biomarker analysis in hamster serum was conducted to monitor potential toxic effects.ResultsZapnometinib reduced SARS-CoV-2 viral load in hospitalized COVID-19 patients, in the hamster model and in various highly pathogenic coronaviruses in vitro. Pro-inflammatory cytokines and chemokines decreased in COVID-19 patients, in a lung injury mouse model, and in vitro in primary human blood cells treated with zapnometinib. In the hamster model, zapnometinib alleviated SARS-CoV-2-mediated lung pathology. In patients with COVID-19, zapnometinib increased T and plasma B cells.ConclusionUnlike direct-acting antivirals, zapnometinib’s dual effect highlights its therapeutic potential in the treatment of severe acute viral infections, with favorable antiviral and immunomodulatory properties.

ABSTRACT The current outbreak of HPAI H5N1 virus infections in dairy cattle in the USA underscores the need for easily accessible methods to rapidly assess host susceptibility for infection with known and emerging influenza viruses. Here we show that ex vivo lung slice cultures from calves provide a useful method to rapidly screen host susceptibility to a range of influenza A viruses.

Human milk is important for antimicrobial defense in infants and has well demonstrated antiviral activity. We evaluated the protective ability of human milk against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in a human fetal intestinal cell culture model. We found that, in this model, human milk blocks SARS-CoV-2 replication, irrespective of the presence of SARS-CoV-2 spike-specific antibodies. Complete inhibition of both enveloped Middle East Respiratory Syndrome Coronavirus and human respiratory syncytial virus infections was also observed while no inhibition of non-enveloped enterovirus A71 infection was seen. Transcriptome analysis after 24h of the intestinal monolayers treated with human milk showed large transcriptomic changes from human milk treatment and subsequent analysis suggested that ATP1A1 downregulation by milk might be of importance. Inhibition of ATP1A1 blocked SARS-CoV-2 infection in our intestinal model, while no effect on EV-A71 infection was seen. Our data indicate that human milk has potent antiviral activity against particular (enveloped) viruses by potentially blocking the ATP1A1-mediated endocytic process.

Abstract Coronaviruses, in particular the current pandemic strains of SARS-CoV-2, represent an ever-evolving threat to human life. Currently available antiviral drugs are not suitable for severely infected patients in later hyperinflammatory stages of the disease. New therapeutics that inhibit virus propagation and target inflammation would be ideal. We demonstrate that the host targeted MEK inhibitor zapnometinib displays such a dual effect. The drug efficiently reduced virus titers of different SARS-CoV-2 variants and other highly pathogenic human coronaviruses such as SARS-CoV-1 and MERS-CoV in vitro. In a Syrian hamster infection model, zapnometinib reduced SARS-CoV-2 viral load and alleviated lung pathology. Drug safety biomarkers, body weight change and clinical observations, indicated that zapnometinib was well tolerated and showed no toxicity. Moreover, the immune dampening effect could be confirmed in an acute lung injury mouse model and in vitro experiments in primary human blood cells that demonstrated the reduction of disease related cytokines and chemokines. Thus, in contrast to direct-acting antivirals, zapnometinib displays a dual therapeutic effect highlighting its potential in the treatment of severe COVID-19 and other acute viral infections leading to hyperinflammation.

Abstract The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential. Many of its mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of most therapeutic monoclonal antibodies. Here we describe a receptor-blocking human monoclonal antibody, 87G7, that retains ultrapotent neutralization against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) Variants-of-Concern (VOCs). Structural analysis reveals that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protects mice and/or hamsters against challenge with all current SARS-CoV-2 VOCs. Our findings may aid the development of sustainable antibody-based strategies against COVID-19 that are more resilient to SARS-CoV-2 antigenic diversity.One sentence summaryA human monoclonal antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants

Previously we have shown that a single dose of recombinant adenovirus serotype 26 (Ad26) vaccine expressing a prefusion stabilized SARS-CoV-2 spike antigen (Ad26.COV2.S) is immunogenic and provides protection in Syrian hamster and non-human primate SARS-CoV-2 infection models. Here, we investigated the immunogenicity, protective efficacy, and potential for vaccine-associated enhanced respiratory disease (VAERD) mediated by Ad26.COV2.S in a moderate disease Syrian hamster challenge model, using the currently most prevalent G614 spike SARS-CoV-2 variant. Vaccine doses of 1 × 109 and 1 × 1010 VP elicited substantial neutralizing antibodies titers and completely protected over 80% of SARS-CoV-2 inoculated Syrian hamsters from lung infection and pneumonia but not upper respiratory tract infection. A second vaccine dose further increased neutralizing antibody titers that was associated with decreased infectious viral load in the upper respiratory tract after SARS-CoV-2 challenge. Suboptimal non-protective immune responses elicited by low-dose A26.COV2.S vaccination did not exacerbate respiratory disease in SARS-CoV-2-inoculated Syrian hamsters with breakthrough infection. In addition, dosing down the vaccine allowed to establish that binding and neutralizing antibody titers correlate with lower respiratory tract protection probability. Overall, these preclinical data confirm efficacy of a one-dose vaccine regimen with Ad26.COV2.S in this G614 spike SARS-CoV-2 virus variant Syrian hamster model, show the added benefit of a second vaccine dose, and demonstrate that there are no signs of VAERD under conditions of suboptimal immunity.

ABSTRACT Transmission of severe acute respiratory coronavirus-2 (SARS-CoV-2) between livestock and humans is a potential public health concern. We demonstrate the susceptibility of rabbits to SARS-CoV-2, which excrete infectious virus from the nose and throat upon experimental inoculation. Therefore, investigations on the presence of SARS-CoV-2 in farmed rabbits should be considered.