International Society for Antiviral Research

Developing SARS-CoV2 infection models, antiviral strategies and a vaccine

Johan Neyts, PhD

Rega Institute for Medical Research, KU Leuven, Belgium

To aid in the development of therapeutics we established a high throughput screenings assays, that was used for the screening of repurposing libraries as well for the de novo drug development programs.  During the first months of the SARS-CoV2 pandemic, the urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established a SARS-CoV2 infection model in human airway epithelial cell cultures grown at the air/liquid interface to further assess the potential of the in vitro identified inhibitors of viral replication.  Next a robust SARS-CoV2 infection model in Syrian hamster was developed to aid in drug and vaccine development. In wild-type hamsters, intranasal SARS-CoV-2 infection triggers bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. An exuberant innate response was identified as key player of the immune pathogenesis, in which STAT2 signaling plays a double-edged role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. The results endorse hamsters as pre-clinical model to assess the therapeutic benefit of antiviral strategies, immune modulators and vaccines for the treatment and prevention of COVID-19. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in respectively a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir prevented virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modelling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate for the first time that an antiviral drug at non-toxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. We are currently assessing the efficacy of various drugs or combinations thereof  in the hamster model. Finally we aimed at developing a potent single dose COVID19 vaccine; to that end we employed the live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express the prefusion form of the SARS-CoV-2 Spike antigen. In mice, the vaccine candidate, tentatively named YF-S0, induces high levels of SARS-CoV-2 neutralizing antibodies and a favorable Th1 cell-mediated immune response. In the hamster model even a single dose of the vaccine confers protection from lung disease. These results warrant further development of YF-S0 as a potent SARS-CoV-2 vaccine.