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Contains fulltext : 248638.pdf (Publisher’s version ) (Open Access) Repurposing drugs is a promising strategy to identify therapeutic interventions against novel and re-emerging viruses. Posaconazole is an antifungal drug used to treat invasive aspergillosis and candidiasis. Recently, posaconazole and its structural analog, itraconazole were shown to inhibit replication of multiple viruses by modifying intracellular cholesterol homeostasis. Here, we show that posaconazole inhibits replication of the alphaviruses Semliki Forest virus (SFV), Sindbis virus and chikungunya virus with EC(50) values ranging from 1.4 μM to 9.5 μM. Posaconazole treatment led to a significant reduction of virus entry in an assay using a temperature-sensitive SFV mutant, but time-of-addition and RNA transfection assays indicated that posaconazole also inhibits post-entry stages of the viral replication cycle. Virus replication in the presence of posaconazole was partially rescued by the addition of exogenous cholesterol. A transferrin uptake assay revealed that posaconazole considerably slowed down cellular endocytosis. A single point mutation in the SFV E2 glycoprotein, H255R, provided partial resistance to posaconazole as well as to methyl-β-cyclodextrin, corroborating the effect of posaconazole on cholesterol and viral entry. Our results indicate that posaconazole inhibits multiple steps of the alphavirus replication cycle and broaden the spectrum of viruses that can be targeted in vitro by posaconazole, which could be further explored as a therapeutic agent against emerging viruses.

The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are leveraged for a rapid emergency response1. We describe the discovery of a live virus-vectored SARS-CoV-2 vaccine candidate using the yellow fever 17D (YF17D) vaccine as vector to express a non-cleavable prefusion form of the SARS-CoV-2 Spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. Vaccine candidate YF-S0 has an outstanding safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters, mice and cynomolgus macaques and concomitantly a protective immunity against YFV. Humoral immunity is complemented by a favourable Th1 cell-mediated immune response as profiled in mice. In a stringent hamster model2 as well as in non-human primates, YF-S0 prevents infection with SARS-CoV-2. Moreover, in hamsters, a single dose confers protection from lung disease in most vaccinated animals within 10 days. Taken together, the quality of immune responses triggered and the rapid kinetics by which protective immunity can be mounted already after a single dose warrant further development this potent SARS-CoV-2 vaccine candidate. The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are leveraged for a rapid emergency response1. We describe the discovery of a live virus-vectored SARS-CoV-2 vaccine candidate using the yellow fever 17D (YF17D) vaccine as vector to express a non-cleavable prefusion form of the SARS-CoV-2 Spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. Vaccine candidate YF-S0 has an outstanding safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters, mice and cynomolgus macaques and concomitantly a protective immunity against YFV. Humoral immunity is complemented by a favourable Th1 cell-mediated immune response as profiled in mice. In a stringent hamster model2 as well as in non-human primates, YF-S0 prevents infection with SARS-CoV-2. Moreover, in hamsters, a single dose confers protection from lung disease in most vaccinated animals within 10 days. Taken together, the quality of immune responses triggered and the rapid kinetics by which protective immunity can be mounted already after a single dose warrant further development this potent SARS-CoV-2 vaccine candidate. ispartof: Nature vol:590 issue:7845 pages:320-325 ispartof: location:England status: published

Significance The previous lack of consensus around the use of hydroxychloroquine for COVID-19 patients underlines the need to thoroughly assess the in vivo efficacy of drugs against SARS-CoV-2. Small animal infection models, such as the hamster model, have a pivotal place herein. We here show in vivo preclinical results with favipiravir which indicate that antiviral efficacy against SARS-CoV-2 might only be achieved with a very high dose. Hydroxychloroquine, on the other hand, completely lacks antiviral activity, thus providing no scientific basis for its further use in COVID-19 patients. With this study on two key antiviral candidates, we establish the baseline for SARS-CoV-2 antiviral treatment, which will allow us to identify superior antiviral candidates in the near future., Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. 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 an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. 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 decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.

The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines to quench the unrestrained spread of SARS-CoV-2. Several promising vaccine platforms, developed in recent years, are leveraged for a rapid emergency response to COVID-191. 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 a stringent hamster SARS-CoV-2 challenge model2, vaccine candidate YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose confers protection from lung disease in most vaccinated animals even within 10 days. These results warrant further development of YF-S0 as a potent SARS-CoV-2 vaccine candidate.

SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus was able to infect millions of people. To date, close to half a million patients succumbed to the viral disease, COVID-19. The high need for treatment options, together with the lack of small animal models of infection has led to clinical trials with repurposed drugs before any preclinicalin vivoevidence attesting their efficacy was available. We used Syrian hamsters to establish a model to evaluate antiviral activity of small molecules in both an infection and a transmission setting. Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated animals, which was confirmed by histopathology. In addition, both compounds did not prevent virus transmission through direct contact and thus failed as prophylactic treatments. By modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster infection and transmission model to be a robust model for studyingin vivoefficacy of antiviral compounds. The information acquired using hydroxychloroquine and favipiravir in this model is of critical value to those designing (current and) future clinical trials. At this point, the data here presented on hydroxychloroquine either alone or combined with azithromycin (together with previously reportedin vivodata in macaques and ferrets) provide no scientific basis for further use of the drug in humans.