Introductory paragraphSince the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.

27SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 28 2019. With no specific therapeutic and prophylactic options available, the virus was able to 29 infect millions of people. To date, close to half a million patients succumbed to the viral disease, 30 COVID-19. The high need for treatment options, together with the lack of small animal models 31 of infection has led to clinical trials with repurposed drugs before any preclinical in vivo 32 evidence attesting their efficacy was available. We used Syrian hamsters to establish a model 33 to evaluate antiviral activity of small molecules in both an infection and a transmission setting. 34Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and 35 pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-36 infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) 37 resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan 38 analysis of the lungs showed no improvement compared to non-treated animals, which was 39 confirmed by histopathology. In addition, both compounds did not prevent virus transmission 40 through direct contact and thus failed as prophylactic treatments. By modelling the PK profile 41 of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung 42 exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster 43 infection and transmission model to be a robust model for studying in vivo efficacy of antiviral 44 compounds. The information acquired using hydroxychloroquine and favipiravir in this model 45 is of critical value to those designing (current and) future clinical trials. At this point, the data 46 here presented on hydroxychloroquine either alone or combined with azithromycin (together 47 with previously reported in vivo data in macaques and ferrets) provide no scientific basis for 48 further use of the drug in humans. 49

Background The histological evaluation of estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer lesions from biopsy tissue can stratify patients to receive endocrine therapy. Furthermore, PR expression can predict response to selective estrogen receptor modulators (SERMs). Current immunohistochemical approaches to PR detection are limited by sampling error associated with biopsy and lack of standardised protocols; positron emission tomography (PET) using receptor targeted radiopharmaceuticals to provide quantitative, whole-body imaging may overcome these limitations. PR expression has been successfully imaged with PET in the clinical setting, however investigation into new radioligands with improved pharmacokinetics and metabolic stability is desirable. Results We report the synthesis of a focused library of non-steroidal PR ligands evaluated for use as PET radioligands. A lead candidate ( [ 18 F]2 ) with low nanomolar activity was selected and radiolabelled with a radiochemical yield of 2.29 ± 2.31% (decay-corrected), radiochemical purity (RCP) > 95% and a molar activity of 2.5 ± 1.6 GBq/μmol. Cell uptake studies showed a significant and specific accumulation of [ 18 F]2 in T47D (PR++) breast cancer cell compared to MDA-MB-231 (PR-) control; however, in vivo evaluation was confounded by rapid defluorination of the radioligand. In vitro metabolite analysis of 2 in MLM confirmed defluorination and oxidative metabolism of the thiocarbamate to oxocarbamate moiety by mass spectrometry. Conclusions A route to access [ 18 F]2 was developed to allow in vitro and in vivo evaluation, albeit with low radiochemical yield and modest molar activity. [ 18 F]2 demonstrated selective uptake in PR++ T47D cells which could be blocked in a dose dependent manner with progesterone. However, [ 18 F]2 showed poor in vivo metabolic stability with rapid defluorination within the time frame of the imaging protocol. Electronic supplementary material The online version of this article (10.1186/s41181-018-0054-z) contains supplementary material, which is available to authorized users.

AbstractThe 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.