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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

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