Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge

Abstract

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

Keywords: Animal model; COVID-19; Clinical trial; Pandemic; Pre-clinical research; Vaccine.

Fig. 1

The current landscape of animal models and their utility in the SARS-CoV-2/COVID-19 pandemic. The figure includes four species currently indicated by the WHO as reproducible COVID-19 models. Vaccines in their developmental phase are commonly tested in Rhesus macaque and mice (shown); infrequently in other species such as hamster and ferret (shown) as well as rat, guinea pig, pig, sheep and others (not shown). A current list of species reported to be used for COVID-19 vaccine and drug development outside of peer-reviewed press is detailed in an interactive map of the European Animal Research Association (https://public.flourish.studio/visualisation/1698667/). To date (February 2021), hydroxychloquine, favipiravir and TLR2/6 agonist were the only peer-reviewed therapeutics preventively tested in animals (NHP, ferret, hamster). Lethal COVID-19 phenotype was reported in three studies employing the mouse model. Aged (but not young) NHP displayed a moderate pneumonia (accompanied by relatively mild clinical symptoms) presentation after infection with SARS-CoV-2. Ferrets typically displayed mild symptoms accompanied by a matching pneumonia severity. In hamsters, an advanced lung pathology can be produced but it is concurrent with mild disease symptoms. In all tested species a non-symptomatic phenotype upon infection with SARS-CoV-2 was demonstrated. No animal study focused on the chronic COVID-19 phenotype and its sequelae has been conducted yet. NH: non-humane (primate), ARDS: Acute respiratory distress syndrome. The top of each gray bar indicates the maximal severity specific for a given species; all milder phenotypes, visualized by the gray bar area, can also be produced. The number overlaid on bars depicts an approximate count of the PubMed-listed studies (prevention, vaccination and disease model) utilizing a given species (PubMed queried on February 18, 2021).