Résumé: SARS-CoV-2 is a betacoronavirus that has recently emerged as a human pathogen in the city of Wuhan in China’s Hubei province. The disease caused by this newly identified virus has been named COVID-19 and symptoms include fever, severe respiratory illness and pneumonia. As of March 2020, the World Health Organization (WHO) has declared that SARS-CoV-2 is pandemic, and the number of confirmed cases is exponentially increasing. SARS-CoV-2 virus is closely related to SARS-CoV, which was responsible for the Severe Acute Respiratory Syndrome (SARS) in 2002. Similarly, to SARS-CoV, SARS-CoV-2 is of zoonotic origin and was demonstrated to cause life-threatening diseases in humans. So far, there is no vaccine or treatment for COVID-19. It is therefore critical to generate vaccines and drugs that will either prevent or treat COVID-19. At present, there are 8 candidate vaccines in clinical evaluation and more than 100 candidate vaccines in preclinical evaluation. Vaccine in clinical trials are represented by inactivated SARS-CoV-2 virus, non-replicating viral vectors, DNA and RNA vaccines (https://www.who.int). Surprisingly, no protein subunit vaccine are reported to be tested currently in clinical trial, as proposed in this project, which are generally safer and easier to produce. Moreover, all Human coronaviruses enter their host cells using the trimeric transmembrane spike (S) glycoprotein. The coronavirus’ S protein represents a major target for the human humoral immune response following SARS-CoV-2 infection. However, a large set of data from previous SARS-CoV-1 or CoV-2 infected individuals, or generated in preclinical models, pointed out the potential protective effect of cellular immunity. In this study, we propose to test the immunogenicity and the preventative effect of a combination of two vaccine platforms already in phase 1 to 3 clinical development; i.e the DNA-derived DREP platform and the anti-Dendritic cell (DC) targeting epitope-based vaccine. A series of DREP and DC-targeting constructs against SARS-CoV-2 are already available. A large set of data showed that these vaccines, either administered alone, or in a prime boost combination, elicited strong and durable T and B-cell immune responses against infectious agents. We develop here an original strategy aimed to induce a polyepitopic T and B cell responses. These vaccines are ready to be tested in two preclinical models, in humanized mice (mice reconstituted with a human immune system), allowing to study in depth human immune responses of different vaccine combinations, and in transgenic knock-in mice expressing the human CD40 and human ACE2, the receptor of SARS-CoV-2 to demonstrate the protective effect of these vaccines. The overreaching goal of this study is to identify within the 12-months time line of this project, vaccine (s) that will be moved forward to the clinical development.

In order to understand what causes severe cases of Covid19, and therefore to improve their medical management, it is essential to better understand the natural history of this disease caused by the SARS-CoV2 coronavirus. Specifically, we propose to solve the puzzle of the much debated role of type I interferons (IFN-I) and of their major cellular source during many viral infections, namely plasmacytoid dendritic cells (pDCs). We will take advantage of mutant mouse models that can be infected with Covid-Cov2 SARS, develop a disease very similar to Covid19, and have been modified for tracing or inactivating pDCs in vivo and for following IFN-I-producing cells with a high degree of resolution. This approach will allow us testing the hypothesis that IFN-I and pDCs play either beneficial or deleterious roles, depending on their activation dynamics in the first days following infection; this activation dynamics being itself dependent on the infectious dose of the virus received or on the initial efficacy of viral control.