Acronimo: ICOVA

Titolo: Impact of SARS-CoV-2 variability on antiviral agents

Codice Progetto: 2022R8A2FW

Responsabile scientifico per il DMM: Prof. Saverio Parisi
Coordinatore: Università degli Studi di SIENA - Prof. Maurizio ZAZZI

Partner-Unità di ricerca: Università degli Studi di PADOVA - Università degli Studi di PERUGIA

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 218.785,00 - CUP C53D23000650006

 

Abstract del progetto

Despite massive worldwide vaccination, SARS-CoV-2 infections still occur at a high pace. Repeated vaccine doses protect most individuals from severe disease, however protection from infection is suboptimal. Thus, viral spread remains sustained by both unvaccinated and vaccinated individuals, with morbidity and mortality driven by local differences in vaccine coverage. Factors contributing to the limited success of vaccination include (i) rapid waning of natural and artificial immunity to coronaviruses, (ii) newly emergent SARS-CoV-2 variants with increased adaptation to humans and (iii) use of obsolete vaccine preparations based on the ancestral Wuhan wild type viral strain from which subsequent SARS-CoV-2 variants have substantially diverged. Indeed, SARS-CoV-2 has shown a striking ability to evolve into newly divergent variants which may become dominant in a matter of weeks, challenging the strategy of updating vaccines to cope with virus variability. Antiviral treatments have become available, mostly in the last few months, as an eagerly awaited complement to vaccination. These include monoclonal antibodies (mAbs) and direct acting antivirals (DAAs), both to be administered within a few days from diagnosis to people at risk of progression to severe disease. In addition, one mAb cocktail has been approved as pre-exposure prophylaxis in high-risk subjects who are unlikely to mount an adequate immune response to COVID-19 vaccination or for whom COVID-19 vaccination is not recommended. In light of SARS-CoV-2 variability and evolution, it is crucial to define the activity of mAbs and DAAs against current and future viral variants as well as the potential for viral resistance to such treatments.

This proposal aims at investigating the following areas: 1. Activity of mAbs and DAAs vs. SARS-CoV-2 variants in vitro 2. Genetic barrier to resistance to mAbs and DAAs in vitro 3. Emergent resistance to mAbs and DAAs in vivo 4. Persistence of mAb activity in vivo over time.

The first two activities will be performed at the University of Siena (UNISI) where prototype viral variants, anti-SARS-CoV-2 DAAs and mAbs are available and dedicated lab assays have been developed. Activities 3 and 4 will be performed through observational studies led by researchers at the University of Padua (UNIPD) and Perugia (UNIPG) who have been extensively involved in SARS-CoV-2 clinical research. Importantly, the three academic groups have been collaborating for more than one year in this research area, thus connections functional to the conduct of the study are well established.

Gaining knowledge in the above areas is fundamental to define the role of anti-SARS-CoV-2 treatment as a complement of the continued global vaccination campaign. In addition, the combined investigation of natural and drug-selected virus variability will be an extraordinarily effective way to define the viral genetic space and the potential for virus evolution in the upcoming years.