SARS-CoV-2 Specific Nanobodies Neutralize Different Variants of Concern and Reduce Virus Load in the Brain of h-ACE2 Transgenic Mice

PAVAN, MARÍA FLORENCIA; BOK, MARINA; BETANZOS SAN JUAN, RAFAEL; MALITO, JUAN PABLO; MARCOPPIDO, GISELA ARIANA; FRANCO, DIEGO RAFAEL; MILITELO, DANIELA AYELEN; SCHAMMAS, JUAN MANUEL; BARI, SARA ELIZABETH; STONE, WILLIAM; LÓPEZ, KRISANGEL; PORIER, DANIELLE LABRIE; MULLER, JOHN ANTHONY; AUGUSTE, ALBERT JONATHAN; YUAN, LIJUAN; WIGDOROVITZ, ANDRÉS; PARREÑO, VIVIANA GLADYS; IBAÑEZ, LORENA ITATI

Viruses

MDPI

Lugar: Basel; Año: 2024 vol. 16

Since thebeginning of the COVID-19 pandemic, there has been a significant need todevelop antivirals and vaccines to combat the disease. In this work, wedeveloped llama-derived nanobodies (Nbs) directed against the receptor bindingdomain (RBD) and other domains of the Spike (S) protein of SARS-CoV-2. Most ofthe Nbs with neutralizing properties were directed to RBD and were able to blockS-2P/ACE2 interaction. Three neutralizing Nbs recognized the N-terminal domain(NTD) of the S-2P protein. Intranasal administration of Nbs induced protectionranging from 40% to 80% after challenge with the WA1/2020 strain in k18-hACE2transgenic mice. Interestingly, protection was associated with a significantreduction in virus replication in nasal turbinates and a reduction in virus loadin the brain. Employing pseudovirus neutralization assays, we identified Nbswith neutralizing capacity against the Alpha, Beta, Delta, and Omicronvariants, including a Nb capable of neutralizing all variants tested.Furthermore, cocktails of different Nbs performed better than individual Nbs atneutralizing two Omicron variants (B.1.529 and BA.2). Altogether, the datasuggest the potential of SARS-CoV-2 specific Nbs for intranasal treatment ofCOVID-19 encephalitis.