Postdoctoral Fellow Centre for Virology, Vaccinology and Therapeutics Hong Kong, Hong Kong
Abstract: The high transmissibility of SARS-CoV-2 Omicron subvariants is generally attributed to immune escape. However, it remains unclear whether these emerging variants have gradually acquired replicative fitness in human respiratory epithelial cells. We sought to evaluate the replicative fitness of BA.5 and earlier variants in physiologically active respiratory organoids. BA.5 exhibited a dramatically increased replicative capacity and infectivity compared to B.1.1.529 and the ancestral wildtype (WT) strain in human nasal and airway organoids. The BA.5 spike pseudovirus demonstrated significantly higher entry efficiency than those carrying the WT or B.1.1.529 spike. Notably, we observed prominent syncytium formation in BA.5-infected nasal and airway organoids, which was elusive in WT- and B.1.1.529-infected organoids. BA.5 spike-triggered syncytium formation was verified through lentiviral overexpression of the spike in nasal organoids. Moreover, BA.5 replicated modestly in alveolar organoids, with a significantly lower titer than B.1.1.529 and WT. Collectively, the higher entry efficiency and fusogenic activity of the BA.5 spike facilitated viral spread through syncytium formation in the human airway epithelium, leading to enhanced replicative fitness and immune evasion. In contrast, the attenuated replicative capacity of BA.5 in alveolar organoids may account for its benign clinical manifestation.
