Pathogenicity of SARS-CoV-2 Omicron subvariants JN.1, EG.5.1, and BA.2.86.1 in immunologically naïve cynomolgus...

Since the emergence of the SARS-CoV-2 Omicron variant, decreased morbidity and mortality relative to early strains have been widely reported. However, the virological characteristics of recent subvariants dominating the post-pandemic era remain to be fully elucidated. In the present study, the intrinsic pathogenicities of the Omicron subvariants JN.1, EG.5.1, and BA.2.86.1 were investigated using an immunologically naïve cynomolgus macaque model. All three variants exhibited robust replication in the upper respiratory tract, surpassing the viral titers observed with the early Wuhan strain. Omicron subvariant infection caused prolonged fever and sustained viral shedding in the nasal mucosa for at least seven days, indicating enhanced adaptation to upper airway tissues. Despite this shift in viral replication tropism, histological analysis showed that these variants retained the characteristics to induce lower respiratory tract disease. All infected macaques developed bronchopneumonia characterized by cellular exudates in the alveolar spaces. The histological scores were comparable to those observed with the early strain. These findings demonstrate that the pathogenicity of the Omicron subvariants has not been fully attenuated in the absence of pre-existing immunity, since they caused severe lung disease in immunologically naïve macaques. Furthermore, their enhanced propagation in the upper airway likely facilitates efficient transmission among humans. The continuous circulation of SARS-CoV-2 variants underscores the necessity of ongoing surveillance of viral gene variations and the maintenance of protective immunity in vulnerable populations.