Omicron Sub-Lineage BA.5 Infection Causes Attenuated Pathology and Results in Robust Protection in Omicron Recovered hACE2 Transgenic Mice

Omicron sub-lineage BA.5 emerged recently and was, along with BA.4, the cause of the 5th coronavirus disease (COVID-19) wave in South Africa and subsequently emerged as the predominant strain globally due to its high transmissibility. The lethality of BA.5 infection has not been studied in acute hACE2 transgenic (hACE2.Tg) mice. Here, we investigated tissue-tropism and immuno-pathology induced by BA.5 infection by using hACE2.Tg mice. Our data shows that intranasal BA.5 infection in hACE2.Tg mice results in attenuated pulmonary infection and pathology without showing the clinical and pathological features characteristic of COVID-19. BA.5, similar to its parental lineage Omicron (B.1.1.529), infection was characterized by attenuated expression of inflammatory cytokines, anti-viral response, and Th1 cell response, as compared to ancestral Wuhan-Hu-1 strain. Nonetheless, mice recovered from B.1.1.529 infection showed robust protection against BA.5 infection with reduced lung viral load and pathology. Together, we provide insights into why BA.5 infection may escape previous SARS-CoV-2 exposure induced-T cell immunity, but may result in milder immuno-pathology and alleviated chances of re-infectivity in Omicron recovered individuals.Funding: Financial support to the AA laboratory from THSTI core, Translational Research Program (TRP), BIRAC grants (BT/CS0054/21 and BT/CTH/0004/21) Department of Biotechnology (DBT) and DST-SERB. ZAR is supported by intramural funding (THSTI).Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: Institutional animal ethics committee (IAEC) THSTI approved 384 the protocols and procedures (approval number: IAEC/THSTI/217).