Protection against viruses is most often measured by levels of plasma binding and neutralizing antibodies (Abs) in vitro, which do not capture the full picture of Ab immunity, including Fc functions. The continuing evolution of SARS-CoV-2 underscores the need to understand protection mediated by Abs. We generated triple knock-in (TKI) mice expressing human ACE2, TMPRSS2, and FCGRT in place of murine genes. A human anti-SARS-CoV-2 IgG1 with a half-life extending mutation but not wild-type IgG1 exhibited long half-life and protected against BA.2 infection in lungs, thereby validating our TKI mice for evaluating human Ab clearance and function. We next evaluated protective efficacy of plasma samples from vaccinated San Diegans against Delta or BA.5 by performing passive transfer experiments. Treatment with pooled plasma from vaccination plus infection but not triple vaccination individuals cleared infectious Delta in lungs of TKI mice, although Delta-binding and -neutralizing Ab titers in vitro were similar between the two groups of people. In contrast, neither group’s plasma impacted lung viral burden upon BA.5 challenge. Thus, Abs elicited by vaccination plus infection but not triple vaccination reduce Delta infection in this mouse model, and Abs from both groups are ineffective against BA.5. These results are consistent with epidemiological data, and show that in vitro Ab titers do not predict in vivo protection. Our TKI mouse model represents an important tool to test efficacy of human monoclonal Abs against SARS-CoV-2/related CoVs, predict human polyclonal Ab-mediated protection against newly emerging variants/CoVs, and dissect mechanisms of Ab-mediated protection in vivo. Results will aid development of pan CoV vaccines.

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