Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection

Breakthrough infections in vaccinated population and continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants make it imperative to develop more efficacious medical countermeasures. Previously, an anti-SARS-CoV-2 nanobody, Nanosota-3A, that neutralizes the infection of live Omicron BA.1 with picomolar potency, is identified. Herein, Nanosota-3A is fused with the crystallizable fragment (Fc) domain of human IgG1 that contains M252Y/S254T/T256E (YTE) substitutions, named Nanosota-3A-Fc-YTE. Compared to Nanosota-3A-Fc, Nanosota-3A-Fc-YTE exhibits identical binding to the SARS-CoV-2 spike protein yet displays eightfold higher binding affinity for human neonatal Fc receptor (hFcRn) at pH 6.0. In hFcRn transgenic mice, the half-life of Nanosota-3A-Fc and Nanosota-3A-Fc-YTE is 5.1 days and 24.8 days, respectively. The mice are challenged with intranasal exposure of Omicron B.1.1.529 virus 55 days after a single dose of Nanosota-3A fusions (20 mg kg^-1) is administered. Compared to the untreated controls, the lung viral titers in mice receiving Nanosota-3A-Fc-YTE are reduced by 104.7-fold (<i>p</i> = 0.007) with 50% of the mice free of detectable virus. By contrast, Nanosota-3A-Fc-treated mice show only 3.5-fold reduction in the viral titers (<i>p</i> = 0.41). The durable protection conferred by a single dose of Nanosota-3A-Fc-YTE administered nearly 2 months prior to the virus exposure demonstrates the promise of long-circulating nanobodies as powerful prophylactics against SARS-CoV-2.