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- Title
A bispecific nanobody dimer broadly neutralizes SARS-CoV-1 & 2 variants of concern and offers substantial protection against Omicron via low-dose intranasal administration.
- Authors
Ma, Huan; Zhang, Xinghai; Zeng, Weihong; Zhou, Junhui; Chi, Xiangyang; Chen, Shaohong; Zheng, Peiyi; Wang, Meihua; Wu, Yan; Zhao, Dan; Gong, Fanwu; Lin, Haofeng; Sun, Hancong; Yu, Changming; Shi, Zhengli; Hu, Xiaowen; Zhang, Huajun; Jin, Tengchuan; Chiu, Sandra
- Abstract
Current SARS-CoV-2 Omicron subvariants impose a heavy burden on global health systems by evading immunity from most developed neutralizing antibodies and vaccines. Here, we identified a nanobody (aSA3) that strongly cross-reacts with the receptor binding domain (RBD) of both SARS-CoV-1 and wild-type (WT) SARS-CoV-2. The dimeric construct of aSA3 (aSA3-Fc) tightly binds and potently neutralizes both SARS-CoV-1 and WT SARS-CoV-2. Based on X-ray crystallography, we engineered a bispecific nanobody dimer (2-3-Fc) by fusing aSA3-Fc to aRBD-2, a previously identified broad-spectrum nanobody targeting an RBD epitope distinct from aSA3. 2-3-Fc exhibits single-digit ng/mL neutralizing potency against all major variants of concerns including BA.5. In hamsters, a single systemic dose of 2-3-Fc at 10 mg/kg conferred substantial efficacy against Omicron infection. More importantly, even at three low doses of 0.5 mg/kg, 2-3-Fc prophylactically administered through the intranasal route drastically reduced viral RNA loads and completely eliminated infectious Omicron particles in the trachea and lungs. Finally, we discovered that 2(Y29G)-3-Fc containing a Y29G substitution in aRBD-2 showed better activity than 2-3-Fc in neutralizing BA.2.75, a recent Omicron subvariant that emerged in India. This study expands the arsenal against SARS-CoV-1, provides potential therapeutic and prophylactic candidates that fully cover major SARS-CoV-2 variants, and may offer a simple preventive approach against Omicron and its subvariants.
- Subjects
INDIA; SARS-CoV-2 Omicron variant; SARS virus; INTRANASAL administration; SARS-CoV-2; BISPECIFIC antibodies; X-ray crystallography; LUNGS; MONOCLONAL antibodies
- Publication
Cell Discovery, 2022, Vol 8, Issue 1, p1
- ISSN
2056-5968
- Publication type
Article
- DOI
10.1038/s41421-022-00497-w