Abstract
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge and spread around the world, antibodies and vaccines to confer broad and potent neutralizing activity are urgently needed. Through the isolation and characterization of monoclonal antibodies (mAbs) from individuals infected with SARS-CoV-2, we identified one antibody, P36-5D2, capable of neutralizing the major SARS-CoV-2 variants of concern. Crystal and electron cryo-microscopy (cryo-EM) structure analyses revealed that P36-5D2 targeted to a conserved epitope on the receptor-binding domain of the spike protein, withstanding the three key mutations—K417N, E484K, and N501Y—found in the variants that are responsible for escape from many potent neutralizing mAbs, including some already approved for emergency use authorization (EUA). A single intraperitoneal (IP) injection of P36-5D2 as a prophylactic treatment completely protected animals from challenge of infectious SARS-CoV-2 Alpha and Beta. Treated animals manifested normal body weight and were devoid of infection-associated death up to 14 days. A substantial decrease of the infectious virus in the lungs and brain, as well as reduced lung pathology, was found in these animals compared to the controls. Thus, P36-5D2 represents a new and desirable human antibody against the current and emerging SARS-CoV-2 variants.
Highlights
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to rage around the world, multiple variants have emerged and spread rapidly
At a resolution of 3.1 Å, we found that P36-5D2 recognized an epitope consisting of 11 residues (T345, R346, L441, K444, V445, G446, G447, Y449, N450, T470, and F490) on receptor-binding domain (RBD), devoid of the three key mutant residues K417N, E484K, and N501Y that facilitated escape from the neutralization of many monoclonal antibodies (mAbs), including some approved for emergency use authorization (EUA) (Figure 2A)
We report here the structural and functional characterization of the human neutralizing antibody P36-5D2 isolated from SARS-CoV-2 convalescent individuals
Summary
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to rage around the world, multiple variants have emerged and spread rapidly. Four major variants of concern (VOCs) have been designated: Alpha (B.1.1.7), initially identified in the UK; Beta (B.1.351) in South Africa; Gamma (P.1) in Brazil; and Delta (B.1.617.2) in India [1,2,3,4,5,6,7] These VOCs are rapidly displacing local SARS-CoV2 variants but are carrying mutations in the N-terminal domain (NTD) and receptor-binding domain (RBD) on the spike protein that are critical for interactions with the ACE2 receptor and neutralizing antibodies [8,9,10,11,12,13,14,15,16,17,18,19,20,21]. The chimpanzee adenovirus-based vaccine, ChAdOx1 nCoV-19, given to individuals as a two-dose regimen failed to protect against mild to moderate coronavirus disease 2019 (COVID-19) caused by the Beta variant [25]
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