ABSTRACT
Following Delta, Omicron variant triggered a new wave of SARS-CoV-2 infection globally, adaptive evolution of the virus may not stop, the development of broad-spectrum antivirals is still urgent. We previously developed two hetero-bivalent nanobodies with potent neutralization against original WT SARS-CoV-2, termed aRBD-2-5 and aRBD-2-7, by fusing aRBD-2 with aRBD-5 or aRBD-7, respectively. Here, we resolved crystal structures of these nanobodies in complex with RBD, and found the epitope of aRBD-2 differs from that of aRBD-5, aRBD-7. aRBD-2 binds to a conserved epitope which renders its binding activity to all variants of concern (VOCs) including Omicron. Interestingly, although monovalent aRBD-5 and aRBD-7 lost binding to some variants, they effectively improved the overall affinity when transformed into the hetero-bivalent form after being fused with aRBD-2. Consistent with the high binding affinities, aRBD-2-5-Fc and aRBD-2-7-Fc exhibited ultra-potent neutralization to all five VOCs; particularly, aRBD-2-5-Fc neutralized authentic virus of Beta, Delta and Omicron with the IC50of 5.98[~]9.65 ng/mL or 54.3[~]87.6 pM. Importantly, aRBD-2-5-Fc provided in vivo prophylactic protection for mice against WT and mouse-adapted SARS-CoV-2, and provided full protection against Omicron in hamster model when administrated either prophylactically or therapeutically. Taken together, we found a conserved epitope on RBD, and hetero-bivalent nanobodies had increased affinity for VOCs over its monovalent form, and provided potent and broad-spectrum protection both in vitro and in vivo against all tested major variants, and potentially future emerging variants. Our strategy provides a new solution in the development of therapeutic antibodies for COVID-19 caused by newly emergent VOCs.
ABSTRACT
@#patients with steady vital signs and affected by combined somnipathy at the early stage of stroke were divided into three groups according to the date of admission:the experimental group(Group E)and the control groups(Group C1 and Group C2).The rehabilitation programs to all patients are the same,except the somnipathy,(1) patients of Group E were adopted the method of acupuncture and moxibustion coupled with taping and pressing their ear acupuncture points to improve their quality of sleep,(2) patients of Group C1 were asked to administer orally the traquilizers,and (3) no interference was conducted to the patients of Group C2.After 8 weeks of treatment,it is found that,(1) the speed of recovery of the motor function of the patients of both Group E and Group C1 is faster than that of Group C2 (P<0.01).(2) The total sleeping hours of Group E is significantly compared with that of Group C1(P<0.05).This shows that the long-term effects of the acupuncture therapy on sleep are superior to that of the tranquilizer.It suggests that the acupuncture therapy is an improtant method to treat the sequelae and syndrome of stroke.