Neutralizing monoclonal antibodies (NAbs) with prophylactic and therapeutic efficacy have demonstrated fundamental importance in the control of SARS-CoV-2 transmission. However, their wide application has been largely limited by high cost and inconvenience in administration. Here, we developed an intranasal spray containing two synergetic human NAbs that could broadly neutralize the emerging Omicron variants in vitro. A unique synergetic neutralizing mechanism was identified that the two NAbs bound to exclusive epitopes on the RBD and structurally compensate each other in blocking the Spike-ACE2 interaction. Importantly, when given at low dosages for three consecutive days through the intranasal mucosal route, this cocktail showed significant improvement in the emergency preventive and therapeutic effects in hamsters challenged with authentic Omicron BA.1. Further, we performed an investigator-initiated trail in healthy volunteers (ChiCTR2200066525) to study the safety and pharmacokinetics of the antibody cocktail administrated as nasal spray. The nasal spray is generally safe and well tolerated without treatment related severe abnormal effects. The antibody cocktail nasal spray demonstrated nasal concentrations higher than the IC90of neutralization activity against Omicron BA.4/5 even at 24 hours post dosing. Furthermore, nasal samples from the study subjects demonstrated potent neutralization activity against Omicron BA.4/5 in an ex vivo pseudovirus neutralization assay. Together, we provide a novel approach for NAb regimens, a potentially highly effective product with broad applicable perspective in depressing the infection risk of new epidemic variant and ameliorating the heavy medical burden of hospital.One Sentence SummaryAn intranasal spray of two synergetic antibodies cocktail neutralizing Omicron BA.4/5 and an initial clinical evaluation in healthy volunteers.
