A First-in-human Clinical Study of an Intranasal Spray of a Cocktail Containing Two Synergetic Antibodies Neutralizes Omicron BA.4/5

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 IC90 of 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 Summary An intranasal spray of two synergetic antibodies cocktail neutralizing Omicron BA.4/5 and an initial clinical evaluation in healthy volunteers.### Competing Interest StatementAilong Huang and Aishun Jin declare the following competing interests: Patent has been filed for some of the antibodies presented here (patent application number: PCT/CN2020/115480, PCT/CN2021/078150, PCT/CN2021/113261; patent applicants: Chongqing Medical University). All other authors declare no competing interests.### Clinical TrialChiCTR2200066525### Funding StatementThis study was funded by the Natural Science Foundation of Hubei Province of China (2019CFA076) The National Natural Science Foundation of China (32170949, 81871639, 92169109, 81871656 and 8181101099); the National Science and Technology Major Project (2017ZX10202203) The National Key Research and Development Program of China (2018YFA0507100 and 2016YFD0500300); Guangzhou National Laboratory (SRPG22-015) Lingang Laboratory (LG202101-01-07); Science and Technology Commission of Shanghai Municipality YDZX20213100001556 and 20XD1422900). The first-in-human Investigator Initiated Study was funded by the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001)### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee of the Second Affiliated Hospital of Chongqing Medical University (Chongqing, China) gave ethical approval for this work (Study # AY-62-8001).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors