AUTHOR=Li Qi , Humphries Fiachra , Girardin Roxie C. , Wallace Aaron , Ejemel Monir , Amcheslavsky Alla , McMahon Conor T. , Schiller Zachary A. , Ma Zepei , Cruz John , Dupuis Alan P. , Payne Anne F. , Maryam Arooma , Yilmaz Nese Kurt , McDonough Kathleen A. , Pierce Brian G. , Schiffer Celia A. , Kruse Andrew C. , Klempner Mark S. , Cavacini Lisa A. , Fitzgerald Katherine A. , Wang Yang TITLE=Mucosal nanobody IgA as inhalable and affordable prophylactic and therapeutic treatment against SARS-CoV-2 and emerging variants JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.995412 DOI=10.3389/fimmu.2022.995412 ISSN=1664-3224 ABSTRACT=

Anti-COVID antibody therapeutics have been developed but not widely used due to their high cost and escape of neutralization from the emerging variants. Here, we describe the development of VHH-IgA1.1, a nanobody IgA fusion molecule as an inhalable, affordable and less invasive prophylactic and therapeutic treatment against SARS-CoV-2 Omicron variants. VHH-IgA1.1 recognizes a conserved epitope of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) and potently neutralizes major global SARS-CoV-2 variants of concern (VOC) including the Omicron variant and its sub lineages BA.1.1, BA.2 and BA.2.12.1. VHH-IgA1.1 is also much more potent against Omicron variants as compared to an IgG Fc fusion construct, demonstrating the importance of IgA mediated mucosal protection for Omicron infection. Intranasal administration of VHH-IgA1.1 prior to or after challenge conferred significant protection from severe respiratory disease in K18-ACE2 transgenic mice infected with SARS-CoV-2 VOC. More importantly, for cost-effective production, VHH-IgA1.1 produced in Pichia pastoris had comparable potency to mammalian produced antibodies. Our study demonstrates that intranasal administration of affordably produced VHH-IgA fusion protein provides effective mucosal immunity against infection of SARS-CoV-2 including emerging variants.