Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

Afkhami, Sam; D’Agostino, Michael R.; Zhang, Ali; Stacey, Hannah D.; Marzok, Art; Kang, Alisha; Singh, Ramandeep; Bavananthasivam, Jegarubee; Ye, Gluke; Luo, Xiangqian; Wang, Fuan; Ang, Jann C.; Zganiacz, Anna; Sankar, Uma; Kazhdan, Natallia; Koenig, Joshua F. E.; Phelps, Allyssa; Jordana, Manel; Wan, Yonghong; Mossman, Karen L.; Jeyanathan, Mangalakumari; Gillgrass, Amy; Medina, Maria Fe C.; Smaill, Fiona; Lichty, Brian D.; Miller, Matthew S.; Xing, Zhou

The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.