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

• Published in: bioRxiv
• Main Authors: 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 Fe, 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, Zhou, Xing
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 19.07.2021
• Subjects: Animal models; Antigens; Coronaviruses; COVID-19; COVID-19 vaccines; Expression vectors; Immunization; Immunological memory; Innate immunity; Lymphocytes T; Memory cells; Mucosa; Mucosal immunity; Nucleocapsids; Severe acute respiratory syndrome coronavirus 2; Spike protein; Vaccines
• DOI: 10.1101/2021.07.16.452721

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. Competing Interest Statement The authors have declared no competing interest.