Poster Presentation & Lightning Talk Asia-Pacific Vaccine and Immunotherapy Congress 2024

Targeting Clec9A on type-I conventional dendritic cells to induce broad and durable systemic and mucosal immune responses against sarbecoviruses. (#144)

Nicholas YZ Cheang 1 2 , Peck Szee Tan 3 , Kiren Purushotorma 2 4 , Wee Chee Yap 5 , Kirsteen McInnes Tullett 3 , Aileen Ying-Yan Yeoh 5 , Xinlei Qian 2 4 , Yee Joo Tan 1 , Paul A Macary 2 4 , Chee Wah Tan 5 , Mireille H Lahoud 3 , Sylvie Alonso 1 2
  1. Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, National University of Singapore, Singapore
  2. Life Sciences Institute, Immunology Programme, National University of Singapore, Singapore
  3. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Australia
  4. Department of Microbiology and Immunology, Immunology Translational Research Programme, National University of Singapore, Singapore
  5. Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore

COVID-19 mRNA vaccines face limitations in their immune response generated, which include waning immunity, poor induction of mucosal immunity, and limited breadth across the different sarbecovirus clades. We have been developing a dendritic cell (DC) targeting vaccine delivery platform that consists of an anti-Clec9A monoclonal antibody and the vaccine antigen candidate fused at the heavy chains. Here, we engineered two Clec9A-RBD constructs harboring SARS-CoV-2 or SARS-CoV-1 spike receptor binding domain (RBD), and we evaluated their immunogenicity when administered either systemically or mucosally to mRNA (Pfizer BioNTech)-vaccinated mice. Boosting with either Clec9A-RBD-CoV2 or Clec9A-RBD-CoV1 induced strong systemic neutralizing antibody responses against pre-Omicron and Omicron SARS-CoV-2, and clade 1b animal sarbecoviruses that were non-inferior to boosting with Pfizer BioNTech Omicron BA.4/5 bivalent mRNA vaccine. Furthermore, boosting with Clec9A-RBD-CoV1 induced cross-clade neutralizing antibodies against SARS-CoV-1 and clade 1a sarbecoviruses. Uniquely, mucosal delivery of the Clec9A-RBD constructs resulted in RBD-specific IgA and the abovementioned neutralizing antibody responses within lung tissues, which were undetectable in mRNA-boosted mice. While waning occurred following mRNA boosting, the systemic and mucosal antibody responses remained highly persistent in Clec9A-RBD-CoV2 boosted mice. On the contrary, the antibody responses induced upon Clec9A-RBD-CoV1 boosting waned significantly over time. These observations correlated well with the magnitude of T cell recall responses. To overcome the limited T cell activation observed with Clec9A-RBD-CoV1, both constructs were combined into a single bivalent formulation, which demonstrated potent, sustained, and cross-clade systemic and mucosal neutralizing antibody and T cell responses. Taken together, Clec9A-RBD immunization has the potential to trigger robust, broad, and sustained systemic and mucosal immune responses against sarbecoviruses through the targeting of cDC1 residing in systemic and mucosal tissues. This work supports Clec9A-RBD as a promising booster shot to enhance the breadth, durability, and mucosal immunity of COVID-19 mRNA vaccines.