The development of a vaccine that protects against SARS-CoV-2, the coronavirus responsible for the current pandemic (COVID-19), is urgently needed. We have developed camelid-derived antibody fragments ? nanobodies ? that target surface proteins on mouse and human antigen presenting cells. These targets include class II MHC products and the integrin alpha M (CD11b). By attaching to these nanobodies various antigens in the form of proteins or peptides, we can elicit stronger B and T cell responses against the attached payloads when compared to the corresponding ?free? antigens. In particular, adducts composed of the anti-CD11b nanobody with peptides of viral origin induced a protective cytotoxic CD8 T cell response in a human papillomavirus model and inspire confidence that a similar outcome may be accomplished for SARS-CoV-2. We propose to apply these strategies to generate strong adaptive immune responses against SARS-CoV-2 antigens. The anti-mouse and anti-human class II MHC-specific nanobodies recognize all allotypes and will be used to target antigens to mouse and human class II MHC products in normal and HLA-DR4 transgenic mice. CD4 T cell and antibody responses will be analyzed in these studies. Adducts composed of the CD11b nanobody and COVID-19 antigenic peptides will be used to elicit CD8 T cell responses in normal and HLA-A2 transgenic mice. For the most immunogenic SARS-CoV-2 antigens, we shall identify the minimal peptides recognized for possible inclusion in future vaccine preparations.
We propose to enhance immunogenicity to SARS-CoV-2 (the virus that causes COVID-19) through direct targeting to antigen presenting cells via specific antibody fragments (nanobodies). This will elicit CD4, CD8, and B cell responses against SARS-CoV-2 structural elements using purely protein-based, non-replicating vaccine preparations. Our strategy complements passive immunization efforts and vaccination strategies that rely on vector-based or non-targeted approaches.
