Delivery of vaccine genes and proteins into dendritic cells using the bacteriophage T4 DNA packaging machine (P3273)

Abstract

Abstract Traditionally, vaccines are produced by empirical methods and current platforms generally do not allow complex designs to modify the quality and quantity of immune responses. We have developed a bacteriophage T4 platform that allows construction and delivery of multivalent vaccines containing both DNA and protein. Using this system, the composition of vaccines can be customized to address mechanistic questions as well as develop efficacious vaccines. The phage T4 DNA packaging machine consists of a molecular motor assembled at the portal vertex of an icosahedral head. The ATP-powered motor packages the 56µm-long 170-kb viral genome into 120nm x 86nm head to near crystalline density. We engineered this machine to deliver genes and proteins into mammalian cells. DNA molecules were translocated into emptied phage head and its outer surface was decorated with proteins fused to outer capsid proteins, Hoc and Soc. T4 nanoparticles carrying reporter genes, vaccine candidates, functional enzymes, and targeting ligands were efficiently delivered into cells, or targeted to antigen-presenting dendritic cells, and the delivered genes were abundantly expressed in vitro and in vivo. Mice delivered with a single dose of F1-V plague vaccine containing both gene and protein elicited robust antibody and cellular immune responses. This “progene delivery” approach might lead to new types of genetic therapies and prime-boost vaccines against complex infectious diseases such as HIV and malaria.