title: Combinatorial approach to hepadnavirus-like particle vaccine design.
abstract: The particulate hepatitis core protein (HBcAg) represents an efficient carrier platform with many of the characteristics uniquely required for the delivery of weak immunogens to the immune system. Although the HBcAg is highly immunogenic, the existing HBcAg-based platform technology has a number of theoretical and practical limitations, most notably the "preexisting immunity" and "assembly" problems. To address the assembly problem, we have developed the core protein from the woodchuck hepadnavirus (WHcAg) as a new particulate carrier platform system. WHcAg appears to tolerate insertions of foreign epitopes at a greater number of positions than HBcAg. For example, both within the external loop region and outside the loop region a total of 17 insertion sites were identified on WHcAg. Importantly, the identification of an expanded number of insertion sites was dependent on additional modifications to the C terminus that appear to stabilize the various internal insertions. Indeed, 21 separate C-terminal modifications have been generated that can be used in combination with the 17 insertion sites to ensure efficient hybrid WHcAg particle assembly. This combinatorial technology is also dependent on the sequence of the heterologous insert. Therefore, the three variables of insert position, C terminus, and epitope sequence are relevant in the design of hybrid WHcAg particles for vaccine purposes.
authors.affiliation: Vaccine Research Institute of San Diego, 3030 Bunker Hill Street, Suite 300, San Diego, CA 92109, USA.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Billaud
authors.forename: Darrell
authors.initials: D
authors.lastname: Peterson
authors.forename: Margaret
authors.initials: M
authors.lastname: Barr
authors.forename: Antony
authors.initials: A
authors.lastname: Chen
authors.forename: Matti
authors.initials: M
authors.lastname: Sallberg
authors.forename: Fermin
authors.initials: F
authors.lastname: Garduno
authors.forename: Phillip
authors.initials: P
authors.lastname: Goldstein
authors.forename: Wendy
authors.initials: W
authors.lastname: McDowell
authors.forename: Janice
authors.initials: J
authors.lastname: Hughes
authors.forename: Joyce
authors.initials: J
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Milich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D015195:Drug Design; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D017919:Hepatitis B Virus, Woodchuck / Q000737:chemistry*; D007114:Immunization; D051379:Mice; D008969:Molecular Sequence Data; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D000939:Epitopes; D014614:Vaccines, Synthetic; D014758:Viral Core Proteins