title: Development of a recombinant tetravalent dengue virus vaccine: immunogenicity and efficacy studies in mice and monkeys.
abstract: Truncated recombinant dengue virus envelope protein subunits (80E) are efficiently expressed using the Drosophila Schneider-2 (S2) cell expression system. Binding of conformationally sensitive antibodies as well as X-ray crystal structural studies indicate that the recombinant 80E subunits are properly folded native-like proteins. Combining the 80E subunits from each of the four dengue serotypes with ISCOMATRIX adjuvant, an adjuvant selected from a set of adjuvants tested for maximal and long lasting immune responses, results in high titer virus neutralizing antibody responses. Immunization of mice with a mixture of all four 80E subunits and ISCOMATRIX adjuvant resulted in potent virus neutralizing antibody responses to each of the four serotypes. The responses to the components of the tetravalent mixture were equivalent to the responses to each of the subunits administered individually. In an effort to evaluate the potential protective efficacy of the Drosophila expressed 80E, the dengue serotype 2 (DEN2-80E) subunit was tested in both the mouse and monkey challenge models. In both models protection against viral challenge was achieved with low doses of antigen in the vaccine formulation. In non-human primates, low doses of the tetravalent formulation induced good virus neutralizing antibody titers to all four serotypes and protection against challenge with the two dengue virus serotypes tested. In contrast to previous reports, where subunit vaccine candidates have generally failed to induce potent, protective responses, native-like soluble 80E proteins expressed in the Drosophila S2 cells and administered with appropriate adjuvants are highly immunogenic and capable of eliciting protective responses in both mice and monkeys. These results support the development of a dengue virus tetravalent vaccine based on the four 80E subunits produced in the Drosophila S2 cell expression system.
authors.affiliation: Hawaii Biotech, Inc., 99-193 Aiea Heights Drive, Aiea, HI 96701, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Clements
authors.forename: Beth-Ann G
authors.initials: BA
authors.lastname: Coller
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lieberman
authors.forename: Steven
authors.initials: S
authors.lastname: Ogata
authors.forename: Gordon
authors.initials: G
authors.lastname: Wang
authors.forename: Kent E
authors.initials: KE
authors.lastname: Harada
authors.forename: J Robert
authors.initials: JR
authors.lastname: Putnak
authors.forename: John M
authors.initials: JM
authors.lastname: Ivy
authors.forename: Michael
authors.initials: M
authors.lastname: McDonell
authors.forename: Gary S
authors.initials: GS
authors.lastname: Bignami
authors.forename: Iain D
authors.initials: ID
authors.lastname: Peters
authors.forename: Julia
authors.initials: J
authors.lastname: Leung
authors.forename: Carolyn
authors.initials: C
authors.lastname: Weeks-Levy
authors.forename: Eileen T
authors.initials: ET
authors.lastname: Nakano
authors.forename: Tom
authors.initials: T
authors.lastname: Humphreys
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D002460:Cell Line; D002784:Cholesterol / Q000008:administration & dosage; D018360:Crystallography, X-Ray; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004330:Drosophila; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010743:Phospholipids / Q000008:administration & dosage; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012503:Saponins / Q000008:administration & dosage; D022223:Vaccines, Subunit / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D004338:Drug Combinations; C493786:ISCOMATRIX; D010743:Phospholipids; D012503:Saponins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins; D002784:Cholesterol