title: Preclinical and clinical development of a dengue recombinant subunit vaccine.
abstract: This review focuses on a dengue virus (DENV) vaccine candidate based on a recombinant subunit approach which targets the DENV envelope glycoprotein (E). Truncated versions of E consisting of the N-terminal portion of E (DEN-80E) have been expressed recombinantly in the Drosophila S2 expression system and shown to have native-like conformation. Preclinical studies demonstrate that formulations containing tetravalent DEN-80E adjuvanted with ISCOMATRIX™ adjuvant induce high titer virus neutralizing antibodies and IFN-γ producing T cells in flavivirus-naïve non-human primates. The preclinical data further suggest that administration of such formulations on a 0, 1, 6 month schedule may result in higher maximum virus neutralizing antibody titers and better durability of those titers compared to administration on a 0, 1, 2 month schedule. In addition, the virus neutralizing antibody titers induced by adjuvanted tetravalent DEN-80E compare favorably to the titers induced by a tetravalent live virus comparator. Furthermore, DEN-80E was demonstrated to be able to boost virus neutralizing antibody titers in macaques that have had a prior DENV exposure. A monovalent version of the vaccine candidate, DEN1-80E, was formulated with Alhydrogel™ and studied in a proof-of-principle Phase I clinical trial by Hawaii Biotech, Inc. (NCT00936429). The clinical trial results demonstrate that both the 10 μg and 50 μg formulations of DEN1-80E with 1.25 mg of elemental aluminum were immunogenic when administered in a 3-injection series (0, 1, 2 months) to healthy, flavivirus-naïve adults. The vaccine formulations induced DENV-1 neutralizing antibodies in the majority of subjects, although the titers in most subjects were modest and waned over time. Both the 10 μg DEN1-80E and the 50 μg DEN1-80E formulations with Alhydrogel™ were generally well tolerated.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Manoff
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States; St. Louis Veterans Administration Medical Center, Saint Louis, MO, United States.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: George
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bett
authors.affiliation: Hawaii Biotech Inc., Aiea, HI, United States.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Yelmene
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Dhanasekaran
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States; St. Louis Veterans Administration Medical Center, Saint Louis, MO, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Eggemeyer
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Sausser
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Sheri A
authors.initials: SA
authors.lastname: Dubey
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.affiliation: Hawaii Biotech Inc., Aiea, HI, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Clements
authors.affiliation: Hawaii Biotech Inc., Aiea, HI, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Martyak
authors.affiliation: Hawaii Biotech Inc., Aiea, HI, United States.
authors.forename: Vidya
authors.initials: V
authors.lastname: Pai
authors.affiliation: Hawaii Biotech Inc., Aiea, HI, United States.
authors.forename: D Elliot
authors.initials: DE
authors.lastname: Parks
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States. Electronic address: beth-ann.coller@merck.com.
authors.forename: Beth-Ann G
authors.initials: BA
authors.lastname: Coller
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000536:Aluminum Hydroxide / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D002784:Cholesterol / Q000008:administration & dosage; D017321:Clinical Trials, Phase I as Topic; D003715:Dengue / Q000453:epidemiology / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007115:Immunization Schedule; D007371:Interferon-gamma / Q000378:metabolism; D008251:Macaca; D010743:Phospholipids / Q000008:administration & dosage; D012503:Saponins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification
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; D000536:Aluminum Hydroxide; D007371:Interferon-gamma; D002784:Cholesterol
keywords: Dengue vaccine; Recombinant; Subunit