Preclinical and clinical development of a dengue recombinant subunit vaccine. Issue 50 (10th December 2015)

• Record Type: Journal Article
• Authors: Manoff, Susan B.; George, Sarah L.; Bett, Andrew J.; Yelmene, Michele L.; Dhanasekaran, Govindarajan; Eggemeyer, Linda; Sausser, Michele L.; Dubey, Sheri A.; Casimiro, Danilo R.; Clements, David E.; Martyak, Timothy; Pai, Vidya; Parks, D. Elliot; Coller, Beth-Ann G.
• Is Part Of: Vaccine. Volume 33:Issue 50(2015)
• Page Start: 7126
• Page End: 7134
• Publication Date: 2015-12-10
• Subjects: Dengue vaccine -- Recombinant -- Subunit; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2015.09.101
• Languages: English
• ISSNs: 0264-410X

Abstract

Highlights: DEN-80E formulated with ISCOMATRIX™ adjuvant is immunogenic in non-human primates. A 0, 1, 6 month schedule results in higher antibody titers compared to 0, 1, 2 months. The monovalent DEN1-80E vaccine was safe and immunogenic in human subjects. 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.