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Review
. 2015 Dec 10;33(50):7126-34.
doi: 10.1016/j.vaccine.2015.09.101. Epub 2015 Oct 14.

Preclinical and clinical development of a dengue recombinant subunit vaccine

Susan B Manoff  1 , Sarah L George  2 , Andrew J Bett  1 , Michele L Yelmene  3 , Govindarajan Dhanasekaran  1 , Linda Eggemeyer  2 , Michele L Sausser  1 , Sheri A Dubey  1 , Danilo R Casimiro  1 , David E Clements  3 , Timothy Martyak  3 , Vidya Pai  3 , D Elliot Parks  3 , Beth-Ann G Coller  4
Affiliations
Review

Preclinical and clinical development of a dengue recombinant subunit vaccine

Susan B Manoff et al. 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.

Keywords: Dengue vaccine; Recombinant; Subunit.

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