Preclinical and clinical development of a dengue recombinant subunit vaccine

• Published in: Vaccine Vol. 33; no. 50; pp. 7126 - 7134
• Main 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.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 10.12.2015; Elsevier Limited
• Subjects: adjuvants; Adjuvants, Immunologic - administration & dosage; adults; Allergy and Immunology; Aluminum; Aluminum Hydroxide - administration & dosage; Animals; Antibodies, Neutralizing - blood; Antibodies, Viral - blood; Antigens; Cholesterol - administration & dosage; Clinical trials; Clinical Trials, Phase I as Topic; dengue; Dengue - epidemiology; Dengue - prevention & control; Dengue fever; Dengue vaccine; Dengue Vaccines - administration & dosage; Dengue Vaccines - genetics; Dengue Vaccines - immunology; Dengue Vaccines - isolation & purification; Dengue virus; Deoxyribonucleic acid; Disease; DNA; Drosophila; Drug Combinations; Drug Evaluation, Preclinical; durability; Flaviviridae; glycoproteins; Hawaii; Humans; Immunization Schedule; Infections; interferon-gamma; Interferon-gamma - secretion; Macaca; Monkeys & apes; Mortality; neutralization; neutralizing antibodies; Phospholipids - administration & dosage; Proteins; Recombinant; Saponins - administration & dosage; Studies; Subunit; subunit vaccines; T-lymphocytes; T-Lymphocytes - immunology; Vaccines; Vaccines, Subunit - administration & dosage; Vaccines, Subunit - genetics; Vaccines, Subunit - immunology; Vaccines, Subunit - isolation & purification; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Vaccines, Synthetic - isolation & purification; Vector-borne diseases; viral load; Viruses; ISE, USA, Hawaii; Hawaii; Subunit; Dengue vaccine; Recombinant
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2015.09.101

•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. 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 10μg and 50μg formulations of DEN1-80E with 1.25mg 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 10μg DEN1-80E and the 50μg DEN1-80E formulations with Alhydrogel™ were generally well tolerated.