Research Article: Safety and Immunogenicity of a Tetravalent Dengue DNA Vaccine Administered with a Cationic Lipid-Based Adjuvant in a Phase 1 Clinical Trial

Date Published: March 22, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

Author(s): Janine R. Danko, Tadeusz Kochel, Nimfa Teneza-Mora, Thomas C. Luke, Kanakatte Raviprakash, Peifang Sun, Monika Simmons, James E. Moon, Rafael De La Barrera, Luis Javier Martinez, Stephen J. Thomas, Richard T. Kenney, Larry Smith, Kevin R. Porter.


We conducted an open label, dose escalation Phase 1 clinical trial of a tetravalent dengue DNA vaccine (TVDV) formulated in Vaxfectin® to assess safety and immunogenicity. A total of 40 dengue- and flavivirus-naive volunteers received either low-dose (1 mg) TVDV alone (N = 10, group 1), low-dose TVDV (1 mg) formulated in Vaxfectin (N = 10, group 2), or high-dose TVDV (2 mg, group 3) formulated in Vaxfectin® (N = 20). Subjects were immunized intramuscularly with three doses on a 0-, 30-, 90-day schedule and monitored. Blood samples were obtained after each immunization and various time points thereafter to assess anti-dengue antibody and interferon gamma (IFNγ) T-cell immune responses. The most common adverse events (AEs) across all groups included mild to moderate pain and tenderness at the injection site, which typically resolved within 7 days. Common solicited signs and symptoms included fatigue (42.5%), headache (45%), and myalgias (47.5%). There were no serious AEs related to the vaccine or study procedures. No anti-dengue antibody responses were detected in group 1 subjects who received all three immunizations. There were minimal enzyme-linked immunosorbent assay and neutralizing antibody responses among groups 2 and 3 subjects who completed the immunization schedule. By contrast, IFNγ T-cell responses, regardless of serotype specificity, occurred in 70%, 50%, and 79% of subjects in groups 1, 2, and 3, respectively. The largest IFNγ T-cell responses were among group 3 subjects. We conclude that TVDV was safe and well-tolerated and elicited predominately anti-dengue T-cell IFNγ responses in a dose-related fashion.

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Recent publications suggest that the global impact of dengue infections is greater than that previously published by the World Health Organization. An estimated 96 million apparent infections and an additional 294 million inapparent infections occur worldwide annually.1 There are four serologically distinct dengue RNA viruses designated DENV-1, DENV-2, DENV-3, and DENV-4. Complications from acute infection can lead to hospitalization, debilitation, and death. An effective dengue vaccine is a high priority for countries where the disease is endemic, and for travelers and military populations that frequently travel to endemic regions. We have pursued the nucleic acid immunization approach to develop a candidate tetravalent dengue vaccine. Toward this goal, a prototype monovalent dengue-1 DNA vaccine construct (D1ME) containing the premembrane (prM) and envelope (E) genes of dengue-1 WestPac was evaluated in a Phase 1 clinical trial and determined to be safe but poorly immunogenic and did not produce a robust neutralizing antibody response.2 T-cell interferon gamma (IFNγ) responses, however, were much more pronounced.

The aim of dengue vaccine development programs is to produce a candidate vaccine that elicits solid long-lasting protective immune responses against all four dengue serotypes to reduce the incidence of symptomatic infection. Although anti-dengue neutralizing antibodies are capable of protecting against dengue infection, there is growing consensus that the optimal tetravalent dengue vaccine should generate long-lasting neutralizing antibodies as well as T-cell responses against all four dengue serotypes. Because dengue live–attenuated vaccines induce these types of immune responses, theoretically they should provide the best protection. However, immune interference resulting from the tetravalent components giving rise to an imbalanced immune response remains a concern. Several dengue vaccine approaches have been tested in human clinical trials and there are numerous candidates in preclinical development.11




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