The randomization was performed using MATEX, a program developed for use in SAS (SAS Institute Inc., Cary, NC). support continuation of the medical development of this dengue vaccine candidate (clinicaltrials.gov: NCT01666652). Intro Dengue is definitely a mosquito-borne disease caused by any of the four types of serologically unique, yet antigenically related flaviviruses (dengue disease [DENV]-1, 2, 3, and 4). It is estimated that 390 million dengue infections happen every year, of which 96 million are clinically apparent.1,2 Several vaccine candidates are at numerous stages TLK117 of clinical development.3C5 Results from three efficacy trials of the Chimerivax (Dengvaxia?, Lyon, France; Sanofi Pasteur) live attenuated vaccine have been published6C8; and the vaccine has recently received marketing authorization in a number of dengue-endemic countries for use in individuals 9C45 years of age. The Walter Reed Army Institute of Study (WRAIR), GlaxoSmithKline (GSK) Vaccines, and Fiocruz are going after development of a tetravalent dengue purified inactivated PCDH8 vaccine (DPIV) candidate. This approach was urged from the security and effectiveness of related inactivated whole disease vaccines against additional flaviviruses, such as the Japanese encephalitis disease (JEV) vaccine Ixiaro? (Valneva Austria GmbH, Vienna, Austria) and the tick-borne encephalitis disease (TBEV) vaccines FSME-IMMUN?/TicoVac? (Pfizer Inc., Austria GmbH, Donau, Austria) and Encepur? (GSK Vaccines, Rixensart, Belgium).9 Evaluation of adjuvanted DPIV candidates in nonhuman primates recognized several DPIV formulations that were highly immunogenic, even at a relatively low antigen dose.10 Two doses of DPIV given 4 weeks apart protected nonhuman primates from viremia (as measured in Vero cell infectivity assays) following challenge with live, near wild-type DENV-1 and DENV-2 given 8 months and 10 months post-dose 2, respectively. However, antibody titers rose and viral RNA was detectable indicating that immunity in nonhuman primates was not sterile at 8 and 10 weeks postvaccination.10 The WRAIR conducted a proof TLK117 of concept phase 1 human trial in a small set of healthy, flavivirus-na?ve TLK117 volunteers with monovalent alum-adjuvanted DENV-1 DPIV (2.5 or 5 g). The security profile was suitable and the immunogenicity was low to moderate but supported moving forward with tetravalent DPIV preparations.11 We statement a first-time-in-human (FTiH) placebo-controlled clinical trial assessing the safety and immunogenicity of four different DPIV formulations at two antigen dose levels, adjuvanted with either aluminium hydroxide (alum) or GSK’s adjuvant systems AS01E or AS03B, administered intramuscularly on Day time 0 and Day time 28. The primary objectives of this study were 1) to evaluate the security and reactogenicity of four DPIV formulations from Day time 0 through Day time 28 after the second dose (D56), and 2) to evaluate the humoral immunogenicity to each DENV serotype 28 days after the second dose (D56). The secondary objectives were 1) to evaluate the security of the four DPIV formulations from Day time 0 through 12 months after the second dose (M13) and 2) to evaluate the humoral immunogenicity to each DENV serotype up to M13. In the booster phase, the primary objective was to evaluate the security, reactogenicity, and immunogenicity of a booster dose administered remote from the primary vaccination series. The security, reactogenicity, and humoral immunogenicity of the four DPIV formulations are reported up to 1 1 year after the second vaccine dose. A small subset of subjects received a booster dose adjuvanted with alum or AS01E in the second yr after vaccination, and the security and immunogenicity of the booster dose are included here. Materials and Methods Study design. This study was a phase 1, randomized (1:1:1:1:1), placebo-controlled, observer-blind main vaccination trial with five parallel organizations designed to evaluate the security and immunogenicity of four DPIV formulations, given as two doses 4 weeks apart (clinicaltrials.gov: NCT01666652). The study was conducted in the Clinical Tests Center (CTC) in the WRAIR, Metallic Spring, MD, in accordance with the Declaration of Helsinki, International Conference on Harmonization, Good Clinical Practice Belmont Principles, and other relevant regulatory and Division of Defense requirements. The protocol and associated paperwork were examined and authorized by the WRAIR Institutional Review Table, the Office of Study Protections, Human Research Safety Office, the U.S. Army Medical Materiel Development Activity (USAMMDA), and GSK Vaccines..
