Preclinical and clinical development of a dengue recombinant subunit vaccine.

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.

Safety and Immunogenicity of a Live Attenuated Tetravalent Dengue Vaccine Candidate in Flavivirus-Naive Adults: A Randomized, Double-Blinded Phase 1 Clinical Trial.

BACKGROUND: Dengue viruses (DENVs) infect >300 million people annually, causing 96 million cases of dengue disease and 22 000 deaths [1]. A safe vaccine that protects against DENV disease is a global health priority [2]. METHODS: We enrolled 72 flavivirus-naive healthy adults in a phase 1 double-blinded, randomized, placebo-controlled dose-escalation trial (low and high dose) of a live attenuated recombinant tetravalent dengue vaccine candidate (TDV) given in 2 doses 90 days apart. Volunteers were followed for safety, vaccine component viremia, and development of neutralizing antibodies to the 4 DENV serotypes. RESULTS: The majority of adverse events were mild, with no vaccine-related serious adverse events. Vaccinees reported injection site pain (52% vs 17%) and erythema (73% vs 25%) more frequently than placebo recipients. Low levels of TDV-serotype 2 (TDV-2), TDV-3, and TDV-4 viremia were observed after the first but not second administration of vaccine. Overall seroconversion rates and geometric mean neutralization titers after 2 doses were 84.2% and 54.1, respectively, for DENV serotype 1 (DENV-1); 92.1% and 292.8, respectively, for DENV-2; 86.8% and 32.3, respectively, for DENV-3; and 71.1% and 15.0, respectively, for DENV-4. More than 90.0% of high-dose recipients had trivalent or broader responses. CONCLUSIONS: TDV was generally well tolerated, induced trivalent or broader neutralizing antibodies to DENV in most flavivirus-naive vaccinees, and is undergoing further development. CLINICAL TRIALS REGISTRATION: NCT01110551.

A controlled, randomized, comparative study of a radiant heat bandage on the healing of stage 3-4 pressure ulcers: a pilot study.

OBJECTIVES: Pressure ulcers, like other chronic wounds, fail to proceed through an orderly and timely process to produce anatomical or functional integrity. Treatment of pressure ulcers is directed to improving host factors and providing an optimum wound environment. In addition to providing a moist wound environment, it has been theorized that preventing hypothermia in a wound and maintaining a normothermic state might improve wound healing. DESIGN/SETTING: Forty-one subjects with a stage 3 or stage 4 truncal pressure ulcer >1.0 cm(2) were recruited from outpatient clinics, long-term care nursing homes, and a rehabilitation center. The experimental group was randomized to a radiant-heat dressing device and the control group was randomized to a hydrocolloid dressing, with or without a calcium alginate filler. Subjects were followed until healed or for 12 weeks. RESULTS: Eight subjects (57%) in the experimental group had complete healing of their pressure ulcer compared with 7 subjects (44%) with complete healing in the control group (P = .46). CONCLUSION: Although a 13% difference in healing rate between the two arms of the study was found, this difference was not statistically significant. At almost all points along the healing curve, the proportion not healed was higher in the control arm.