A Double-Blind Randomized Phase I Clinical Trial Targeting ALVAC-HIV Vaccine to Human Dendritic Cells

BACKGROUND: We conducted a novel pilot study comparing different delivery routes of ALVAC-HIV (vCP205), a canarypox vaccine containing HIV gene inserts: env, gag and pol. We explored the concept that direct ex vivo targeting of human dendritic cells (DC) would enhance the immune response compared to either conventional intramuscular or intradermal injections of the vaccine alone. METHODOLOGY/PRINCIPAL FINDINGS: Healthy HIV-1 uninfected volunteers were administered ALVAC-HIV or placebo by intramuscular injection (i.m.), intradermal injection (i.d.) or subcutaneous injection (s.q.) of autologous ex vivo transfected DC at months 0, 1, 3 and 6. All vaccine delivery routes were well tolerated. Binding antibodies were observed to both the ALVAC vector and HIV-1 gp160 proteins. Modest cellular responses were observed in 2/7 individuals in the DC arm and 1/8 in the i.m. arm as determined by IFN-γ ELISPOT. Proliferative responses were most frequent in the DC arm where 4/7 individuals had measurable responses to multiple HIV-1 antigens. Loading DC after maturation resulted in lower gene expression, but overall better responses to both HIV-1 and control antigens, and were associated with better IL-2, TNF-α and IFN-γ production. CONCLUSIONS/SIGNIFICANCE: ALVAC-HIV delivered i.m., i.d. or s.q. with autologous ex vivo transfected DC proved to be safe. The DC arm was most immunogenic. Proliferative immune responses were readily detected with only modest cytotoxic CD8 T cell responses. Loading mature DC with the live viral vaccine induced stronger immune responses than loading immature DC, despite increased transgene expression with the latter approach. Volunteers who received the autologous vaccine loaded mature DC developed a broader and durable immune response compared to those vaccinated by conventional routes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00013572

Integrated Ecosystem Assessment: Lake Ontario Water Management

BACKGROUND: Ecosystem management requires organizing, synthesizing, and projecting information at a large scale while simultaneously addressing public interests, dynamic ecological properties, and a continuum of physicochemical conditions. We compared the impacts of seven water level management plans for Lake Ontario on a set of environmental attributes of public relevance. METHODOLOGY AND FINDINGS: Our assessment method was developed with a set of established impact assessment tools (checklists, classifications, matrices, simulations, representative taxa, and performance relations) and the concept of archetypal geomorphic shoreline classes. We considered each environmental attribute and shoreline class in its typical and essential form and predicted how water level change would interact with defining properties. The analysis indicated that about half the shoreline of Lake Ontario is potentially sensitive to water level change with a small portion being highly sensitive. The current water management plan may be best for maintaining the environmental resources. In contrast, a natural water regime plan designed for greatest environmental benefits most often had adverse impacts, impacted most shoreline classes, and the largest portion of the lake coast. Plans that balanced multiple objectives and avoided hydrologic extremes were found to be similar relative to the environment, low on adverse impacts, and had many minor impacts across many shoreline classes. SIGNIFICANCE: The Lake Ontario ecosystem assessment provided information that can inform decisions about water management and the environment. No approach and set of methods will perfectly and unarguably accomplish integrated ecosystem assessment. For managing water levels in Lake Ontario, we found that there are no uniformly good and bad options for environmental conservation. The scientific challenge was selecting a set of tools and practices to present broad, relevant, unbiased, and accessible information to guide decision-making on a set of management options

Predicting In Vivo Efficacy of Potential Restenosis Therapies by Cell Culture Studies: Species-Dependent Susceptibility of Vascular Smooth Muscle Cells

Although drug-eluting stents (DES) are successfully utilized for restenosis therapy, the development of local and systemic therapeutic means including nanoparticles (NP) continues. Lack of correlation between in vitro and in vivo studies is one of the major drawbacks in developing new drug delivery systems. The present study was designed to examine the applicability of the arterial explant outgrowth model, and of smooth muscle cells (SMC) cultures for prescreening of possible drugs. Elucidation of different species sensitivity (rat, rabbit, porcine and human) to diverse drugs (tyrphostins, heparin and bisphsophonates) and a delivery system (nanoparticles) could provide a valuable screening tool for further in vivo studies. The anticipated sensitivity ranking from the explant outgrowth model and SMC mitotic rates (porcine>rat>>rabbit>human) do not correlate with the observed relative sensitivity of those animals to antiproliferative therapy in restenosis models (rat≥rabbit>porcine>human). Similarly, the inhibitory profile of the various antirestenotic drugs in SMC cultures (rabbit>porcine>rat>>human) do not correlate with animal studies, the rabbit- and porcine-derived SMC being highly sensitive. The validity of in vitro culture studies for the screening of controlled release delivery systems such as nanoparticles is limited. It is suggested that prescreening studies of possible drug candidates for restenosis therapy should include both SMC cell cultures of rat and human, appropriately designed with a suitable serum