Idri Bk Srl

The advent of vaccines contributed to major improvements in human morbidity and mortality due to infectious diseases such as polio, small pox, measles and diphtheria. However infectious diseases like HIV, malaria and tuberculosis continue to be major causes of death worldwide and conventional vaccine strategies have not been successful. The fundamental problem is that current protein based vaccines do not elicit the necessary T-cell immunity. Experimentally, adjuvants can be given in conjunction with a vaccine to activate and mature the dendritic cell (DC), which can then direct an immune response to enhance T-cell immunity. One family of potential adjuvants functions through the activation of Toll-like receptors (TLR) on the DC. Major gaps exist in our understanding of adjuvant effects in humans. We hypothesize that a synthetic adjuvant directed to activate TLR4 (GLA) will safely stimulate the innate immune system when administered subcutaneously (SC) or intramuscularly (IM). Importantly, in contrast to other adjuvant trials in which adjuvant is combined with an antigen or vaccine, GLA will be tested in isolation. This is because we anticipate the future administration of GLA with our dendritic cell targeted HIV vaccine. A DC-targeted vaccine cannot be given without an immune stimulating adjuvant due to potential risk of inducing immune tolerance. Therefore, in order to understand the specific contributions of GLA versus the DC-targeted vaccine, we need to understand the GLA effects in isolation. The safety and tolerability of 2 different formulations of GLA (GLA-SE vs. GLA-AF) administered by 3 different routes (SC, ID, IM) will be the major focus of this trial. The second focus will be characterizing the innate immune response by assessing systemic cytokine and chemokine levels and determining global gene regulation following GLA stimulation. The third focus will be on the cellular effects of GLA, specifically on blood monocytes and dendritic cells. Monocytes may represent a large pool of inducible potent DC (monocyte-derived DC), however these cells have not been well characterized in humans. We will investigate the effects of GLA stimulation on the peripheral blood monocyte subsets that might give rise to monocyte-derived DC.