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.