Pattern Recognition Response Agonists as Malaria Vaccine Adjuvants

A critical obstacle to malaria vaccine development is the lack of appropriate adjuvants to elicit potent and protective immune responses that are long lasting. Recent studies on pattern recognition receptors (PRRs) of the innate immune response enable a rational approach to vaccine adjuvant selection. Specifically, systematic evaluations of PRR agonists that activate dendritic cells (DCs) through distinct intracellular signaling pathways may be fruitful: toll-like receptor (TLR) agonists signaling through the MyD88-dependent pathway (TLR7/8 agonist R848), TLR agonists signaling through the MyD88-independent/TRIF-dependent pathway (TLR3 agonist poly I:C), TLR agonists signaling through both MyD88-dependent and independent pathways (TLR4 agonist GLA, a synthetic lipid A), agonists of the intracellular nucleotide-binding oligomerization domain protein Nod1 (C12-iE-DAP) that signals through RIP2, and an agonist for the C-type lectin Mincle (synthetic trehalosedibehenate) that signals through a FcRgamma Src-family kinase.

Central hypothesis

Specific combinations of PRR agonists will be effective in inducing optimal dendritic cell activation for a potent immune response to a model blood-stage antigen, MSP1.42.

Objective

Identify new molecular adjuvants and molecular adjuvant cocktails that may be used selectively to obtain immune responses with specific characteristics required for protective immunity to malaria blood stages.

Specific Aim 1

Determine whether combinations of PRR agonists drive the differentiation of dendritic cells to express specific cell-surface activation receptors and cytokines associated with polarization to a Th1 response, a Th2 response, or a mixed Th1/Th2 response.

Specific Aim 2

Determine whether selected combinations of PRR agonists that induce Th1- and Th2-polarizing or mixed Th1/Th2 DC responses in vitro will be effective as adjuvant components in vivo. Mice will be immunized with selected PRR ligand combinations formulated with MSP1.42. The humoral immune response will be evaluated by ELISA. Th1 and Th2 cytokine responses will be evaluated in splenic T cells restimulated with the immunogen.

Significance

These studies will identify novel adjuvant formulations that elicit distinct immune response mechanisms to malaria blood-stage antigens and will provide insight into the role of DC activation in the in vivo response to malaria vaccines.

Experimental Approach for Specific Aim 1:

Specific Aim 1: