The testing of new formulations for vaccines and adjuvants is important in order to increase the current very limited pools of approved adjuvants. Beta-glucan particles (GP) are a new type of experimental vaccine carriers that to a high degree target phagocytic antigen-presenting cells. The biodegradable particles can contain both antigen and adjuvants, and can be immunized at different injection sites. A number of adjuvants, including innate immunity activators of Toll-like receptor (TLR) and inflammasome signaling, carry significant inflammatory potential that can contribute to vaccine reactogenicity. Adjuvant activators of these pathways include monophosphoryl lipid A (MPLA, activating TLR4) and QS-21 containing saponins (activating the NLRP3 inflammasome). Reactogenicity by adjuvant can be reduced by the inclusion into particular vaccine formulations. We hypothesize that combinations of more than one adjuvant together with antigens into beta- glucan particle vaccines are safe and effective, induce strong antigen-specific responses to experimental plague vaccines, and that the vaccine responses are impacted by innate immune responses. These responses may be both to the specific adjuvant and to the beta-glucan in the particle itself. Yersinia pestis is a highly virulent pathogen causing plague, and licensed vaccines are lacking. We propose to perform mouse experiments using MPLA and QS-21 individually or in combinations in GP vaccines containing clinically relevant vaccine candidates - plague V/F1 antigens for antigen-specific responses, to investigate the specific innate immunity receptors that contribute to vaccine responses, and to test selected vaccine formulations in protection in mouse models of bubonic and pneumonic plague.
The project will seek to evaluate new vaccines that combine plague protein antigens together with adjuvants into particles consisting of specific yeast components. We will evaluate responses to the vaccines, and if successful, these particles may be further considered as part of future vaccines.
| Ratner, Dmitry; Orning, M Pontus A; Lien, Egil (2017) Bacterial secretion systems and regulation of inflammasome activation. J Leukoc Biol 101:165-181 |
| Marty-Roix, Robyn; Vladimer, Gregory I; Pouliot, Kimberly et al. (2016) Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants. J Biol Chem 291:1123-36 |
