Beyond antigens and adjuvants: formulating future vaccines.

The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines.

Positive Charge of "Sticky" Peptides and Proteins Impedes Release From Negatively Charged PLGA Matrices.

The influence of electrostatic interactions and/or acylation on release of charged ("sticky") agents from biodegradable polymer matrices was systematically characterized. We hypothesized that release of peptides with positive charge would be hindered from negatively charged poly(lactic-co-glycolic acid) (PLGA) microparticles. Thus, we investigated release of peptides with different degrees of positive charge from several PLGA microparticle formulations, with different molecular weights and/or end groups (acid- or ester-terminated). Indeed, release studies revealed distinct inverse correlations between the amount of positive charge on peptides and their release rates from each PLGA microparticle formulation. Furthermore, we examined the case of peptides with net charge that changes from negative to positive within the pH range observed in degrading microparticles. These charge changing peptides displayed counterintuitive release kinetics, initially releasing faster from slower degrading (less acidic) microparticles, and releasing slower from the faster degrading (more acidic) microparticles. Importantly, trends between agent charge and release rates for model peptides also translated to larger, therapeutically relevant proteins and oligonucleotides. The results of these studies may improve future design of controlled release systems for numerous therapeutic biomolecules exhibiting positive charge, ultimately reducing time-consuming and costly trial and error iterations of such formulations.