Titration of T cell help into epitope-based self-assembling vaccines (VAC12P.1017)

Distinct ratios of T effector cells are necessary for effective protective immunity. T cell epitope content plays a critical role in determining T effector cell outcome, but its effects are nonlinear and difficult to predict when designing vaccines. Here, we developed a precise experimental approach to generate vaccines with optimized antibody and CD4+ T cell responses, using non-covalent self-assembly of peptides to titrate a high-affinity universal T cell epitope (PADRE) into a nanoparticulate vaccine. Co-assembly of a B cell epitope (B peptide) from methicillin-resistant Staphylococcus aureus with PADRE produced a modular vaccine that resembled a traditional protein conjugate, requiring cognate T-B interactions to raise an antibody response. Varying the PADRE concentration over nearly three orders of magnitude, from 5 μM to 1 mM, elicited bell-shaped dose-response curves for the anti-B peptide titers and PADRE-specific CD4+ cells, but these peaked at 10-fold different concentrations (0.05 and 0.005 mM, respectively). The antibody titer correlated with a peak in the T follicular helper response, while the total PADRE-specific T cell count reflected a peak in the Th1 and Th2 cells. Peak titers and affinities were similar to those obtained from an alum-adjuvanted B peptide-conjugate vaccine, indicating that titrating the T cell epitope provides a means to optimize the T effectors cells and generate strong responses in chemically precise vaccines.