The use of self-adjuvanting nanofiber vaccines to elicit high-affinity B cell responses to peptide antigens without inflammation

Abstract

Balancing immunogenicity with inflammation is a central tenet of vaccine design, especially for subunit vaccines that utilize traditional pro-inflammatory adjuvants. Here we report that by using a nanoparticulate peptide-based vaccine, immunogenicity and local inflammation could be decoupled. Self-assembled β-sheet-rich peptide nanofibers, previously shown to elicit potent antibody responses in mice, were found to be non-cytotoxic in vitro and, remarkably, elicited no measurable inflammation in vivo—with none of the swelling at the injection site, accumulation of inflammatory cells or cytokines, or production of allergic IgE that were elicited by an alum-adjuvanted vaccine. Nanofibers were internalized by dendritic cells and macrophages at the injection site, and only dendritic cells that acquired the material increased their expression of the activation markers CD80 and CD86. Immunization with epitope-bearing nanofibers elicited antigen-specific differentiation of T cells into T follicular helper cells and B cells into germinal center cells, as well as high-titer, high-affinity IgG that cross-reacted with the native protein antigen and was neutralizing in an in vitro influenza hemagglutination inhibition assay. These responses were superior to those induced by alum and comparable to those induced by complete Freund’s adjuvant. Thus, nanoparticulate assemblies may provide a new route to non-inflammatory immunotherapies and vaccines.

Peptide Amphiphile Micelles Self-Adjuvant Group A Streptococcal Vaccination

“…3 and 4). While some adjuvants like IFA can induce antibody responses for co-delivered antigens, peptide amphiphile micelles must directly deliver the peptide antigen in order to function as an adjuvant which is similar to other self-assembled peptide vaccines (60,61). With regard to PRR stimulation, while diC 16 has a chemical structure quite similar to Pam 3 Cys, it was found unable to stimulate TLR-2, the cognate receptor for Pam 3 Cys (Fig.…”

Toll-like receptor 3-induced immune response by poly(D,L-lactide-co-glycolide) nanoparticles for dendritic cell-based cancer immunotherapy

“…In addition, single-adjuvant delivery may require higher doses for effective intracellular delivery to DCs. These systems include microparticles, 31 nanofibers, 32 metal-based particles, 33 and emulsions. 34 Although many types of compounds have potential utility as delivery agents, some are associated with concerns regarding their safety and evoked immune responses.…”

Enhanced immunostimulatory effects of DNA-encapsulated peptide hydrogels

“…For example, peptide nanofibers condensed with DNA for HIV immunotherapy achieved four week titer levels in mice that were on the order of 10 4 [37]. Although not utilized to deliver DNA, the Collier lab have designed clever self-assembling fibrillar systems capable of presenting ovalbumin [38,39] and malaria-associated [40] antigens that generate similar titer values over the same time period. Taken together, the data indicates that the DNA-loaded HLT2 gel stimulates a humoral response mediated by CD4þ/IFN g þ expressing Th1 cells.…”