A self-assembling peptide acting as an immune adjuvant

Abstract

The development of vaccines and other immunotherapies has been complicated by heterogeneous antigen display and the use of incompletely defined immune adjuvants with complex mechanisms of action. We have observed strong antibody responses in mice without the coadministration of any additional adjuvant by noncovalently assembling a Tand B cell epitope peptide into nanofibers using a short C-terminal peptide extension. Self-assembling peptides have been explored recently as scaffolds for tissue engineering and regenerative medicine, but our results indicate that these materials may also be useful as chemically defined adjuvants. In physiological conditions, these peptides self-assembled into long, unbranched fibrils that displayed the epitope on their surfaces. IgG1, IgG2a, and IgG3 were raised against epitope-bearing fibrils in levels similar to the epitope peptide delivered in complete Freund's adjuvant (CFA), and IgM production was even greater for the self-assembled epitope. This response was dependent on self-assembly, and the self-assembling sequence was not immunogenic by itself, even when delivered in CFA. Undetectable levels of interferon-gamma, IL-2, and IL-4 in cultures of peptide-challenged splenocytes from immunized mice suggested that the antibody responses did not involve significant T cell help.The development of vaccines and other immunotherapies has been challenged by imprecise antigen display and the use of heterogeneous immune adjuvants whose mechanisms of action are complex and incompletely understood. Synthetic peptides are useful as antigens because their precise chemical definition allows one to specify the exact epitopes against which an immune response is to be raised. However, peptides are poorly immunogenic by themselves and require coadministration with strong adjuvants. Although many adjuvants have been investigated for peptide immunotherapies to date, current strategies such as particulates (1, 2), oil emulsions (3), toll-like receptor (TLR) ligands (4), immunostimulating complexes (ISCOMs) (5), and other biologically sourced materials (6, 7) utilize chemically or structurally heterogeneous materials, making their characterization, mechanistic understanding, and regulatory approval challenging (1,8,9). This situation has motivated the pursuit of self-adjuvanting or adjuvant-free systems (10-12).A broad goal in the field of biomaterials is to produce synthetic scaffolds capable of presenting multiple cell-interactive components in spatially resolved networks (13,14). To accomplish this, supramolecular self-assembly is rapidly becoming a synthetic method of choice (15-17). One strategy that has received attention recently is based on fibrillized peptides, peptidomimetics, and peptide derivatives, which are being explored for a variety of biomedical and biotechnological applications, most notably as scaffolds for regenerative medicine (18,19) and defined matrices for cell culture (20,21). In these applications, selfassembled materials provide several advantages, including multifunctiona...

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.…”

Beyond antigens and adjuvants: formulating future vaccines

“…The licensed human papilloma virus vaccines, hepatitis B vaccine, and the most-studied malaria vaccine candidate, RTS,S, are all examples of vaccines based on the use of self-assembled VLPs that exploit these principles (88). Recently, it has been demonstrated that multivalent antigens formed by supramolecular assembly of peptides from ovalbumin or model protein antigens into nanoscale-diameter fibers (presenting thousands of copies of antigen per fiber) elicit robust humoral immune responses in mice (89,90). Interestingly, nanofibers carrying a malaria antigen elicited robust T-dependent antibody responses in a manner dependent on MyD88 signaling but independent of the NALP3 inflammasome (91).…”

Nanoparticles and direct immunosuppression

“…As described by Tirrell et al, a majority of peptide amphiphile delivery systems are developed to induce immunostimulatory effects in the innate and adaptive immune system. [113][114][115] Although these reports describe the capability of peptide amphiphile micelles to cause immunostimulation, based on their direct interaction with the immune system, there may be future potential to use similar nanomaterials generate immunosuppressive responses.…”