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Peptide antigens have been widely used in the development of vaccines, especially for those against autoimmunity-inducing pathogens and cancers. However, peptide-based vaccines require adjuvant and/or a delivery system to stimulate desired immune responses. Here, we explored the potential of self-adjuvanting poly­(hydrophobic amino acids) (pHAAs) to deliver peptide-based vaccine against Group A Streptococcus (GAS). We designed and synthesized self-assembled nanoparticles with a variety of conjugates bearing a peptide antigen (J8-PADRE) and polymerized hydrophobic amino acids to evaluate the effects of structural arrangement and pHAAs properties on a system’s ability to induce humoral immune responses. Immunogenicity of the developed conjugates was also compared to commercially available human adjuvants. We found that a linear conjugate bearing J8-PADRE and 15 copies of leucine induced equally effective, or greater, immune responses than commercial adjuvants. Our fully defined, adjuvant-free, single molecule-based vaccine induced the production of antibodies capable of killing GAS bacteria.

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The use of peptides and proteins in the pharmaceutical field has increased dramatically over recent years. They have been especially relevant to advances in the treatment of cancer, rheumatoid arthritis, leukemia, and cardiovascular, ophthalmological, metabolic, and infectious diseases. Despite the great potential of peptides and proteins, their use in pharmaceuticals has failed to reach its full potential because of some outstanding challenges. They are unstable under storage conditions and in biological milieus, and their high molecular weight limits permeation through biological membranes. A variety of delivery systems have been investigated to overcome these limitations. Polyelectrolytes (PEs) are molecules that bear multiple negative or positive charges. These molecules play an important role in various platforms relating to the delivery of peptide/protein-based drugs and subunit vaccines. The most commonly utilized PEs include chitosan, alginate, chondroitin sulfate, and poly(γ-glutamic acid). PE-based delivery systems, such as polyelectrolyte complexes (PECs), PE-coated nanocarriers, and PE multilayers, were designed to protect peptides and proteins from degradation and facilitate their absorption. These delivery systems are especially effective when administered orally or intranasally. This review emphasizes the important role of PEs and PE-based delivery vehicles in peptide/protein-based drugs and vaccines.