Influence of Physicochemical Properties of Lipopeptide Adjuvants on the Immune Response: A Rationale for Engineering a Potent Vaccine

Abstract

Adjuvant development and understanding the physicochemical properties of particles and interpreting the subsequent immunological responses is a challenge faced by many researchers in the vaccine field. We synthesized and investigated the physicochemical properties and immunogenicity of a library of multiple epitope self-adjuvant lipopeptides in a novel asymmetric arrangement. Vaccine candidates were synthesized using a combination of solid-phase peptide synthesis and copper-mediated click chemistry. In vivo studies showed that vaccine constructs containing a single OVA CD8 T-cell epitope and two N-terminally located C16 lipid moieties were more effective at generating robust cellular immune responses compared to the same molecule containing multiple copies of the OVA CD8 T-cell epitope with or without the C16 moieties. Furthermore, attachment of the two C16 lipids to the N-terminus provoked formation of long β-sheet fibrils and was shown to induce a higher CD8 donor T-cell frequency and IFN-γ secretion, compared to vaccine constructs with an internal lipid placement. A regression analysis indicated that particle secondary structure had a significant impact on CD8 donor T-cell frequency and cytolytic activity. In addition, IFN-γ production was influenced significantly by particle shape. The findings of this research will impact the future design of a vaccine intended to elicit cellular immune responses.

Recent Advances in the Development of Peptide Vaccines and Their Delivery Systems against Group A Streptococcus

“…The lipopeptides formed have an amphiphilic structure and can self-assemble into particles. The size of the nanoparticle may be controlled by the number of LAA residues and the length of the LAA alkyl chain [29,150,151]. Moreover, the induction of immunological responses can be improved by changing the structural arrangement of epitopes and lipid moieties in a single construct [136,152].…”

Poly(hydrophobic amino acid)-Based Self-Adjuvanting Nanoparticles for Group A Streptococcus Vaccine Delivery

“…The importance of spatial arrangement in peptide vaccine components on the quality of immune responses has been reported previously. − Thus, to optimize the adjuvanting capacity of pHAAs, we designed vaccine constructs composed of (i) conserved B-cell epitope J8 (QAEDKVKQSREAKKQVEKALKQLEDKVQ) derived from GAS M protein, (ii) universal T-helper cell epitope (pan HLA DR-binding epitope, PADRE: AKFVAAWTLKAAA), and (iii) polyleucine moieties conjugated in different spatial arrangements (Figure b). PADRE is commonly used to enhance the quality and longevity of humoral immune responses .…”

Immunological Evaluation of Co‐Assembling a Lipidated Peptide Antigen and Lipophilic Adjuvants: Self‐Adjuvanting Anti‐Breast‐Cancer Vaccine Candidates

“…Actually,vaccine particle shape was reported to affect cytotoxic Tc ell responses. [35] Thus,o ur future work will include the optimization of co-assembling vaccine platform having ideal size,s hape,a nd rigidity by investigating number, length, and position of lipids introduced to the CH401 antigen. Them ixing ratio of lipidated antigen and lipophilic adjuvants will be also examined.…”