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Review

Self-Assembling Peptides for Vaccine Adjuvant Discovery

by
Jingyi Fan
1,
Istvan Toth
1,2,3 and
Rachel J. Stephenson
1,*
1
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia
2
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
3
School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia
*
Author to whom correspondence should be addressed.
Immuno 2024, 4(4), 325-343; https://doi.org/10.3390/immuno4040021
Submission received: 12 August 2024 / Revised: 21 September 2024 / Accepted: 25 September 2024 / Published: 1 October 2024
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Abstract

:
Vaccination is credited as a significant medical achievement contributing to the decline in morbidity and mortality of infectious diseases. Traditional vaccines composed of inactivated and live-attenuated whole pathogens confer the induction of potent and long-term immune responses; however, traditional vaccines pose a high risk of eliciting autoimmune and allergic responses as well as inflammations. New modern vaccines, such as subunit vaccines, employ minimum pathogenic components (such as carbohydrates, proteins, or peptides), overcome the drawbacks of traditional vaccines and stimulate effective immunity against infections. However, the low immunogenicity of subunit vaccines requires effective immune stimulants (adjuvants), which are an indispensable factor in vaccine development. Although there are several approved adjuvants in human vaccines, the challenges of matching and designing appropriate adjuvants for specific vaccines, along with managing the side effects and toxicity of existing adjuvants in humans, are driving the development of new adjuvants. Self-assembling peptides are a promising biomaterial rapidly emerging in the fields of biomedicine, vaccination and material science. Here, peptides self-assemble into ordered supramolecular structures, forming different building blocks in nanoparticle size, including fibrils, tapes, nanotubes, micelles, hydrogels or nanocages, with great biostability, biocompatibility, low toxicity and effectiveness at controlled release. Self-assembling peptides are effective immunostimulatory agents used in vaccine development to enhance and prolong immune responses. This review describes the predominant structures of self-assembling peptides and summarises their recent applications as vaccine adjuvants. Challenges and future perspectives on self-assembled peptides as vaccine adjuvants are also highlighted.

1. Introduction

Vaccination is a significant and promising therapeutic tool to generate effective immune responses with lasting immunological memory against infectious diseases [1,2]. The first vaccine is traced back to 1796, when Edward Jenner developed the vaccine technology that lead to the worldwide elimination of smallpox [3]. Traditional vaccines using inactivated and live-attenuated whole pathogens are still employed against infectious diseases due to their induction of robust and long-term immune responses [4]. Drawbacks of these traditional vaccines include autoimmunity, allergic responses or inflammations and manufacturing difficulties [5]. Further, traditional vaccines require strict cold-chain delivery and storage conditions, which cannot be achieved in low-income countries [6]. Finally, there are also safety concerns when the whole pathogen is inactivated or during the culture of live attenuated pathogens on a large manufacturing scale [7,8]. Thus, more recently, several modern types of vaccines, including subunit, virus-like particle and RNA vaccines, have been widely developed.
Subunit vaccines, composed of minimal microbial components derived from whole pathogens, elicit appropriate immunity and successfully address the drawbacks of traditional vaccines [5,9]. Advantages of subunit vaccines include large-scale production by chemical synthesis without any risk of biological contamination, high yield and purity and the achievement of batch-to-batch consistency [4]. However, the removal of unnecessary components often reduces immunogenic necessitates, with small molecules having limited immunogenicity [5]. Co-administration of adjuvants with subunit vaccines is a crucial pathway to improve low immunogenicity and elicit and shape a strong immunity against infections [3]. Adjuvants are indispensable parts of subunit vaccines, however, only six adjuvants, including aluminium hydroxide (alum), MF59, AS04, AS03, AS01 and CpG 1018®, have been commercialised for use in human vaccines [10].
Adjuvants range from small synthetic molecules to complex natural extracts and particulate materials, but we often lack the in-depth understanding of their mechanisms of enhancing an immune response, leading to challenges around matching or designing appropriate adjuvants for specific vaccines [10,11,12]. Moreover, certain adjuvants (e.g., Freund’s adjuvant, lipopolysaccharides) stimulate potent immunity in preclinical studies and as a result have not been licensed for use in human vaccines due to their toxicity and/or side effects to humans [3,10].
In the 1970s, Cram and Lehn discovered supramolecular chemistry, which provided a new perspective on non-covalent molecular interactions, building up the molecular recognition self-assembling process [13,14]. Here, peptides were shown to self-assemble into supramolecular structures representing promising biomaterials in vaccine delivery. This was achieved by their facile design and synthesis, stable biocompatibility, degradability and ability to induce adaptive immunity. Furthermore, the chemical versatility of self-assembling peptides offers a high degree of tunability and adjuvanticity, enabling these peptides to accurately target cells or organs, effectively responding to stimulus-responsiveness and widely interacting with organic and/or inorganic molecules [2]. The multi-antigen displays on self-assembling peptides promoted immune cell uptake leading to strong antibody titers compared to monovalent antigens [2,15]. Further, self-assembling peptides form an antigen depot effect, directing the vaccine to antigen-presenting cells and significantly enhancing immune cell priming [16]. Notably, the elimination of toxicity and reduction in the total amount of antigen required significantly minimized vaccine side effects.
This review describes the four principal structures, and their characteristics, of supramolecular self-assembling peptides and highlights their applications in preclinical vaccine development over the last decade. The future perspective and challenges of self-assembling peptides as vaccine adjuvants are also highlighted.

2. Structure and Characteristics of Self-Assembling Peptides

Self-assembling peptides are formulated by short or repeat amino acids. In the aqueous phase, peptide sequences self-assemble into various supramolecular nanostructures (Figure 1) by ionic, hydrogen bonding, hydrophobic and π–π stacking interactions) [13,17]. Additionally, (poly)peptides modified with lipids, sugars or synthetic and natural polymers increased tunability and flexibility in their self-assembling properties, resulting in supramolecular structures for diverse biomedical applications [18]. Four structures of supramolecular self-assembling peptides are introduced in this review (Figure 1).

2.1. α-Helical

α-helices represent the secondary structure formed by water-soluble globular proteins formulating a stable supramolecular structure (such as nanofibers and nanotubes) via non-covalent interactions (including hydrogen bonds, hydrophobic and van der Waals interactions) in aqueous media [2,19,20]. α-helices significantly increase conformational stability of proteins and improve the biocompatibility of proteins, leading to impeded enzymatic degradation. α-helices are often involved in protein interactions with other proteins, nucleic acids and the lipids of cell membranes [2,19,20]. For example, Dieckmann et al. used an amphiphilic α-helical peptide structure to modify and coat carbon nanotubes, which are difficult to solubilise. They found that α-helices are not only responsible for increasing the solubility of carbon nanotubes in aqueous solution but also for significantly controlling their size and morphology [21]. The conformational stability of α-helical peptides is determined by several factors, including covalent structures of peptides, the hydrophobic interaction between peptide side chains, electrostatic interactions between charged polar residues and the electric macro-dipole properties of peptides in solution [19].
Far-UV circular dichroism (CD) spectroscopy is a classical method for the indentation of a polypeptide’s secondary structure in solution [22]. Advantages of CD spectroscopy include it being a fast and inexpensive technique with easy data processing. In the far-UV region, between 170 nm and 250 nm, mostly electronic transitions of peptide bonds contribute to the CD spectrum. Within this region, the α-helix CD spectra reveal peaks expressed at negative 222 nm and 208 nm and a positive peak around 190 nm [22].
The coiled-coil structure is a common α-helix found in nature (Figure 2a) [23]. In the 1950s, Crick and colleagues described that two or more typical α-helices wrapped around each other into a left-handed helix to form a rod-like supercoil structure [23,24]. This coiled-coil is composed of a heptad repetition of nonpolar (hydrophobic) and polar amino acid residues, resulting in a ‘nonpolar-polar-polar-nonpolar-polar-polar-polar’ pattern, known as (a-b-c-d-e-f-g)n where ‘n’ is the number of repeats and ‘a–g’ facilities the relative positions of amino acids in a helical wheel schematic (Figure 2b) [24,25].
The majority of folding in a stable coiled-coil structure is impacted by the hydrophobicity of amino acids, where nonpolar amino acids in the ‘a’ and ‘d’ positions interact together in a ‘knobs-into-hole’ manner by hydrophobic interactions, minimizing their interaction with water (Figure 2b) [23]. Moreover, the ionic interaction between charged amino acids ‘e’ and ‘g’ is polar and solvent-exposed, leading to repulsion and destabilization [23,26]. The advantages of the coiled-coil structure include control over chemistry, reversibility, and particle size [21]. Following the advantages of coiled-coil structure, Fletcher et al. formed a self-assembling cage, which is approximately 100 nm in diameter with hexagonal networks, in the aqueous solution (Figure 3). Notably, the particle size and physiochemical properties of nanocages are controlled by coiled-coil peptides [21,27].
Morris and colleagues explored the immunological potential of the self-assembling nanocage composed of α-helical coiled-coil peptides (Figure 3) [28]. This work demonstrates that 100 nm diameter self-assembling nanocages act as a modular scaffold for antigen delivery, capable of inducing and boosting adaptive immune response with nontoxic particles [28].
When two or more α-helices are arranged into a superhelix, coiled-coils form a typical and distinct structure. However, there are the underlying challenges of designing and forming coiled-coils, including unwanted interactions in the aqueous phase or undesired folded species, which can be minimized by (1) pinpointing charge interactions at specific ‘e’ and ‘g’ positions, which reduces stability of the intended structures, and (2) using more nonpolar amino acids at ‘a’ and ‘d’ positions [29].

2.2. β-Sheets

β-sheets, composed of parallel or antiparallel β-strands connected by a network of intermolecular interactions, are naturally occurring in many proteins [30]. CD spectra of the β-sheet secondary structure confer a negative peak at 218 nm and a positive peak around 195 nm [22]. In the early 1950s, Pauling et al. discovered self-assembled β-sheets in polypeptide chains of β-keratin [31,32,33]. The primary sequence of these β-sheets is generally (XZXZ)n, wherein ‘X’ is a hydrophobic amino acid and ‘Z’ is a hydrophilic amino acid (Figure 4) [34]. These alternating hydrophilic and hydrophobic amino acids self-assemble into amphiphilic sheets by hydrogen bonding between peptide side chains, displaying a characteristic right-handed twist [35,36,37,38]. Furthermore, electrostatic and hydrophobic interactions between the amino acid side chains on the same face of the β-sheet contribute to its stability [37,39]. Amphipathic β-sheets rise to coplanar bilayers in which the hydrophobic motifs are located in the interior of the peptide, while the hydrophilic side chains are exposed in the aqueous phases [34].
β-sheet self-assembly leads to stable bilayer fibrils with excellent solubility due to the formation of amyloid-inspired structures, which are soluble in aqueous media instead of precipitating from solution [34,40]. The increases in stability and improvement of tunability of β-sheets are manipulated by varying the sequences and/or hydrophilicity of amino acids [2]. Optimized β-sheets confer more of the stable physiochemical properties of peptides, including low toxicity, inherent biodegradability and good biocompatibility in addition to improved fast responsiveness to immune system [41]. Furthermore, at high concentrations of aqueous solution, β-sheets that were competent to self-assemble formed self-supporting nanohydrogels [34,42]. Nanohydrogels are soft, water-swollen and three-dimensional structures that possess significant features including good biodegradability, tunable physiochemical properties and injectability compared to other nanostructures, and recently they have been conferred enormous attention for use in medical therapy [43]. In 2016, Gilam and coworkers developed the nano hydrogel delivery system where miRNA sequences miR-96/miR-182 (related to downregulating breast cancer protein levels) were embedded in a hydrogel scaffold. In the breast cancer mouse model, injection of this nanohydrogel component reduced breast cancer cell migration and invasion [44]. Furthermore, Zhang et al. identified a 16-residue peptide, AC-(AEAWAKAK)2-NH2, that had a characteristic β-sheet circular dichroism spectrum in water, and upon the addition of high concentrations of salt, the peptide spontaneously self-assembled to form a macroscopic membrane as hydrogel facilitating approximately 10–20 nm in diameter [42]. The formulated hydrogel did not dissolve in heat, acidic or alkaline solutions, or by proteolytic enzymes [42]. Therefore, self-assembling β-sheet nanogel and nanofibril supramolecules have wide implications for biomaterials, drugs, vaccines or origin-of-life research [42,45].

2.3. Peptide Amphiphiles

Peptide amphiphiles are self-assembled peptides that combine the structural features of amphiphilic surfactants and bioactive peptides, expressing immuno-genic properties [46]. Over the past decade, peptide amphiphiles have shown great promise in biomaterials and vaccine development, owing to their ability to form a wide range of supramolecular nanostructures, including nanofibers, hydrogels, nanotubes and micelles (Figure 1) [47,48]. Peptide amphiphiles contain four crucial domains, including hydrophobic domains, β-sheet/α-helix segment, charged amino acids and epitope section as a bioactive head (Figure 5) [49].
The full profiles of amphiphilic peptides often contain charged amino acids and stabilizing β-sheet/α-helix-forming domains for enhanced stability and self-assembly functions [49]. Furthermore, the head region of an amphiphilic peptide also contains epitope peptides as bioactive signals, interacting with cells or proteins with the induction of effective immunity [49,50]. Hydrophilic and hydrophobic residues from peptides have a tendency to self-assemble into nanostructures by the interplay of hydrogen bonding along with hydrophobic and electrostatic interactions in aqueous media.
Three structures of peptide amphiphiles are classified following different components in hydrophobic domains: (1) amphiphilic peptides that only consist of both polar and nonpolar amino acids, offering both hydrophobic and hydrophilic properties [47,51,52]; (2) lipidatad peptides composed of lipid alkyl chains located into the hydrophobic domains [47,51] and (3) supramolecular peptide amphiphile conjugates providing hydrophobicity by using hydrophobic macrocyclic hosts, aromatic guests and crown ethers (e.g., phenyl, pyrene and cucurbiturils) (Figure 5) [53,54]. Peptide amphiphiles can self-assemble into nanostructures of diverse size and shapes in response to changing environmental conditions (including pH, temperature and ionic strength) [47,49]. In the last decade, peptide amphiphiles as self-assembling materials have performed promising and wide applications in vaccine development, tissue engineering and regenerative medicine due to their stable and effective bioavailability [50,55].

2.4. Cyclic Peptides

Cyclic peptides are polypeptide chains formed into a cyclic ring structure through an amide, lactone, ether, thioether or disulfide bond [56]. There are four different types of peptide cyclisation, including side chain-to-side chain cyclisation, head-to-tail cyclisation, head-to-side chain cyclisation, and tail-to-side chain cyclisation [57]. N-terminal to C-terminal cyclisation, also referred to as head-to-tail cyclisation or backbone cyclisation, is achieved by amide bond formation between amino and carboxyl termini (Figure 6) [58].
Numerous cyclic peptides derived from natural sources, such as hormones and antibiotics like daptomycin and polymyxin B, have been extensively utilized in clinical trials for combating bacterial or viral infections [59]. Over the last decade, the biomaterial potential of cyclic peptides has been granted by forming supramolecular building blocks [60]. Cyclic peptides can form synthetic nanotubes in aqueous solution, driven by hydrogen bonding. Amino acid side chains point outward, and the carbonyl and amide protons of the peptide backbone are oriented perpendicular to the plane of the ring, forming flat ring-like constructions [61]. Peptide cyclisation enhances the rigidity of the peptide structure, increasing receptor binding affinity when compared with the linear peptide [46]. In cyclic peptide nanotubes (Figure 6), the hydrophobic inner layer prevents the peptide core from the hydrogen bonding competition of water molecules, improving the stability of nanotubular structures in water [61]. Additionally, the nanotubes’ hydrophilic outer layer dramatically increases their solubility in aqueous media [61]. Furthermore, cyclic peptides have two remarkable advantages of formulating nanotubes, including the control of the nanotube diameter by varying the number of amino acids in each ring, and the properties of the nanotube outer surface by modification of the amino acid side chains [62]. Therefore, applications of self-assembling cyclic peptides have been explored in vaccine development, drug delivery and material bioscience due to their limited toxicity, stable biocompatibility and promising biostability [59].

3. Applications of Self-Assembling Peptides in Vaccine Development

Self-assembling peptides are exceptional biomaterials that form supramolecular nanostructures in aqueous environments. The structural diversity of self-assembling peptides provides enhanced biostability, excellent biocompatibility, non-toxicity and effective delivery capabilities [2]. When assembled into various nanostructures, they serve as promising scaffolds or delivery materials with applications in diverse life-science fields such as drug release, vaccines, tissue engineering and cosmetics. Advancements of self-assembling peptides for applications in vaccine adjuvants over the last decade are listed in Table 1.
Both α-helix and β-sheet are capable of forming self-assembling peptides in aqueous media. However, a β-sheet is flatter, thinner and generally more flexible than an α-helix, providing more capabilities of β-sheets to build the desired a variety of supramolecular nanostructure [63]. Therefore, there are more β-sheet self-assembling peptides in vaccine development. The advantage of α-helix is the expression of much higher environmental stability than a β-sheet [63]. Peptide amphiphiles are the predominant type of self-assembling peptides. The design of peptide amphiphiles achieve by modifying their four different domains (Figure 5), thereby stability, solubility, biocompatibility and turnability of self-assembling peptides can be controlled by artificial design [47]. Cyclic peptides self-assemble into different-size nanotubes due to the number of amino acids in each ring and the properties of the nanotube outer surface [62].
Table 1. Recent examples of self-assembling peptides in vaccine development.
Table 1. Recent examples of self-assembling peptides in vaccine development.
Self-Assembling PeptideType of NanostructureTarget EpitopeResultsRef.
α-helix
Coil29NanofibersCD8+ T-cell epitopeInduction of tune the humoral response and CD8+ immune response.[64]
NanofibersOvalbumin (OVA323–33) from S. aureus.Stimulation of higher antibody titers and activities and raising follicular helper T cells compared to a β-sheet self-assembling peptide[65]
P41NanocomplexesHepatitis C virus nonstructural protein C5Decrease of viral loading in mice with adjuvanticity of antiviral immune activation properties.[66,67]
P6HRC1 polypeptideCoiled-coil poly-nanostructureSevere acute respiratory syndrome B cell epitope from C-terminal virus spike proteinProduction of antibodies with high affinity for pathogenic protein and intensive use against coiled-coil confirmational viruses or other enveloped viruses.[68]
Pentamer and trimer sequence peptide5-stranded and 3-stranded coiled-coil nanofiberCytotoxic T lymphocytes from PspA and CbpA from Streptococcus pneumoniae.Stimulation of potent immune response against S. pneumoniae.[69]
β-sheet
Q11β-sheet nanofibersOvalbumin (OVA) OVA323–339Protection of IgG1, IgG2a, IgG3 in similar to the peptide epitope delivered in complete Freund’s adjuvant and greater level of IgM in secondary protection response[70]
KFE8β-sheet nanotubesMycobacterium tuberculosis CD8+ epitope TB 10.4 and CD4 epitope Ag85B240–254 fromElicitation of anti- Mycobacterium tuberculosis specific CD8+ and CD4+ immunity with the secretion of antigen-specific effector memory T cells and interferon-γ and interlekin-2 cytokines.[71,72]
PAS-Q11β-sheet nanofibersModel peptide antigen OVA323–339 and small molecule epitope, phosphorylcholineInduction of anti-OVA and anti- phosphorylcholine humoral immune response and significant mucosal immunity following oral administration.[73]
RADA16β-sheet nanofibrous hydrogelPhysical mixture of anti-PD-1 antibodies, dendritic cells, and OVA tumor antigenInduction of superior antitumor immunotherapy efficiency in both prophylactic and therapeutic models via anti-tumor T-cell and potent CD8+ T cell response[74]
EAK16-IIβ-sheet nanofibersHIV-1 CD8+ epitope SL9Stimulation of potent SL9 specific cytotoxic T lymphocyte and long-term secondary response.[75]
K2-(SL)6-K2NanohydrogelModel antigen OVAElicitation of potent humoral immune response while evoking limited cellular immune response.[76]
E-(SL)6-ENanofiberSpike-binding peptide sequence from SARS-CoV-2Antiviral abilities to reduce the strength of multivalent binding to the viral receptors[77]
Peptide amphiphile
15 (Poly)leucine residuesNanofibersJ8 antigen from group A StreptococcusInduction of high IgG titers and clear bacterial load from target organs without triggering the release of soluble inflammatory mediators[78]
Fmoc-KCRGDE (FK)NanohydrogelA bromodomain containing protein 4 inhibitor JQ1and indocyanine green (ICG) co-loaded tumor cellsIrradiation significantly inhibits of cytotoxic T lymphocytes and the induction of patient-specific memory immune response, contributing to prevent tumor recurrence and metastasis,[79]
Ac-I3SLKG-NH2NanohydrogelTumor peptide G(IIKK)3I-NH2 (G3)Induction of inhibitory tumor growth with an effective antitumor immune response[80]
DiC16-OVANanomicelleCD8+ T-cell epitope SIINFEKL from OVA protein.Promotion of a cellular immune response and significant protective response in vivo.[81]
Lipid-core peptideNanoparticleJ8 antigen from group A StreptococcusInduction of high titers of antigen specific IgG antigens[82,83]
J8-DiC16Cylindrical micelle nanoparticleJ8 antigen from group A StreptococcusProduction of J8-specific IgG2a immune response compared with J8 alone[84]
Ada-GFFYGKKK-NH2NanofibersModel antigen OVAInduction of a potent innate and adaptive immune response, with loading antigen with high efficiency[85]
Nap-GFFYNanohydrogelModel antigen OVAStimulation of strong cellular immune response and inhibition of tumor growth[86]
Nap-GFFY-OMeNanohydrogelHIV EnV DNA encoding the HIV-1 envelope protein gp145Induction of strong humoral and cellular immune responses.[87]
Ac-AAVVLLLW-COOHNanovesicular structureHuman papillomavirus (HPV) peptide E743–57Production of antitumor immunity and increase of mice survival, delaying tumor cell growth[88]
Cyclic peptide
Cyclic decapeptideNanoparticle or microparticleJ8 antigen from group A StreptococcusInduction of J8-specific systemic immune response without an additional adjuvant[89]
Eight residue cyclic D, L-α cyclic peptidesNanotubeHepatitis C viral envelope protein (E2) antigenAntiviral activity of cyclic peptide inhibited hepatitis C viruses entered into host cells.[90]
Cyclo-(D-Trp-Tyr)NanotubeVP2 protein of goose parvovirusInduction of significant antibody response and highest IgA levels in serum and tract after oral immunization.[91]
Other Self-Assembling Vaccines
Polyacrylate-based self-adjuvantingNanoparticle8Qmin (E744–57)Decrease of tumor cell growth and induction of a strong cellular immune response and portion of up taken by dendritic cells dendritic cells and macrophages, and efficiently activated CD4+ T-helper cells and CD8+ cytotoxic T lymphocyte cells.[92]
Cholesteryl PADRE-EGFRvIII lipopeptideMicelle nanoparticlePositive cutaneous melanoma EGFRvIII epitopeStimulation of potent humoral immunoreaction and cellular immunity with significant tumor inhibitory capacity.[93]
Natural hepatitis B core protein nanocageNanocageCD8+ T-cell epitope SIINFEKLGeneration of cellular response and protective antitumor response, delaying tumor growth.[94]
Protein annexin V (ANXA5)NanoparticlePeptide major histocompatibility complexIncrease of fusion augments lymphocyte response with inducing potent cellular immunity.[95]

3.1. α-Helical

In the last decade, the adjuvanticity of self-assembling peptides with α-helical structure has been indicated in various in vivo studies by the potentiation of adaptive immunity. For example, the potential immunogenicity of Coil29 (Table 1), a typical α-helical structure, has been demonstrated by Wu et al., where Coil29 conjugated with antigenic peptide epitopes OVA resulted in inducing humoral immune response against infectious diseases [65].The immunogenicity of Coil29 conjugated to a CD8+ T cell epitope SIINFEKL were assessed by subcutaneous immunization into mice, leading to higher levels of antigen-specific CD8+ T cells as induced by Coil29 conjugated groups, promoting multivalent antigen presentation and indicating potential adjuvanticity of Coil29 (Figure 7) [64].
Formulation of a vaccine composed of a peptide derived from the hepatitis C virus non-structural protein C5 coupled with an anionic poly (amino acid)-based block copolymers P41 significantly decreased viral loading in mice, eliciting antiviral immunogenic properties after intramuscular immunization [66,67]. Additionally, Pimentel and coworkers designed a promising platform, denoted herein P6HRC1, for a severe acute respiratory syndrome subunit vaccine. P6HRC1 included a coiled-coil B cell epitope from the C-terminal heptad repeated region of pathogenic spike protein without using external adjuvants. The size of P6HRC1 was approximately 25 nm and immunization experiments conducted in BALB/c mice showed that P6HRC1 stimulated protective antibodies alone, with no additional adjuvants added into the vaccine formulation [68,69].

3.2. β-Sheets

β-sheets self-assemble into a variety of supramolecular structures, including nanofibers, nanohydrogels and nanotubes. The immunostimulatory properties of β-sheet self-assembling peptides have been demonstrated in preclinical studies. The most common supramolecule of β-sheets is nanofibers due to their ease of fabrication and high porosity in water media. The β-sheet Q11 was discovered by Rudra et al. in 2010, who observed that the OVA antigen and β-sheet Q11 peptide self-assembled into nanofibers in aqueous media (Figure 8a) [70]. Subsequent subcutaneous immunization in mice with this OVA-vaccine resulted in strong antibody responses and long-term protective immunity without the coadministration of any additional adjuvant; however, cellular immune response was limited [70].
Additionally, Curvino et al. coupled Q11 with sequences rich in proline, alanine and serine (PAS) (Q11-PAS) (Figure 8b) which were co-administered with antigens OVA or phosphorylcholine in mice to produce an antigenic immune response and significant mucosal immunity upon oral administration [73]. Wu and colleagues compared the immune response raised by two structural peptides, Q11 β-sheet and Coil29 α-helix, where both peptides were conjugated to the model OVA epitope for subcutaneous vaccination into mice against S. aureus [65]. The immunological result showed that Coil29 with nanofibers possessed internal CD4+ T cell epitopes, whereas Q11 nanofibers required a critical role for adding CD4+ T cell epitopes in the induction of humoral response [65]. Although Q11 and Coil29 were minimally inflammatory, synthetic α-helix Coil29 produced higher antibody titers and avidities against S. aureus [65].
In addition to this, several well-characterized β-sheet self-assembling peptides, including FKFE8, RADA16 and EAK16-II form nanofibers/nanotubes, have been used in vaccine development due to their optimal physicochemical properties [71,72,74,75]. Rice University reported that the multidomain peptide composed of canonical amino acids K2-(SL)6-K2 formulated into injectable supramolecular hydrogels under physiological salt and pH conditions [76]. A preclinical study of this with the model antigen OVA with self-assembling K2-(SL)6-K2 subcutaneously injected into mice indicated that K2-(SL)6-K2 stimulated potent humoral and long-term protective immunity, while the level of cellular immune response was limited [76]. In 2024, Dodd-o et al. designed a tunable and scalable antiviral therapeutical platform based on suitable SARS-CoV-2 peptide domains conjugated to a short peptide capable of E-(SL)6-E self-assembling into functionalized β-fibrils [77]. Preclinical studies by subcutaneous immunization into mice demonstrated that inter-peptide coupling with the self-assembling antivirals confers abilities to reduce the strength of multivalent binding to the viral receptors, providing inexpensive, productive, and stable with excellent tolerability [77].

3.3. Peptide Amphiphiles

Peptide amphiphiles have offered predominant immunogenic capability in vaccine development. The hydrophilic head and hydrophobic tail of amphiphilic peptides interacted/coupled with each other to construct diverse supramolecular nanostructures in water solution via inter- and/or intramolecular forces [96]. Skwarczyski et al. coupled a group A Streptococcus B cell peptide, J8 conjugated to a T helper peptide PADRE (J8-PADRE) with poly-hydrophobic amino acids (PHAA) made up of 15 leucine amino acids linked together as a self-adjuvanting vaccine [78]. Following subcutaneous immunization into mice, this PHAA vaccine induced the robust J8-specific immune response and produced a significant opsonized reaction with group A Streptococcus clinic strains (Figure 9a) [78]. A further study evaluated the efficacy of 15 polyleucine (Leu15) conjugated with J8-PADRE antigen in the murine model, resulting in the stimulation of stronger IgG titres compared to commercial adjuvants [97]. Furthermore, hydrophobic and hydrophilic amino acids are arranged into sequences of different lengths to form self-assembling peptides (including Fmoc-KCRGDE (FK), Ac-I3SLKG-NH2 and Ac-AAVVLLLW-COOH) in vaccine development [79,80,88].
The second type of peptide amphiphiles referred to lipopeptides. In 2003, a lipid core peptide was developed by Toth et al. [98]. Formulation of a new lipid core peptide technology comprised of lipoamino acids (e.g., 2-amino-D, L hexadecenoic acid [C16]) coupled to a poly-lysine core (Figure 9b) [98]. In this lipid core system, two lipid alkyl chains covalently conjugated to antigenic peptides, which is uniquely designed to incorporate peptide antigens, carrier and adjuvant in a single molecule entity, forming nanostructure peptide-based subunit vaccines [98]. In addition, Black and colleagues also conjugated C16 to a CD8+ epitope SIINFEKL as an anticancer vaccine, which was administered subcutaneously in mice. In vivo studies demonstrated that the T cellular epitope coupled with synthetic lipid tail self-assembled into cylindrical micelles, inducing a cytotoxic T cell response and delaying tumour growth [81].
Over the past decade, various acids serving as the hydrophobic domains of peptide amphiphiles (e.g., 1-adamantaneacetic acid, Figure 9c) have been coupled with short peptides to formulate nanohydrogel or nanofibers structures with potent adjuvanticity in preclinical studies against cancers or HIV [85,86,87].

3.4. Cyclic Peptide

Cyclic peptides confer immunogenicity due to their antiviral and antibacterial capabilities and formation of nanotubes in aqueous solutions. Madge et al. successfully formulated a cyclic decapeptide that co-administered with J8 antigen and induced a J8-specific response in mice following subcutaneous injection, production of antigenic specific response (Figure 10a) [89,99]. Furthermore, cyclo-(D-Trp-Tyr) (Figure 10b) served as a safe and effective oral adjuvant when combined with DNA to form a nanotube vaccine that elicited strong antibody responses and significant mucosal immunity through the secretion of high levels of IgG and IgA, respectively [91].

3.5. Other Self-Assembling Vaccines

Other biomaterials such as polysaccharides and proteins still hold potential for self-assembling supermolecules capable of inducing effective immune responses against infections or cancers [93,94,95].

4. Challenges of Self-Assembling Peptides and Future Perspectives

Self-assembling peptides demonstrate significant potential in the fields of drug delivery, tissue engineering, vaccine development, and cosmetics due to their significant biocompatibility, sufficient biostability, low toxicity, and effectiveness at controlled release [41]. The adjuvanticity of self-assembling peptides (including α-helical, β-sheet, peptide amphiphiles and cyclic peptide) is achieved by formulating diverse supramolecular nanostructures in aqueous media via inter- or intramolecular forces [100]. In recent decades, self-assembling peptides have been conferred into improving immunogenicity of vaccinations in various preclinical studies. There are still challenges in vaccine development, including rational systematic design of self-assembling peptides to formulate more stable and tunable structures required with the induction of potent immunity against diseases in vaccine development [101]. The improvement of stable and tunable capability of self-assembling peptide is achieved by using novel dynamic imine covalent crosslinking. After the covalent cross-linking, the nanohydrogel performs more stably with no structural alterations for temperature up to 85 °C and it does not require any crosslinking agent (such as metal ions, enzyme or catalyst) [101]. Additionally, König and coworkers employed small-angle X-ray/neutron scattering techniques, supported by differential scanning calorimetry (DSC) and CD techniques, to assess the physical stability of the β-sheet Kx (QL)yKz sequence [102]. The results demonstrated that these techniques could assist in finding more stable nanostructures of the short peptide K3W(QL)6K2 [102]. The second challenge is understanding the interactions between self-assembling supramolecular structures and immune cells, cytokines or chemokines [16,103]. Researchers are investigating in vivo studies (animal study) and in vitro research by using simulation techniques (such as silico studies) to assist in understanding the mechanisms between self-assembling peptides and host immune response [16].
There are promising and attractive techniques of designing self-assembling peptides. In 2024, Ren.et.al designed a foundation model, named HydrogelFinder, for the rational design of self-assembling peptides [104]. This model explores the self-assembly properties of non-peptide small molecules to navigate chemical space and improve structural diversity, granting a powerful toolkit and paradigm for future self-assembling peptide discovery endeavours [104]. Molecular dynamics is a another powerful computational technique which allows for the microscopic study of system evolution at the atomic level [105,106] In the self-assembling peptide designs, coarse-grained molecular dynamics are more effective in predicting aggregation tendency and supramolecular structures [107]. For example, Frederix et al. utilized coarse-grained molecular dynamics to screen for the aqueous self-assembly propensity in all 8000 possible tripeptides and evaluated a method for self-assembling sequences based on their aggregation propensity and hydrophilicity [107]. They found tripeptides (such as FFF) offered a significant ability to form a hydrogel at neutral pH [107].
Traditionally, peptide design is guided by human expertise and intuition, forming short peptide sequences; however, these approaches are hard to scale and are susceptible to human bias. Currently, machine learning is the most attractive method of investigating peptide structure, overcoming drawbacks of traditional peptide design. For example, Batra et al. introduced a machine learning workflow, AI-expert, which combines Monte Carlo tree search and random forest with molecular dynamics simulations to develop a fully autonomous computational search engine for screening and designing peptide sequences with high potential for self-assembly [108]. They identified the effectiveness of the AI-expert in discovering self-assembling tripeptides and pentapeptides. This AI-expert platform performs predictably, has huge potential for peptide discovery and overcomes human bias [108]. Therefore, machine learning expresses a huge perspective in the further discovery of self-assembling peptide adjuvants [109].
Notably, biological self-assembling peptides offer an attractive potential area for adjuvant development. Table 1 listed all current examples of self-assembling peptides, in particular, peptide amphiphiles consist of a hydrophobic domain and a hydrophilic head have received the most promising status among adjuvants in vaccine applications. The appropriate physicochemical properties of amphiphilic peptides can be achieved through the design of the hydrophobic domain and the hydrophilic head [110]. Their immunogenic and antibacterial properties can be performed by adding multiple epitopes in the epitope section. Many existing examples in nature (such as lipids, traditional surfactants, surfacing and siderophores) serve as references for amphiphilic peptide design [110]. Moreover, machine learning and computational screening techniques offer rapid and effective approaches to design short amphiphilic peptides with better and more stable secondary structures (including α-helix and β-sheet) [111,112]. Although some self-assembling peptides (e.g., K2-(SL)6-K2, Nap-GFFY, lipid-core peptide, and KFE8) performed significant adjuvanticity in preclinical studies, further design of next-generation vaccines using non-toxic self-assembling peptides to improve the immunogenicity in humans requires deep and wide exploitation.

Author Contributions

Conceptualization: I.T.; Writing—original draft, J.F. and R.J.S.; Writing—review and editing, I.T. and R.J.S.; Funding acquisition, R.J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Health and Medical Research Council (NHMRC) grants, APP1132975 and APP1158748.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Schematic representations of supramolecular self-assembling peptides.
Figure 1. Schematic representations of supramolecular self-assembling peptides.
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Figure 2. (a) Ball and stick model of an α-helical secondary structure (side view), and (b) heptad wheel representation of a coiled-coil α-helical structure.
Figure 2. (a) Ball and stick model of an α-helical secondary structure (side view), and (b) heptad wheel representation of a coiled-coil α-helical structure.
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Figure 3. Self-assembling nanocages from coiled-coil peptides [27].
Figure 3. Self-assembling nanocages from coiled-coil peptides [27].
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Figure 4. (a) Ball and stick model of a β-sheet (side view), and (b) β-sheets secondary structure indicating both antiparallel and parallel β-sheets.
Figure 4. (a) Ball and stick model of a β-sheet (side view), and (b) β-sheets secondary structure indicating both antiparallel and parallel β-sheets.
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Figure 5. Schematic structure of peptide amphiphiles. Region 1 is a hydrophobic domain composed of hydrophobic amino acids/alkyl/aromatic groups. Region 2 is a β-sheet or α-helix segment for the interfacial curvature (β-sheet or α-helix) of self-assembled structures by hydrogen bonds in the aqueous. Region 3 composed of charged amino acids (including arginine (Arg), glutamic acid (Glu), and lysine (Lys)) increase solubility of amphiphilic peptides, and Region 4 confers a functional peptide epitope specific to the disease target [47].
Figure 5. Schematic structure of peptide amphiphiles. Region 1 is a hydrophobic domain composed of hydrophobic amino acids/alkyl/aromatic groups. Region 2 is a β-sheet or α-helix segment for the interfacial curvature (β-sheet or α-helix) of self-assembled structures by hydrogen bonds in the aqueous. Region 3 composed of charged amino acids (including arginine (Arg), glutamic acid (Glu), and lysine (Lys)) increase solubility of amphiphilic peptides, and Region 4 confers a functional peptide epitope specific to the disease target [47].
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Figure 6. Schematic structure of a cyclic peptide self-assembling into a nanotube.
Figure 6. Schematic structure of a cyclic peptide self-assembling into a nanotube.
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Figure 7. Coil29 conjugated to CD8+ T cell epitope. PADRE is a T helper peptide and SIINFEKL is a T cell OVA peptide.
Figure 7. Coil29 conjugated to CD8+ T cell epitope. PADRE is a T helper peptide and SIINFEKL is a T cell OVA peptide.
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Figure 8. Structures of (a) Q11 and (b) Q11-PAS.
Figure 8. Structures of (a) Q11 and (b) Q11-PAS.
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Figure 9. Examples of three classes of peptide amphiphiles (a) Amphiphilic peptide containing 15 leucine (Leu) residues as typical hydrophobic domain. (b) Lipopeptide is composed of two long hydrophobic lipid alkyl chains as a lipidated peptide. (c) Supramolecular peptide amphiphile conjugates composed of 1-adamantaneacetic acid coupled to the short peptide GFFY(K) n (n = 2,3) with formulation of nanofibers in phosphate buffered saline (PBS).
Figure 9. Examples of three classes of peptide amphiphiles (a) Amphiphilic peptide containing 15 leucine (Leu) residues as typical hydrophobic domain. (b) Lipopeptide is composed of two long hydrophobic lipid alkyl chains as a lipidated peptide. (c) Supramolecular peptide amphiphile conjugates composed of 1-adamantaneacetic acid coupled to the short peptide GFFY(K) n (n = 2,3) with formulation of nanofibers in phosphate buffered saline (PBS).
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Figure 10. Structures of example cyclic peptides, (a) cyclic decapeptide and (b) cycl (D-Trp-Tyr) [91].
Figure 10. Structures of example cyclic peptides, (a) cyclic decapeptide and (b) cycl (D-Trp-Tyr) [91].
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Fan, J.; Toth, I.; Stephenson, R.J. Self-Assembling Peptides for Vaccine Adjuvant Discovery. Immuno 2024, 4, 325-343. https://doi.org/10.3390/immuno4040021

AMA Style

Fan J, Toth I, Stephenson RJ. Self-Assembling Peptides for Vaccine Adjuvant Discovery. Immuno. 2024; 4(4):325-343. https://doi.org/10.3390/immuno4040021

Chicago/Turabian Style

Fan, Jingyi, Istvan Toth, and Rachel J. Stephenson. 2024. "Self-Assembling Peptides for Vaccine Adjuvant Discovery" Immuno 4, no. 4: 325-343. https://doi.org/10.3390/immuno4040021

APA Style

Fan, J., Toth, I., & Stephenson, R. J. (2024). Self-Assembling Peptides for Vaccine Adjuvant Discovery. Immuno, 4(4), 325-343. https://doi.org/10.3390/immuno4040021

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