Protein-based Subunit Nanovaccine: History
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Subjects: Nanoscience & Nanotechnology | Biochemistry & Molecular Biology
Contributor:
Lantian Lu
,
Mariusz Skwarczynski
,
Istvan Toth

Protein-based subunit nanovaccines are typically composed of native or altered protein antigens that can self-assemble into nanoparticles, or antigens associated with nanoparticles through covalent or noncovalent interactions. Characteristically, nanovaccines are 1 to 1000 nm in size which generally facilitates the induction of stronger immune responses.

  • Nanoparticles
  • Conjugates
  • Nanovaccines
  • Subunit vaccines
  • Protein vaccines

1. Introduction

Traditional whole-pathogen vaccines utilize whole microorganisms, such as viruses and bacteria, which may be live-attenuated or killed. The utility of vaccines that contain living pathogenic microorganisms is constrained by the requirement for refrigerated transport to preserve potency, and the chance that the pathogens could revert to their virulent forms under particular conditions[1]. Inactivated vaccines, based on killed pathogens, do not usually require refrigeration and are transported in dried forms; however, these vaccines induce weaker immune responses and booster doses may be needed to maintain immune response potency[2]. Unfortunately, traditional whole-pathogen vaccines may induce extensive inflammation, allergies, and autoimmune responses. The drawbacks of traditional vaccines have limited their applications[3]. Albeit, traditional vaccines are still widely used in veterinary science as the safety criteria for veterinary vaccines are far less strict compared to those implemented for human use[4].

Subunit vaccines contain purified or recombinant components derived from a pathogen, such as polysaccharides, peptides, or proteins that have antigenic properties[5][6]. In comparison to their whole-pathogen counterparts, subunit vaccines cause minimal adverse effects, do not require complex storage or transport conditions, and have large-scale manufacturing potential[7][8][9]. However, subunit vaccines, or more precisely subunit antigens, are often unable to trigger a strong immune response and, therefore, require the application of molecular adjuvants or delivery systems to boost immunity[10][11][12][13]. Of the various adjuvants and delivery systems in development over the past few decades, nanoparticles have been extensively investigated for enhancing the efficacy of subunit vaccines.

Nanoparticles (NPs) resemble the size of natural pathogens, such as viruses and nanobacteria, making them easily recognizable by immune cells; especially antigen-presenting cells (APCs). APCs are part of innate immunity and serve as the crucial linker/activator that triggers adaptive immune responses. Although some amphipathic proteins (e.g., ferritins) or peptides may self-assemble into NPs by themselves, most need to be associated with nanomaterials through covalent or noncovalent interactions to form NPs. Peptide antigens can be associated with protein carriers that have self-assembly properties to form protein-based subunit nanovaccines; while protein antigens can be associated with NPs, including lipid NPs, polymeric NPs, protein NPs, or inorganic NPs, to form protein-based subunit nanovaccine.

Covalent linkage between an antigen and a nanoparticulate delivery system is normally stronger than noncovalent linkage. Consequently, covalently linked systems are more stable under complex in vivo conditions, and conjugation techniques are often applied to produce nanovaccines (Figure 1)[14]. In some cases, where proteins function as nanocarriers, recombinant protein expression can be applied to express fused proteins to achieve covalent linkage.

Figure 1. Methods for protein nanoconjugate formation. (a) Protein antigens are conjugated to self-assembling monomers; the conjugates then self-assemble into protein nanoconjugates. (b) Peptide antigens are conjugated to protein monomers; the conjugates then self-assemble into protein nanoconjugates. (c) Protein antigens are conjugated to the surface of nanoparticles (NPs) to form protein nanoconjugates. (d) Peptide antigens are conjugated to the surface of NPs (for example, lipoprotein NPs) to form protein nanoconjugates. Drawing created with Biorender.com.

2. Preparation of Protein Nanovaccines

A wide variety of compositions have been investigated to produce protein-based subunit nanovaccines. Depending on the carriers and immunogens, such vaccines can be divided into protein carrier-based, lipid-based, polymer-based and inorganic particle-based nanovaccines[14][15].

2.1 Protein carrier-based nanovaccines

Virus-like particles (VLPs) are one of the most successful subclasses of protein carrier-based nanovaccines developed to date. VLPs are made up of viral proteins that have the ability to self-assemble into nanoscale particles. Several vaccines based on VLPs targeting human papilloma virus, hepatitis B virus, and malaria have been approved by the FDA, including Gardasil®, Gardasil9®, Cervarix®, Sci-B-VacTM, and MosquirixTM[16]. These proteins not only function as immunogens and carriers, but can also be fused with a variety of non-viral epitopes to induce desired immune responses.

Non-viral proteins have also been reported to have the ability to self-assemble. Cage-like proteins, such as E2 protein derived from the pyruvate dehydrogenase complex of Bacillus stearothermophilus, can self-assemble into 25 nm particles consisting of 60 identical monomers[17]. Chemical methods have been applied to conjugate different antigens onto the surface of E2 protein to obtain protein subunit nanovaccines[17][18][19]. The produced nanoparticles co-delivered antigens and CpG molecules eventually elicited stronger antitumor immune responses compared to the antigens administered with CpG, providing the rationale of using E2 as a protein carrier for vaccine development. Vault proteins isolated from the cytoplasm of eukaryotic cells can also self-assemble into a cage-like barrel-shaped structure (30/60 nm)[20]. Several antigens have been fused with vaults to boost antigen-specific immune responses without the need for an additional adjuvant[21][22][23][24]. Apart from spherical protein carriers, protein carriers with a variety of other morphologies, such as nanofiber and nanodisc, have also been investigated to formulate protein nanovaccines[25][26].

2.2 Lipid-based nanovaccines

Lipidic delivery systems, especially liposomes and lipid NPs, have been extensively used in clinics to combat cancer and infectious diseases[27][28][29]. Liposomes have an aqueous core that is trapped by single or multiple bilayers consisting of natural or synthetic lipids[30]. Although antigens are typically delivered by liposomes in encapsulated form[31], it has been repeatedly demonstrated that covalent linkage of antigens and liposomes, referred to as antigen anchorage onto liposomes, can induce more robust immune responses compared to antigens alone or antigens associated with liposomes through noncovalent interactions[32][33][34]. For example, lipidated and non-lipidated Group A Streptococcus M-protein-derived antigens were formulated into liposomes for intranasal vaccine delivery[34]. Liposomes with covalently anchored antigen (lipidated) elicited a stronger humoral response by producing higher titers of antigen-specific IgG in comparison to the antigen (non-lipidated) encapsulated in liposomes.

2.3 Polymer-based protein nanovaccines

Like lipidic NPs, polymeric NPs are also popular as nanovaccine delivery systems. In many cases, antigens have been encapsulated within the core of polymer NPs, or associated with polymer NPs through electrostatic interactions by opposite charges[35][36][37]. However, as discussed previously, such noncovalent interactions are generally weaker than covalent linkages. Chemical methods have been applied to conjugate a variety of protein antigens with polymeric material, such as poly(glutamic acid), N-trimethylaminoethylmethacrylate chitosan, carboxylated polystyrene, and pluronic-stabilized poly(propylene sulfide) to obtain protein nanovaccines[38][39][40][41]. These polymer-conjugated protein vaccines elicited stronger immune responses against different antigens, in comparison to antigens alone or antigens delivered with polymeric material in physical mixture form.

2.4 Inorganic-based nanovaccines

Inorganic nanoscale particles can also be associated with vaccine components to elevate immune responses. Metallic NPs, especially gold NPs, have been recognized as promising vaccine carriers due to their relatively high biocompatibility, easily controllable size range, and high surface area. Protein antigens have usually been complexed with gold NPs via electrostatic interactions or metal chelating to obtain protein nanovaccines[42][43][44][45][46]; however, covalent linkages can also be formed when gold nanoparticles are functionalized with particular moieties, such as carboxyl groups, through the reaction between sulfur and gold[47][48]. Antigens conjugated to gold nanoparticles were reported to generate higher IgG titers compared to antigens alone. Non-metallic inorganic NPs, such as mesoporous silica NPs, have also been reported to be efficient carriers for the delivery of protein antigens [49].

3. Future Perspective

Subunit vaccines, especially protein-based vaccines, can induce both cellular and humoral responses with the help of an appropriate adjuvant or delivery system. Once produced as nanostructures, protein-based subunit vaccines can elicit stronger immune responses compared to soluble antigens alone. While it might be easier and more cost-efficient to associate these nanocarriers with antigens via noncovalent interactions, such as physical encapsulation or electrostatic interactions, covalent linkage can improve antigen delivery into the APCs, thereby eliciting a stronger and more specific immune response. With advances in nanotechnology, as well as biological and chemical engineering technologies, it is believed that protein-based subunit nanovaccines will help satisfy the unmet demands of preventing and controlling different infectious diseases in the near future.

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