Application of Nanomaterials and Biomaterials in Nanovaccinology

Review Article

Austin J Biosens & Bioelectron. 2023; 8(2): 1047.

Application of Nanomaterials and Biomaterials in Nanovaccinology

Naghmeh Hadidi1*; Mojgan Sheikhpour2*; Maryam Mohebbi3; Seyed Mehdi Sadat4

1Department of Clinical Research and EM Microscope, Pasteur Institute of Iran, Tehran, Iran

2Depetment of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran

3Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

4Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran

*Corresponding author: Naghmeh Hadidi Department of Clinical Research and EM Microscope, Pasteur Institute of Iran, Tehran, Iran; Mojgan Sheikhpour, Depetment of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran. Tel: +98-9122054655, +98 21 64112269; +98-9122969712, +98 21 64112285 Email: hadidi@gmail.com; n_hadidi@pasteur.ac.ir; Iranmshaikhpoor@gmail.com; m_sheikhpour@pasteur.ac.ir

Received: August 30, 2023 Accepted: September 27, 2023 Published: October 04, 2023

Abstract

Over the years, the concept of vaccination has encountered great evolution. Most vaccines have been formulated in a way that mimics pathogens in order to activate immune cascades. However, vaccine development was never assumed as a simple task and it involves several studies to obtain detailed knowledge about antigen presentation and recognition by immune system. Nanovaccination has been proposed as one of the most successful break throughs and procurements in health promotion and diseases prevention. Nano vaccines can be classified into various groups based on shape, source, sizes, features and structural constriction. Therefore they are assumed to offer more opportunities and novel approaches to scientists and researches and address unmet needs in vaccine developments. Novel technologies in vaccinology mostly focus on safety-immunogenicity improvements, synergistic immunomodulation, in vivo stability, reduced toxicity and efficient delivery of stimulatory cues. Biomaterials and nano vaccines were proved as promising strategies with optimal safety and efficacy through controlling the release site and pattern for better adjustment of dosing and timing of vaccines and immunotherapies.

In this review, we have summarized future horizons and cutting-edge advances of biocompatible nano biomaterials-based platforms such as liposomes, nanoparticles, carbon based structures and membrane based vaccines. We also described the remaining challenges, limitations, and possible breakthroughs in nano vaccines’ formulation and biomaterials application in industrial scale.

Keywords: Vaccine; Carbon nanotubes; Nanotechnology; Biomaterials; Vaccinology

Introduction

Vaccine Strategies

Vaccine design generally consists of four main components: antigen, adjuvant, carrier, and delivery strategy. Antigens are foreign materials that can induce an immune response. Vaccines are categorized into four groups: live attenuated vaccine, inactivated vaccine, subunit vaccine (VLPs), and peptide vaccines based on an antigen-presenting approach. Adjuvants are stimulatory agents of vaccine formulation that exist as independent or conjugate entities and would boost the immune response to antigens. Nanoparticles are viral/non-viral Nano carriers applied to encapsulate or present antigens and/or adjuvants in live attenuated and inactivated vaccines. Adenoviral vectors, proteinaceous nanoparticles, and synthetic nanoparticles are the most common carriers for antigen delivery in vaccine formulations. Vaccines are usually administered through syringes, implants, and microneedle patches [1-10].

Contemporary vaccines would induce active immunization against complete or killed pathogens. This type of vaccine is perspective, specifically in SARS-CoV-2 vaccination. On the other hand, live attenuated (LAVs) and Inactivated Vaccines (IVs) are live a virulent viruses that normally induce immunity in single-dose administration. Nowadays, genetic code expansion has been applied to improve productivity and genetic stability of LAVs to be specifically applied in the production of SARS-CoV-2 vaccines. Inactivated Vaccines (IVs) are consisted of physically or chemically inactivated pathogens or antigen fragments. This type of vaccine is administered in multiple doses to induce sufficient immunity. IVs formulation must include adjuvants and are more stable than LAVs. However, both LAVs and IVs require a cold supply chain. The last vaccine type is called the viral vector vaccine. In this type of vaccine, genetically engineered mammalian viruses such as herpes simplex and non-replicating adenoviral vectors like Ad5-nCoV and ChAdOx1 are used [11-17].

Next Generation Vaccines

Nanotechnology and nanomaterials play important roles in the development of the next generation of vaccines and immune engineering. Nucleic acid-based (DNA and mRNA vaccines) and subunit vaccines are promising vaccine technologies. These groups are safer, more stable, and easier to scale up but have more potential in terms of risk and failure during clinical phases. Nucleic acid-based (DNA and mRNA vaccines) elicit cytotoxic T cells’ responses in addition to antibody production and T helper cells activation [18-20]. Inovio, Ethnos pharmaceuticals, and Symvivo are pharmaceutical companies running clinical trials on Covid-19 DNA vaccine candidates [21]. Meanwhile, Moderna and BioNTech-Pfizer-Fosun Pharma performed clinical trials on Covid-19 mRNA vaccine candidate. It should be noted that stability, mutagenesis, and antigen half-life are the main obstacles in the development and commercialization of nucleic acid-based vaccines. Nanotechnology has suggested some solutions for the above problems. Nanomaterials such as polymeric nanoparticles, cationic liposomes, nanoemulsions, carbon-based nanostructures, and dendrimers are supposed to facilitate nuclear translocation, antigen delivery, and trafficking to face more immune cells as well as improve formulation stability and scalability [19,22,23]. Protein nanoparticles or Virus-Like Particles (VLPs) are categorized as subunit vaccines. VLPs are stable, scalable, mono-dispersed formulations generated from antigenic subunits and biomaterials. VLPs might root from bacteriophages and mammalian, insect and plant viruses. VLPs are highly visible to immune cells and are defined as immune activators and amplifiers with non-infectious and adjuvant properties [24-30]. CanSino, AstraZeneca, Shenzhen Geno-Immune Medical Institute, Medicago-iBio’s COVID-19 vaccines, and Johnson & Jonson influenza virus vaccine Crucell are VLP vaccine candidates in the clinical development pipeline. Most of the above vaccine candidates are multivalent platforms that offer simultaneous delivery of antigen and adjuvant to lymph nodes’ Antigen-Presenting Cells (APCs) and long-acting immune stimulus. It also facilitates APCs antigen processing and antiviral antibody production by CD8+ and CD4+ T cells in MHC-I and MHC-II pathways [31-33].

Peptide-based vaccines represent the simplest platform in next generation vaccines. They are generally formulated as peptides and T cell /B cell epitopes plus suitable adjuvant or immune-informatics-derived-peptide–nanoparticle conjugates. The efficacy of Peptide-based vaccines is highly dependent on adjuvant and applied nanocarrier. For example, “albumin hitchhiking” is an emerging targeted hepatitis B virus trafficking strategy to lymph nodes’ dendritic cells and macrophages. Enhanced viral clearance and stronger humoral and cellular immune responses are pursued by antigen encapsulation and antigen surface presentation through this nanotechnology approach [34-36].

Vaccine Scalability and Manufacturing

Production cost, formulation, and scale-up of vaccine formulation are the main concerns in the development of novel, effective vaccines. The traditional manufacturing process of recombinant proteins using mammalian, bacterial, and yeast cells are still expensive and is susceptible to human contamination. Innovative manufacturing platforms are required to meet high demands during viral disease outbreaks. Plant-based expression systems are a promising production technology that was introduced during the 2014 ebola epidemic. Plant molecular farming is scalable, while fermentation-based technologies are highly sensitive to control parameters. Low production cost and safety are other advantages of molecular farming. Conventional vaccines utilize a cold supply chain, while new technologies of implants and microneedle patches exclude cold chain difficulties in product distribution and moderate to high feasibility for rapid global deployment of vaccines [37-40].

Nanomaterials Improve Vaccine Responses: Mechanisms and Mew Approaches

Nanomaterials and nanotechnology have been applied more specifically in the design and development of new vaccines against HIV (Human Immunodeficiency Virus), TB (Tuberculosis), and malaria. These three pathogens are listed by WHO (World Human Organization) among the top ten reasons for mortality in developing and low-income countries. This notification would highlight the importance of developing more efficient prophylactic strategies and more effective antigen delivery to key immune cells, including APCs, B cells, neutrophils, and macrophages [41-44]. Nano materials’ size, shape, blood circulation half-life, adjuvant properties, and complement activation potential are required during vaccine development. Antigen persistence through encapsulation or conjugation with nanostructures would enhance antigen immunogenicity. For example, Moon et al. designed ICMVs (Inter bilayer Cross-linked Multilamellar Vesicles) in which malaria antigen has been both encapsulated and conjugated to the vesicles’ surface in order to extend antigen persistence in lymph nodes [45]. Demento et al. also suggest long acting PLGA ovalbumin encapsulated PLGA nanoparticles would improve APCs' immune response and high-affinity antibody secretion from follicular helper T cells [46]. Long-acting formulation and cross-presentation of HIV, TB, and malaria antigens will potentiate cellular immune response by CD8+ if antigen fragments escape to the cytosol after lysosomal degradation of nanocarrier [47,48]. Nano materials’ physicochemical properties, such as charge, size, and flexibility, show a high impact on Lymph Nodes (LN) draining. Nanoparticles within the size range of 10-50 nm are the most suitable for LN draining. Large 50 nm nanoparticles are passively drained to LNs and are acquired by macrophages better [49-51]. Mucosal immune response and mucosal antigen delivery is an attractive field in HIV and TB vaccine design [52,53]. Mucosal mucin permeability and adhesion are also size and charge-dependent [54]. Average pore size cut-offs of 340 nm for vaginal mucus and 200 nm for respiratory mucus must be considered for appropriate antigen traverse [55]. Large (500-5000 nm) anionic nanoparticles are captured by macrophages, while small targeted (20-200 nm) nanoparticles are endocytosed by DCs (Dendritic Cells) [55-60]. C-Type lectin receptors expressed on Langerhans cells and DCs are highly suggested for targeted follicular dendritic cells that exist in LN [61-,62]. Nanomaterials might also improve adjuvant functionality, minimize their toxicity and decrease their dosing amount [63-65]. Moon et al. reported that lipid vesicles with encapsulated malaria antigen and MPLA, as an adjuvant, required adjuvant amount was reduced to 10 times less than free soluble malaria antigen-adjuvant (MPL4) and stronger induced humoral responses were achieved [66] (Figure 1). Lymph Node (LN) trafficking, persistency, controlled release pattern, APC targeting and mucosal targeting are main strategies for engineering nanomaterial vaccine delivery. Trafficking to lymph nodes is largely dependent on size, charge, hydrophobicity and flexibility. During mucosal targeting hydrophilic positively charged mucoadhesive particles create strong entanglment with mucin fiber of mucosal membrane and induce mucosal immunity. Persistency and controlled release patterns would prolongs antigen uptake through endosomal escape and cross presentation of the antigen on MHC I from reservoir systems at site of injections. Administration of anionic nanoparticles or introducing DEC-205 or B cell epitopes on nanoparticles surface would be another engineered strategy which is entitles APC targeting through Dendritic Cells (DCs) and macrophages.