Vaccine Drug Delivery Systems
Kartheek Siripurapu, Principal Scientist, Deva Holding A.S.
Vaccine drug delivery systems significantly contribute to vaccine technologies, ensuring the most effective delivery of vaccine antigens to the desired site of action to elicit an immune response. This review provides an overview of vaccine delivery systems that use different carriers, such as virus-like particles; virosomes; polymeric nanoparticles; lipid nanoparticles; inorganic nanoparticles; liposomes; and immunestimulating complexes (ISCOM) and nanoemulsions.
The key to successful vaccination is to administer and deliver vaccines in a way that evokes strong immune responses. Due to technological advancements and immunological perspectives, modern vaccine delivery relies on nanoparticle-based platform technologies. Nanotechnology application in vaccine drug delivery has led to significant progress in vaccine development. New vaccine delivery systems enhance immunogenicity and efficacy, overcoming the limitations of conventional vaccines. Apart from the formulation and delivery systems, dosage and route of administration also have an impact on the safety and efficacy of the vaccines. Vaccines can be administered by multiple routes, including intramuscular, subcutaneous, transdermal, oral inhalation, and nasal mucosa. Let’s look at the various vaccine delivery systems.
Virus-like particles and virosomes
Virus-like particles (VLPs) are nanostructures with self-assembling shells consisting of one or more structural proteins derived from the virus coat or envelope. The VLP mimics the form and size of their parent virus but is devoid of genetic material, making it incapable of infection or replication. It is highly immunogenic and is able to elicit both antibody- and cell-mediated immune responses. It ranges in size from 80 to 150 nm and possesses the ability to present multiple proteins to the immune system. The VLP membrane consists of viral phospholipids and glycoproteins; it has an empty core that transports antigens. Based on structure, VLPs are classified into enveloped and non-enveloped VLPs. Depending on the virus source, VLPs self-assemble to form a variety of shapes and structures. VLP vaccines are used to protect against the hepatitis B virus (HBV) and human papillomavirus (HPV) infections. The formulation of a vaccine consists of a vaccine vector, adjuvants, and excipients. Excipients such as buffers, stabilisers, and preservatives improve the physical and chemical stability of VLPs and prevent enzymatic degradation. Optimisation of buffer pH and ionic strength are important for formulating a stable, liquid VLP vaccine. Cryoprotectants like trehalose, sucrose, and glycerol improve the formulation stability. Freeze-drying or lyophilisation can enhance the shelf-life stability of VLPs. The majority of the commercial VLP vaccines are available in liquid suspension form.
Virosomes, which resemble liposomes, serve as vesicles for encapsulating DNA. Virosomes contain viral envelope proteins to fuse with target cells and subsequent DNA delivery into the cells. They act as a vaccine adjuvant, as a delivery vehicle for peptides, nucleic acids, and proteins, and as drug targeting. The virosome-mediated vaccine delivery system is used in the treatment against Ebola, hemorrhagic fever, and HIV.
Polymeric nanoparticles
Polymeric nanoparticles are solid colloidal particles within the size range of 1 to 1000 nm. They are made up of biodegradable and biocompatible polymers where active compounds can be entrapped or encapsulated in a carrier or surface-adsorbed onto the polymeric core. Based on morphology, nanoparticles are categorised into nanocapsules and nanospheres. Selection of the right polymer (either natural or synthetic) may enhance antigen stability, influence release kinetics, and elicit an immune response. Benefits of the polymerbased delivery system include its adjuvant effects, resistance to enzymatic and environmental degradation, and delayed release. Physiochemical properties, including size, shape, charge, and hydrophobicity, of polymeric nanoparticles have an effect on their delivery and uptake. Polymers are nontoxic, biocompatible, and biodegradable materials. Natural and synthetic polymers are the two types of polymers used in nanoparticles. Natural polymers such as alginate, chitosan, dextran, hyaluronic acid, and inulin are the most widely used. Synthetic polymeric nanoparticles have a slow biodegradation rate, entrap antigens for delivery, or sustain antigen release. Commonly used synthetic polymers include poly(lactic-co-glycolic acid) (PLGA) and poly(d,l-lactide-coglycolide) (PLG), which are known for their sustained release, ability to protect drugs or antigens from degradation, coencapsulation capabilities, and safety. Synthetic micelles can be synthesized from diblock or multiblock copolymers. Typical polymers used to form the hydrophilic shell of the micelles include polyethylene glycol (PEG) and polyethylene oxide (PEO).
Lipid nanoparticles (LNP)
The lipid nanoparticles have garnered tremendous interest as prospective delivery systems for various nucleic acid therapies, including oligonucleotides. LNPs deliver small molecules, siRNA drugs, and mRNA. LNPs came to the spotlight as a vital component in mRNA vaccines against COVID-19. LNPs protect the nucleic acid from enzymatic degradation until the delivery of nucleic acid to the target cell. LNPs have several advantages over viral vectors for gene therapy applications, including less immunogenicity, a large payload, and suitable methods for largescale production. The lipid nanocarriers can be categorised into liposomes, niosomes, solid lipid nanoparticles, and nanostructure lipid carriers. LNPs are typically spherical structures with an aqueous interior compartment and at least one lipid bilayer. Due to their structural characteristics, LNPs differ from conventional bilayered liposomes. Lipids are classified into cationic lipids, ionizable lipids, and other types of lipids. Cationic lipids have a catioinic polar head group. Cationic lipids such as DOTMA, DOPE, and DOTAP are used for mRNA delivery. Ionizable lipids remain neutral at physiological pH but protonated at low pH. Onpattro®, the first FDA-approved siRNA drug uses (6Z,9Z,28Z,31Z)- heptatriaconta-6,9,28,31 -tetraen19-yl-4-(dimethylamino) Butanoate (DLin-MC3-DMA). Other types of lipids include phospholipids (DSPC, DOPE), cholesterol, or polyethylene glycol-lipids. These lipids can improve nanoparticle stability, delivery efficacy, and enable efficient encapsulation. Cholesterol improves liposome membrane fluidity and rigidity and reduces drug leakage from the core. Cholesterol also affects the delivery efficacy and biodistribution of LNP. PEG-lipids, also known as PEGylated lipids, are composed of PEG esters bonded to a lipid moiety like DSPE or DMG. PEG-lipids affect particle stability, circulation half-life, nucleic acid encapsulation efficiency, and in vivo distribution.
Inorganic nanoparticles
Inorganic nanoparticles have unique physical properties, such as size-dependent optical, magnetic, electronic, and catalytic. Because of their smaller particle sizes, higher permeability, controlled tunability, high drug loading, and triggered release profile, inorganic nanoparticles are perfect for delivering antigens as vaccines. Size and shape of inorganic nanoparticles can affect vaccine delivery. Common inorganic nanoparticles include (a) those prepared from noble metals like gold and silver; (b) magnetic nanoparticles, which modify metallic (Iron, cobalt, nickel, silver) or metal oxide (Iron oxide, ferrites) nanoparticles using magnetic fields; and (c) fluorescent nanoparticles, which absorb and emit light, such as quantum dots, SiO2, etc. Diagnostics, bioimaging, and cancer therapies use inorganic nanoparticles.
Liposomes
Liposomes are spherical lipid vesicles with particle sizes ranging from 50 to 500 nm, composed of one or more lipid bilayers and an internal aqueous chamber. Due to their excellent biocompatibility and low immunogenicity, liposomes find widespread use in vaccine and adjuvant delivery. The composition of lipids, charge and size of liposomes, size distribution, entrapment, and localization of antigens or adjuvants can be optimised based on the desired vaccine characteristics. The internal aqueous volume of liposomes encapsulates water-soluble antigens such as proteins, peptides, nucleic acids, and carbohydrates. The lipid bilayer embeds or intercalates lipophilic/amphiphilic substances such as lipopeptides, glycolipids, adjuvants, etc. Commercial liposomal vaccines are available against malaria, influenza, hepatitis A viruses, and varicella zoster viruses. The availability of highgrade lipids and the emergence of new technologies for large-scale production have led to the progress of liposomes as delivery systems.
Immune-stimulating Complexes (ISCOM)
ISCOMs are open-cage-like complexes and a well-known type of adjuvant delivery system. Immune-stimulating saponins (Quil A or its purified components), cholesterol, and phospholipids combine with a vaccine antigen to form ISCOM. ISCOM as vaccine adjuvants exhibit strong immune-stimulating properties to elicit a stronger immune response and long-lasting protection. ISCOM has the ability to provoke mucosal and systemic immune responses to antigens after both mucosal and parenteral immunisation. The ISCOM matrix, an ISCOM particle without an immunogenic component, serves as a potent adjuvant.
Nanoemulsions
Nanoemulsions represent heterogeneous systems consisting of two immiscible liquids. Nanoemulsion is a thermodynamically unstable system, and globule size ranges from 50–300 nm in diameter. These dispersions are categorised into water-in-oil (W/O) or oil-in-water (O/W) emulsions. Nanoemulsions are used in vaccines as lipid-based adjuvants. The physicochemical stability (droplet/particle size, zeta potential, and surfactant concentration) of the nanoemulsion can influence its adjuvant efficacy and safety. MF59®, which contains 5% v/v of squalene in the oil phase, is one of the most widely used nanoemulsion-based adjuvants. Fluad and fluad quadrivalent influenza vaccines use MF-59. Other squalene-based nanoemulsions include the DETOX® adjuvant system, which contains monophospohoryl lipid A and squalene; ASO3®, which contains alpha-tocopherol and squalene; and AFO3®, which contains sorbitan oleate and polyoxyethylene cetostearyl ether as stabilizers.
Conclusion
This review discusses an array of vaccine delivery systems that enhance immunogenicity and efficacy. Nanoparticles encapsulate target proteins, peptides, antigens, or nucleic acids and deliver vaccine components that are helpful in the treatment of various infectious and immunological diseases. Despite significant progress in vaccine delivery, there are still many challenges. Higher developmental costs, inability to protect against new variants, lack of correlation between physicochemical properties of carriers and immune response outcomes, and incompatibility of delivery systems with diverse antigens are the main challenges. Tailoring delivery systems to specific target populations could enhance the vaccine efficacy and immunogenicity. Multidisciplinary research in nanotechnology, immunology, and pharmaceutical development will bring new perspectives in vaccine delivery systems in the near future.
References
1. Donaldson, B., Lateef, Z., Walker, G. F., Young, S. L., & Ward, V. K. (2018). Virus-like particle vaccines: immunology and formulation for clinical translation. Expert Review of Vaccines, 17(9), 833–849. https://doi.org/10.1080/14760584.2018.1516552
2. Bezbaruah, R., Chavda, V. P., Nongrang, L., Alom, S., Deka, K., Kalita, T., Ali, F., Bhattacharjee, B., & Vora, L. (2022). Nanoparticle-based delivery systems for vaccines. Vaccines, 10(11), 1946. https://doi.org/10.3390/vaccines10111946
3. Zielińska, A., Carreiró, F., Oliveira, A. M., Neves, A., Pires, B., Venkatesh, D. N., Durazzo, A., Lucarini, M., Eder, P., Silva, A. M., Santini, A., & Souto, E. B. (2020). Polymeric nanoparticles: Production, characterization, toxicology and ecotoxicology. Molecules (Basel, Switzerland), 25(16), 3731. https://doi.org/10.3390/molecules25163731
4. Grego, E. A., Siddoway, A. C., Uz, M., Liu, L., Christiansen, J. C., Ross, K. A., Kelly, S. M., Mallapragada, S. K., Wannemuehler, M. J., & Narasimhan, B. (2020). Polymeric nanoparticle-based vaccine adjuvants and delivery vehicles. In Current Topics in Microbiology and Immunology (pp. 29–76). Springer International Publishing.
5. Dhiman, N., Awasthi, R., Sharma, B., Kharkwal, H., & Kulkarni, G. T. (2021). Lipid Nanoparticles as Carriers for Bioactive Delivery. Frontiers in Chemistry, 9. https://doi.org/10.3389/fchem.2021.580118
6. Swetha, K., Kotla, N. G., Tunki, L., Jayaraj, A., Bhargava, S. K., Hu, H., Bonam, S. R., & Kurapati, R. (2023). Recent advances in the lipid nanoparticle-mediated delivery of mRNA vaccines. Vaccines, 11(3), 658. https://doi.org/10.3390/vaccines11030658
7. Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews. Materials, 6(12), 1078–1094. https://doi.org/10.1038/s41578-021-00358-0
8. Paul, W., & Sharma, C. P. (2020). Inorganic nanoparticles for targeted drug delivery. In Biointegration of Medical Implant Materials (pp. 333–373). Elsevier.
9. Nsairat, H., Khater, D., Sayed, U., Odeh, F., Al Bawab, A., & Alshaer, W. (2022). Liposomes: structure, composition, types, and clinical applications. Heliyon, 8(5), e09394. https://doi.org/10.1016/j.heliyon.2022.e09394
10. Tretiakova, D. S., & Vodovozova, E. L. (2022). Liposomes as adjuvants and vaccine delivery systems. Biochemistry (Moscow) Supplement. Series A, Membrane and Cell Biology, 16(1), 1–20. https://doi.org/10.1134/s1990747822020076
11. Immune stimulating complexes (ISCOMs). (n.d.). Creative-biolabs.com. Retrieved October 9, 2024, from https://www.creative-biolabs.com/vaccine/immune-stimulating-complexes-iscoms.htm
12. Filipić, B., Pantelić, I., Nikolić, I., Majhen, D., Stojić-Vukanić, Z., Savić, S., & Krajišnik, D. (2023). Nanoparticle-based adjuvants and delivery systems for modern vaccines. Vaccines, 11(7), 1172. https://doi.org/10.3390/vaccines11071172
Author Bio
Kartheek Siripurapu has 12 years of experience in the CMC arena of pharmaceuticals. He possesses expertise in the formulation and development of parenteral, ophthalmic, and oral drug products for global markets. He is currently leading a team in formulation development at Deva Holding, Turkey. Prior to Deva, he served in leading roles at Mylan Laboratories and Cipla, India.
