Classification of Lipid-Based Vaccine Adjuvants

Vaccine adjuvants refer to a class of substances that can non-specifically change or enhance the body's specific immune response to antigens and play an auxiliary role. Adjuvants can induce the body to produce long-term and efficient specific immune responses, improve the body's protective capabilities, and at the same time reduce the dosage of immune substances and reduce the cost of vaccine production. Generally speaking, traditional live attenuated vaccines and whole cell vaccines do not need to add adjuvants because their own ingredients have adjuvant properties. The immunogenicity of inactivated viruses and recombinant proteins against causes is usually weak, so adjuvants are often used to enhance and regulate the immunogenicity of antigens without increasing side effects.

What Can We Offer for Lipid Adjuvant Research?

• Lipid Adjuvants
• Lipid PEG
• DSPE PEG
• Lipid Nanoparticles Development
• Liposome Encapsulation Services
• Lipid Adjuvant Development
• Lipid Formulation Development
• Lipid & Vaccine Delivery Solutions

Liposome Adjuvant

Liposomes are spheres composed of non-immunogenic, non-toxic and biodegradable phospholipids from natural products that can encapsulate antigens. It can be used as an antigen delivery adjuvant and as a vehicle for vaccine delivery. A key advantage of liposomes as a vaccine carrier system is their versatility and plasticity. Taking advantage of their chemical properties, water-soluble antigens (proteins, peptides, nucleic acids, carbohydrates, haptens) are embedded in the aqueous internal space of liposomes, while lipophilic compounds (lipopeptides, antigens, adjuvants, linker molecules) is embedded in the lipid bilayer. At the same time, antigens or other adjuvants can be attached to the liposome surface through adsorption or stable chemical linkages. The DNA vaccine is encapsulated in liposomes, which can more effectively pass through the cell membrane and be expressed inside the cells. The liposomes play a protective and sustained-release role in this process. Liposomes can be modified by immunostimulatory molecules and targeting molecules and participate in the immune process as a multifunctional vaccine adjuvant delivery system. They can target immune cells and even organelles, produce lysosomal escape, and promote the cross-expression of antibodies. This greatly improves the immune effect of the vaccine.

Fig. 1. Liposomes used as a vaccine adjuvant-delivery system (Journal of Controlled Release. 2019, (303): 130-150).

However, as an adjuvant, liposomes also have some shortcomings. For example, unsaturated fatty acids in phospholipids are gradually oxidized during storage. Liposomes are also prone to fusion, which can lead to the release of encapsulated antigens during the process of mutual fusion. At the same time, the preparation of liposomes is more technical and costly, which may cause pain symptoms at the injection site. At present, through continuous research on liposomes, several new liposomes have been designed, such as ultra-deformable vesicles (transfersome), double-layer cross-linked multi-layer vesicles and solid core liposomes for vaccine delivery.

Lipopolysaccharide Vaccine Adjuvant

Lipopolysaccharide (LPS) is naturally present in the outer membrane of Gram-negative bacteria. It is a strong activator of the natural immune system and a key factor in causing adaptive immune responses after bacterial infection. Lipopolysaccharide and its derivatives can be added to antigen vaccines to act as immune enhancers, but natural lipopolysaccharides tend to increase the reactivity of vaccines and have certain endotoxin activity. It is therefore possible to modify the structure of lipopolysaccharide to reduce its toxicity while triggering the appropriate immune response required against a specific pathogen. Therefore, researchers conducted in-depth studies on its structure and properties and obtained monophosphate lipid A (MPL). In order to develop low-toxic lipid A adjuvants to enhance the immunostimulatory effect, a variety of MPL analogs have been developed and synthesized. The current application of MPL mainly focuses on AS series adjuvants with different delivery systems and newly developed MPL analogs or TLR4 agonists.

MPL Analogs Provided by BOC Sciences

Nanoadjuvant

Nanoadjuvants refer to particles or structures with nanometer dimensions that are used to enhance immune responses and improve vaccine effectiveness. One of the biological properties of nanoparticles is their easy uptake by a variety of cells. Since nanoparticles are comparable in dimension to microorganisms, they can be better engulfed by antigen-presenting cells and bring more antigens into cells, thereby enhancing the immune response caused by proteins and peptides. Nanoparticles can increase the size of small molecule antigens and modify their surfaces. In addition, certain types of nanoparticles themselves have stimulating effects on the immune system. Therefore, as an adjuvant for vaccines, nanoparticles can use their carrier properties to improve the phagocytosis of antigens by antigen-presenting cells. On the other hand, its effect on immune cells can be used to trigger the body's innate immune response and ultimately induce an effective specific immune response. Lipid nanoparticle adjuvants are the most common type of nanoadjuvants. It consists of one or more layers of lipid structures, forming particles in the micrometer to nanometer range. Lipid nanoparticles as adjuvants usually have the following characteristics:

• Efficient drug encapsulation ability: Lipid nanoparticle adjuvants can encapsulate water-soluble and fat-soluble drugs inside the particles to enhance the stability and solubility of the drugs.
• Good biocompatibility: Lipid nanoparticle adjuvants are recognized as lipid structures in the body, have good biocompatibility, and reduce immune reactions and toxicity.
• Controlled release characteristics: Polymer nanoparticle adjuvants can achieve controlled release of drugs by adjusting the structure and chemical and physical properties of the polymer, improving the efficacy and stability of the drug.
• Highly customized shell design: The shell of polymeric nanoparticle adjuvants can be surface modified by changing the ligands of the polymer or chemical reactions, thereby changing the bioactivity or targeting of the nanoparticles.
• Excellent optical and electronic properties: Metal nanoparticle adjuvants have unique optical and electronic properties and can be used in applications such as optical imaging, biosensing, and photothermal therapy.
• Targeted delivery: Through surface modification or functionalization, metal nanoparticle adjuvants can achieve specific recognition and targeted delivery of targets.

Currently, lipid adjuvants have been widely used in clinical practice. One of the best-known lipid adjuvants is MF59, an oil-in-water emulsion that has been used in several commercial vaccines, including seasonal influenza vaccines. MF59 is typically composed of squalene, sorbitol trioleate, Tween 80, and citrate buffer. Mechanistically, it delivers antigens in an indirect manner, enhances the phagocytosis and pinocytosis of antigenic substances by antigen-presenting cells (APCs), and stimulates monocytes, macrophages, and granulocytes to secrete factors such as CCL2, CXCL8, CCL3, and CCL4, and promote the differentiation of monocytes into DCs. Another commonly used lipid adjuvant is AS03, which has been used in vaccines such as H1N1 influenza vaccine. AS03 is an oil-in-water emulsifier containing α-tocopherol, squalene, and Tween 80. It promotes the recruitment of monocytes and granulocytes, and antigen-presenting cells increase the secretion of cytokines (CCL2, CCL3, IL-6, CSF3, and CXCLD), thereby enhancing antigen-specific adaptive immune responses.

Reference

1. Wang, N. et al. Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization. Journal of Controlled Release. 2019, (303): 130-150.