An adjuvant, derived from the Latin word adjuvare meaning 'to help,' is a substance added to a vaccine to enhance the immune response to a co-administered antigen. Historically, adjuvants were discovered empirically, but advancements in immunology have allowed for a more rational classification system. In modern pharmacology, a common classification is based on the adjuvant's primary mechanism of action, separating them into two main categories: delivery systems and immune potentiators. Some adjuvants, known as combined systems, even utilize components from both classes for a synergistic effect.
Delivery Systems (Particulate Adjuvants)
Delivery systems, also known as particulate adjuvants, primarily work by acting as a vehicle to transport and present antigens to the immune system in a highly efficient manner. They are designed to enhance antigen uptake by antigen-presenting cells (APCs) like dendritic cells and macrophages. A traditional mechanism often associated with this class is the 'depot effect,' where the adjuvant traps the antigen at the injection site, leading to its slow, sustained release over time. However, newer research suggests that the depot effect might not be the sole or most important mechanism for all delivery systems, with some being rapidly transported to the lymph nodes.
Examples of Delivery Systems
- Aluminum salts (Alum): The most widely used adjuvant for decades, alum adsorbs antigens to its surface, making them particulate and more easily recognized by APCs. Alum is a component in many common human vaccines.
- Emulsion adjuvants: These are composed of two immiscible liquids mixed together, such as oil-in-water emulsions (e.g., MF59, AS03). They facilitate antigen uptake, induce cellular recruitment, and enhance the inflammatory environment at the injection site. MF59, for instance, has been used in influenza vaccines for older adults.
- Microparticles and nanoparticles: These biodegradable and biocompatible polymeric particles, like poly(lactic-coglycolic acid) (PLGA), can encapsulate antigens for controlled release and enhanced uptake by APCs.
- Liposomes: Lipid-based nanoparticles that can encapsulate antigens, protecting them from degradation and promoting their uptake and presentation by APCs.
Immune Potentiators
Immune potentiators are a class of adjuvants that directly stimulate specific innate immune receptors, known as pathogen recognition receptors (PRRs), on immune cells. This targeted activation mimics the signals the body would recognize during a natural infection, leading to the rapid and specific maturation of APCs. Unlike delivery systems, which are largely antigen carriers, immune potentiators provide the 'danger signal' that tells the immune system to initiate a strong and tailored adaptive response.
Examples of Immune Potentiators
- TLR agonists: These adjuvants activate Toll-like receptors (TLRs) located on the surface or within the endosomes of immune cells. For example, monophosphoryl lipid A (MPLA), a detoxified derivative of bacterial lipopolysaccharide (LPS), is a TLR4 agonist that is part of adjuvants like AS04. CpG oligonucleotides mimic bacterial DNA and activate TLR9, as seen in the Heplisav-B vaccine.
- Saponins: Derived from plants like the soapbark tree (Quillaja saponaria), saponins are detergent-like molecules that can induce inflammation and enhance antigen presentation. The saponin QS-21 is a component of the AS01 adjuvant system.
- Nucleotide-binding oligomerization domain (NOD) agonists: These target cytosolic receptors within immune cells. Muramyl dipeptide (MDP), derived from bacterial cell walls, is one such agonist.
Comparison of Adjuvant Classes
Understanding the distinction between these two primary classes is crucial for developing and tailoring vaccines for different immunological goals.
| Feature | Delivery Systems (Particulate) | Immune Potentiators |
|---|---|---|
| Primary Mechanism | Antigen presentation & Depot effect; enhances APC uptake | Direct activation of innate immune receptors (e.g., TLRs) |
| Key Function | Prolongs antigen availability; improves antigen recognition | Provides inflammatory signals; matures APCs |
| Example Adjuvants | Aluminum salts (alum), oil-in-water emulsions (MF59, AS03), microparticles | MPLA, CpG oligonucleotides, saponins (QS-21) |
| Immune Response Type | Often promotes a Th2-biased (humoral, antibody-centric) response | Can be designed to promote Th1-biased (cellular) or mixed responses |
| Inflammatory Effect | Indirectly through localized cell damage and recruitment | Directly via specific receptor signaling cascades |
| Combinations | Often used as the delivery component in combination adjuvants | Frequently combined with delivery systems for synergistic effects |
Combined Adjuvant Systems
The trend in modern vaccinology is to combine different types of adjuvants to harness their synergistic effects and create a more targeted, potent, and long-lasting immune response. These are referred to as 'Adjuvant Systems' (AS).
A prime example is AS04, which consists of the TLR4 agonist MPL adsorbed onto an aluminum salt. This combination leverages the depot effect of alum while adding the potent immunostimulatory properties of MPL, leading to an improved Th1-biased response compared to alum alone. AS01 is another advanced example, combining MPL and the saponin QS-21 within a liposomal formulation. This system has been shown to be highly effective, such as in the shingles vaccine Shingrix.
Conclusion
In summary, the two principal classes of pharmacological adjuvants, delivery systems and immune potentiators, represent different yet complementary strategies for enhancing vaccine efficacy. Delivery systems, like aluminum salts and emulsions, ensure efficient antigen presentation by concentrating and carrying the antigen to the immune system. Immune potentiators, such as TLR agonists and saponins, actively trigger the innate immune system to create the necessary inflammatory signals for a robust adaptive response. By understanding the distinct mechanisms of these two classes, and by combining them into powerful adjuvant systems like AS01 and AS04, scientists can design next-generation vaccines that are more effective, durable, and tailored to specific diseases. This ongoing evolution in adjuvant research promises to address current vaccine challenges and provide protection against emerging infectious diseases.
