In a recent review published in the Signal Transduction and Targeted Therapy Journal, a group of authors summarized adjuvant mechanisms, characteristics, and applications, seeking to overcome current vaccine limitations and provide valuable insights for future research and development.
Study: Vaccine adjuvants: mechanisms and platforms. Image Credit: TelnovOleksii/Shutterstock.com
Background
Adjuvants are components that enhance vaccine effectiveness by boosting immune responses when combined with vaccine antigens. They can be synthetic compounds or natural extracts. Early experiments in the 1920s demonstrated the adjuvant effects of aluminum salts and later water-in-oil emulsions.
Despite previous limitations, several new adjuvants were licensed for human vaccines, broadening options.
Adjuvants work by activating innate immune cells and pattern recognition receptors, leading to enhanced adaptive immune responses. However, due to complex mechanisms and broad definitions, understanding remains limited.
Adjuvants: mechanisms
Adjuvants play a crucial role in vaccines by enhancing immunity through various mechanisms. For example, immunostimulants, a type of adjuvant, activate antigen-presenting cells (APCs) by interacting with specific receptors such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), or their mimics.
This activation increases innate immune responses, APC maturation, antigen presentation, and co-stimulatory signals, resulting in robust adaptive immune responses.
One important pathway immunostimulants target is the Toll-like receptors (TLRs) on APCs. TLR agonists as adjuvants activate these receptors, leading to enhanced antigen presentation, co-stimulatory signals, and cytokine expression, ultimately strengthening adaptive immune responses.
Different immunostimulants activate distinct TLRs, resulting in diverse adaptive immune outcomes.
Another targeted pathway is the cyclic guanosine monophosphate-adenosine mono-phosphate synthase-stimulator of interferon genes(cGAS-STING) pathway, which coordinates innate and adaptive immunity. Immunostimulants targeting this pathway promote T helper 1 (Th1)-type cell polarization and cytotoxic T lymphocytes (CTLs) production, crucial for mounting effective immune responses.
Carbohydrate-based immunostimulants activate C-type lectin receptors (CLRs) on cell membranes, enhancing adaptive immune responses. Different CLRs trigger specific signaling pathways, influencing the polarization of naive T cells.
Immunostimulants also activate other pattern recognition receptors (PRRs) like retinoic acid-induced gene I (RIG-I), nucleotide-binding oligomerization domain 1 (NOD1), nucleotide-binding oligomerization domain 2 (NOD2) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), which offer potential targets to modulate specific immune responses.
Delivery systems: mechanisms
Delivery systems serve as carriers, boosting antigen uptake and presentation by APCs. They enable prolonged antigen availability through sustained release, improving immune responses. Targeting APCs, they mimic pathogen characteristics, enhancing antigen recognition. Directly binding to APC receptors increases antigen uptake and cellular immunity.
By optimizing size, charge, and hydrophilicity, they effectively traffic to lymph nodes, bolstering immune responses.
Furthermore, they promote antigen cross-presentation through the proton sponge effect, membrane destabilization, and photochemical internalization, enhancing CD8+ T cell-mediated immunity for viral and cancer vaccination. These mechanisms amplify antigen signals and revolutionize vaccine development.
Classical adjuvant platforms
Classical adjuvants significantly boost vaccine effectiveness. Aluminum, MF59, Adjuvant System (AS) 01, AS03, AS04, and CpG oligodeoxynucleotide (CpG ODN) 1018 are prime examples.
Aluminum adjuvants enhance immune responses by steadily releasing antigens and activating innate immune pathways, although their efficacy in inducing cellular immunity is under research.
Emulsion adjuvants, such as MF59 and AS03, slowly release antigens, stimulate innate immune cells, and mainly trigger Th2-biased responses. TLR agonist molecule-based adjuvants, AS04 (TLR4 agonist with aluminum) and CpG ODN 1018 (TLR9 agonist), elicit strong Th1 and cellular responses, enhancing vaccine efficacy.
AS01, a liposomal system with monophosphoryl lipid A (MPLA) and Quillaja Saponaria (QS)-21, induces a Th1-predominant response, improving malaria, zoster, and potential tuberculosis vaccines.
Adjuvant platforms under research
Numerous immunostimulant platforms are being explored as vaccine adjuvants to enhance effectiveness. One approach involves synthetic double-stranded ribonucleic acids (dsRNAs) targeting TLR3 and melanoma differentiation-associated gene 5 (MDA5), promoting Th1-biased immune responses and CTLs.
Polyinosinic: polycytidylic acid (Poly-I:C) and Polyinosinic-Polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) show promise in cancer vaccines. Still, careful delivery systems are vital to minimize side effects.
Glucopyranosyl lipid A (GLA) and its derivatives activate TLR4 on APCs, inducing Th1-type immune responses. GLA -stable emulsion (GLA-SE) boosts protective immune responses in influenza, tuberculosis, and other vaccines. Imidazoquinolines activate TLR7/8, enhancing immune responses in cancer and viral vaccines.
Synthetic DNA molecules (CPG ODNs) acting as TLR9 agonists also show promise in various vaccines. Cyclic dinucleotides (CDNs) activate the cGAS-STING pathway, leading to robust Th1-type and CTL responses. Natural and synthetic CDNs hold potential as vaccine adjuvants when encapsulated in nanoparticles.
Further, metabolic adjuvants, such as lipophilic statins and bisphosphonates, target the mevalonate pathway, prolonging antigen retention and enhancing antigen presentation. Inhibition of mammalian targets of rapamycin (mTOR) complex and activation of general control nonderepressible 2 (GCN2) also show promise as potential adjuvant targets.
Manganese (Mn) and its derivatives also show potential as adjuvants by activating the cGAS-STING pathway, inducing type I interferons, and enhancing antigen presentation and immune responses.
Mn-based nanoadjuvants, like manganese jelly (MnJ), demonstrate promising vaccine efficacy, making them attractive targets for novel adjuvant development. These diverse platforms help advance vaccine development and efficacy.
Delivery systems under research
Various vaccine delivery systems based on engineering materials have emerged in recent years, including water-in-oil nanoemulsions, lipid nanoparticles (LNPs), polymer nanoparticles, virus-like particles (VLPs), caged protein nanoparticles, and inorganic nanomaterials.
These platforms possess distinct mechanisms of action and physicochemical properties, influencing vaccination efficacy. Notably, water-in-oil nanoemulsions Montanide ISA 51 and Montanide ISA 720 are tested in clinical trials as adjuvants, enhancing antibody and CTLs production.
LNPs, such as Pfizer's BNT162b2 and Moderna's messenger RNA-1273 vaccines, have played a significant role in the fight against coronavirus disease-19 (COVID-19).
Other platforms like VLPs, caged protein nanoparticles, and inorganic nanomaterials show promising results in preclinical studies and clinical trials, indicating their potential as innovative vaccine adjuvants. However, safety concerns need further investigation for clinical translation.
Conclusions
To sum up, adjuvants are vital components that enhance vaccine effectiveness by stimulating immune responses. Immunostimulants targeting various PRRs, play a key role in promoting adaptive immunity.
Novel adjuvant platforms under investigation offer promising prospects for overcoming current vaccine limitations and improving vaccine efficacy.
Continued research and development in this field will be essential for developing safer and more effective vaccines to combat infectious diseases and improve global health.
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