The recent advances in vaccine adjuvants

Abstract

Vaccine adjuvants, as key components in enhancing vaccine immunogenicity, play a vital role in modern vaccinology. This review systematically examines the historical evolution and mechanisms of vaccine adjuvants, with particular emphasis on innovative advancements in aluminum-based adjuvants, emulsion-based adjuvants, and nucleic acid adjuvants (e.g., CpG oligonucleotides). Specifically, aluminum adjuvants enhance immune responses through particle formation/antigen adsorption, inflammatory cascade activation, and T-cell stimulation. Emulsion adjuvants amplify immunogenicity via antigen depot effects and localized inflammation, while nucleic acid adjuvants like CpG oligonucleotides directly activate B cells and dendritic cells to promote Th1-type immune responses and memory T-cell generation. The article further explores the prospective applications of these novel adjuvants in combating emerging pathogens (including influenza and SARS-CoV-2), particularly highlighting their significance in improving vaccine potency and durability. Moreover, this review underscores the critical importance of adjuvant development in next-generation vaccine design and provides theoretical foundations for creating safer, effective adjuvant.

Keywords: adjuvants; combinatorial adjuvant strategies; delivery systems; immunostimulants; vaccine.

Figure 1

Timeline of major events in the research history of vaccine adjuvants. Since the first use of aluminum salt adjuvants in diphtheria vaccines in 1926, adjuvant technology has gradually evolved (7). In 1940, the invention of Freund’s adjuvant provided a new direction for enhancing immune responses in vaccines (7). In 1956, the discovery of the adjuvant activity of lipopolysaccharide (LPS) endotoxins further expanded the range of available adjuvants. In 1997, the application of the MF59 adjuvant in the Fluad influenza vaccine marked the significant role of adjuvants in influenza prevention and treatment (7). In 2005, the AS04 adjuvant was first used in HBV and HPV vaccines (Fendrix and Cervarix) (8). In 2009, the AS03 adjuvant was used in the pandemic influenza vaccine Pandemrix (9). In 2017, the CpG-1018 and AS01 adjuvants were applied to the HBV vaccine (Heplisav-B) and malaria and shingles vaccines (Mosquirix and Shingrix), respectively (10, 11). In 2020, Pfizer’s BNT162b2 vaccine (Comirnaty) and Moderna’s mRNA-1273 vaccine (Spikevax) were approved, making a significant contribution to the fight against COVID-19. In 2021, the world’s first malaria vaccine RTS,S/AS01 began large-scale use, further proving the role of adjuvants in enhancing vaccine efficacy (12). This timeline illustrates the continuous innovation and breakthroughs of adjuvants in the field of vaccines.

Figure 2

The action mechanism of aluminum adjuvants. Aluminum adjuvants form microparticles by adsorbing soluble antigens, which promotes the phagocytosis of these antigens by APCs. The phagocytosed aluminum-adjuvant-antigen complexes indirectly promote the production of reactive oxygen species (ROS) (13), activate the release of cathepsin B in the lysosome, triggering the activation of the NLRP3 inflammasome and stimulating the production of IL-1β and IL-18, which play a role in regulating immune responses. At the same time, aluminum adjuvants stimulate the activation and differentiation of CD4⁺ T cells, increasing the levels of IgG1 and IgE. These cytokines and immune factors are essential for effective antibody-mediated immune protection. Additionally, dendritic cells can recruit and deposit antigen-adjuvant-antibody complexes through the CD35 receptor (31), further enhancing receptor signaling on both B cells and dendritic cells, thereby promoting immune effector functions.

Figure 3

The action mechanism of emulsion adjuvants. The adjuvant-antigen complex is taken up and processed by APCs, where it is recognized by MHC II molecules and presented to CD4⁺ T cells, initiating a specific immune response. Activated Th1 cells promote the activation of macrophages and NK cells, thereby enhancing cell-mediated immunity. Meanwhile, Th2 cells promote the differentiation of B cells into plasma cells and memory B cells, boosting antibody production and enhancing humoral immunity. Furthermore, adjuvants activate signaling pathways such as NF-κB, stimulating APCs to secrete chemokines, which attract additional immune cells (e.g., monocytes and DCs) to the site of local immune responses, further strengthening the intensity and persistence of the immune reaction.

Figure 4

The immune activation mechanisms by TLR agonists. TLR2 can form heterodimers with TLR1 or TLR6 (TLR1/2 or TLR2/6), recognizing lipopeptides and lipoteichoic acid, among other ligands. Upon activation, TLR2 recruits the adaptor protein MyD88, initiating downstream signaling pathways, including NF-κB and the MAPK family (ERK, JNK, p38), which leads to the induction of IL-12 and IL-10 expression (72, 73). TLR4 recognizes LPS and forms the TLR4/MD2/LPS complex with the bridging protein myeloid differentiation factor 2 (MD2). It activates the MyD88-dependent pathway, which in turn activates JNK, ERK1/2, p38, and the transcription factor NF-κB, inducing the expression of IL-1β and IL-12. Additionally, TLR4 also signals through the TRIF-dependent pathway, activating interferon regulatory factor 3 (IRF3) to promote the production of type I interferons (74, 75). TLR5 activates upon recognizing flagellin and similarly induces inflammation via the MyD88-dependent pathway (76). TLR7/8 and TLR9, located in endosomes, recognize ssRNA and CpG DNA, respectively. Through their TIR domains, they recruit MyD88, activating the NF-κB and MAPK (such as JNK and p38) pathways, leading to the expression of pro-inflammatory cytokines (such as IL-1β and IL-12). Moreover, TLR7/8 and TLR9 also activate interferon regulatory factor 7 (IRF7) through TRAF3, promoting the production of type I interferons (–79). TLR3 recognizes dsRNA and signals through TRIF, recruiting IRF3 to induce the production of type I interferons. These TLRs play important roles in immune responses through their specific signaling pathways (80).