The immune system distinguishes self from non-self with remarkable precision, even down to single amino acids; but peptide and protein antigens alone do not elicit robust immune responses on their own, because they lack danger signals — pathogen-associated molecular patterns (PAMPs) — needed to activate pattern recognition receptors (PRRs) on innate immune cells (1, 2). These receptors initiate the signals required for T and B cell activation (3, 4). Adjuvants drive innate immune activation by engaging PRRs on antigen-presenting cells (APCs), such as dendritic cells, thereby enabling effective T and B cell responses (5–7). Subsequent CD4+ Th1 cell responses support memory CD8+ T cell development, while CD4+ T follicular helper (TFH) cells help B cells proliferate and mature in germinal centers (GCs) into memory B cells and long-lived, antibody-secreting plasma cells (8).

First introduced in the 1930s, aluminum salts (Alum) — including aluminum potassium sulfate, aluminum hydroxide, and aluminum phosphate — have enhanced antibody responses to diphtheria toxoid and remain cornerstone components of several licensed vaccines (9). In the 1940s, complete Freund’s adjuvant (CFA), an oil-in-water emulsion containing mycobacterial components, was developed. Although CFA is highly potent, toxicity limited its use to experimental autoimmunity models (10, 11). In 1997, the oil-in-water emulsion MF59 was licensed for influenza vaccines for older adults, offering a safer alternative (12, 13). The demand for effective adjuvants capable of eliciting immunity against challenging pathogens such as HIV drove the development of advanced systems, such as AS01, a lipid-based carrier designed to integrate multiple immunostimulatory molecules. AS01, used in the herpes zoster (shingles) vaccine for adults aged 50 and older (14), combines two components: monophosphoryl lipid A (MPLA), a TLR4 agonist that augments APC responses, including in B cells; and QS-21, a saponin that enhances antigen presentation by activating NLRP3 inflammasomes (15) (Figure 1).

Vaccine adjuvants have evolved since 1930 and now include saponin and MPLA nanoparticles (SMNPs). (A) The evolution of vaccine adjuvants started with aluminum salts as the first licensed adjuvant and has advanced to include systems such as SMNP — which integrates the TLR4 agonist MPLA and the saponin QS-21 and has cage-like nanoparticle structure — to amplify immune responses. (B) (i) SMNP engages the immune system by activating APCs via TLR4 and NLRP3 inflammasome pathways, leading to the release of inflammatory cytokines (e.g., IL-1β, IL-6), which drive innate immune responses and induce systemic effects such as fever. Mac, macrophage; DC, dendritic cell. (ii) These signals activate CD4+ T cells and B cells. (iii) Differentiation into Th1 cells supports CD8+ T cell responses for intracellular pathogen clearance and TFH that provide critical support for B cells in GCs. B cells differentiate into plasmablasts and GC B cells. (iv) B cells proliferate and undergo affinity maturation. (v) Long-lived memory B cells (MBC) and long-lived plasma cells (PC) that secrete antibodies contribute to durable immunity. Memory T cells support rapid recall responses.

Adjuvants such as army liposomal formulation Q (ALFQ), similar in composition to AS01, have shown stronger CD4+ TFH cell responses and memory antibody generation in macaques compared with MPLA-alum formulation (ALFA) (15, 16). Likewise, CAF01, a liposomal adjuvant combining cationic vesicles and trehalose dibehenate (TDB), a mincle receptor agonist, has been evaluated against MPL–plus–QS-21 formulations (17, 18), further highlighting the capacity of QS-21–based adjuvants to drive robust TFH responses and humoral immunity. In this issue of the JCI, Parham Ramezani-Rad et al. (19) tested the saponin (QS-21)–MPLA nanoparticle (SMNP) adjuvant system, building on the principles of AS01 by incorporating an immune-stimulating complex–like (ISCOM-like) structure. This design enhanced innate immune activation and optimized antigen delivery to lymph nodes, key factors that bolster effective GC responses and the production of durable antibodies (20).