Transient pain and long-term gain: adjuvant dose directs immune memory
Pabitra B. Pal, Smita S. Iyer
Pabitra B. Pal, Smita S. Iyer
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e190524. https://doi.org/10.1172/JCI190524.
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Commentary

Transient pain and long-term gain: adjuvant dose directs immune memory

Abstract

Vaccine hesitancy is often fueled by fears of side effects; however, most reactions result from innate immune activation and cytokine production, which are required for lasting immunity. For effective vaccines against HIV, innate activation is essential for differentiation of CD4+ T cells into T follicular helper cells (TFH), which guide rare B cells to mature into long-lived plasma cells that produce durable neutralizing antibodies (nAbs). In this issue of the JCI, Parham Ramezani-Rad et al. show that higher doses of saponin QS-21–MPLA nanoparticle (SMNP) adjuvant, combined with BG505 MD39 envelope (Env) protein, enhanced cytokine responses, drove stronger Env-specific TFH responses in blood, and increased Env-specific bone marrow plasma cells compared with lower doses. While tier 2 nAbs were sustained at memory in only a subset of animals, predominantly at the highest adjuvant dose, these findings highlight transient reactogenicity as an essential mechanism — not a flaw — for building durable immune memory.

Authors

Pabitra B. Pal, Smita S. Iyer

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Figure 1

Vaccine adjuvants have evolved since 1930 and now include saponin and MPLA nanoparticles (SMNPs).

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Vaccine adjuvants have evolved since 1930 and now include saponin and MP...
(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.