The saponin monophosphoryl lipid A nanoparticle adjuvant induces dose-dependent HIV vaccine responses in nonhuman primates
Parham Ramezani-Rad, … , Shane Crotty, Darrell J. Irvine
Parham Ramezani-Rad, … , Shane Crotty, Darrell J. Irvine
Published March 4, 2025
Citation Information: J Clin Invest. 2025;135(8):e185292. https://doi.org/10.1172/JCI185292.
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Research Article AIDS/HIV Immunology

The saponin monophosphoryl lipid A nanoparticle adjuvant induces dose-dependent HIV vaccine responses in nonhuman primates

Abstract

Induction of durable protective immune responses is the main goal of prophylactic vaccines, and adjuvants play a role as drivers of such responses. Despite advances in vaccine strategies, development of a safe and effective HIV vaccine remains a significant challenge. Use of an appropriate adjuvant is crucial to the success of HIV vaccines. Here we assessed the saponin/MPLA nanoparticle (SMNP) adjuvant with an HIV envelope (Env) trimer, evaluating the safety and effect of multiple variables — including adjuvant dose (16-fold dose range), immunization route, and adjuvant composition — on the establishment of Env-specific memory T and B cell (TMem and BMem) responses and long-lived plasma cells in nonhuman primates (NHPs). Robust BMem were detected in all groups, but a 6-fold increase was observed in the highest- versus the lowest-SMNP-dose group. Similarly, stronger vaccine responses were induced by the highest SMNP dose in CD40L+OX40+ CD4+ TMem (11-fold), IFN-γ+ CD4+ TMem (15-fold), IL21+ CD4+ TMem (9-fold), circulating T follicular helper cells (TFH; 3.6-fold), BM plasma cells (7-fold), and binding IgG (1.3-fold). Substantial tier 2 neutralizing antibodies were only observed in the higher-SMNP-dose groups. These investigations highlight the dose-dependent potency of SMNP and its relevance for human use and next-generation vaccines.

Authors

Parham Ramezani-Rad, Ester Marina-Zárate, Laura Maiorino, Amber Myers, Katarzyna Kaczmarek Michaels, Ivan S. Pires, Nathaniel I. Bloom, Mariane B. Melo, Ashley A. Lemnios, Paul G. Lopez, Christopher A. Cottrell, Iszac Burton, Bettina Groschel, Arpan Pradhan, Gabriela Stiegler, Magdolna Budai, Daniel Kumar, Sam Pallerla, Eddy Sayeed, Sangeetha L. Sagar, Sudhir Pai Kasturi, Koen K.A. Van Rompay, Lars Hangartner, Andreas Wagner, Dennis R. Burton, William R. Schief, Shane Crotty, Darrell J. Irvine

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Figure 4

Single B cell sequencing of Env-binding BMem in low- and high-dose QS-21 SMNP groups.

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Single B cell sequencing of Env-binding BMem in low- and high-dose QS-21...
(A and B) Number of HC nucleotide mutations in Env-binding BMem (A) and bKO-binding BMem (B) at week 12 in PBMCs. G, group. (C and D) Number of LC κ (C) and LC λ (D) mutations in Env-binding BMem at week 12. (E) Distribution of clonotype sizes for groups 2 and 4. (F) Clonal richness (Chao1) of Env-binding BMem. (G) Clonal abundance curve of Env-binding BMem. (H) Proportion of Ig isotypes among Env-binding BMem, shown as a percentage of total IGH. (I–K) Uniform manifold approximation and projection (UMAP) visualization of single-cell gene expression profiles identifying clusters of total Env-binding BMem at week 12 (I) across groups (J) and for specific markers (K). In A–D, the solid black line and dotted lines represent the median and quartiles, respectively. The error bars in F represent the geometric mean with geometric SD. Animals were excluded from clonal abundance curve in G if fewer than 50 sequences were recovered; otherwise, all data represent n = 6 animals/group. Statistical significance was assessed using an unpaired 2-tailed Mann-Whitney U test.