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 6

Higher induction of Env-specific BM BPC and neutralizing antibodies with high QS-21 SMNP doses.

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Higher induction of Env-specific BM BPC and neutralizing antibodies with...
(A) Mean AUC of Env-binding IgG antibodies at different time points after immunization. Black triangles represent the time of immunization. (B–D) AUC of Env-binding IgG antibodies at week 12 (B), week 24 (C), and week 26 (D). (E–H) Serum dilution at 50% inhibition of BG505 pseudovirus in a neutralization assay (ID50) at week 10 (E), week 12 (F), week 26 (G), and week 30 (H). (I) Correlation between AUC of Env-binding IgG antibodies and neutralization titers at week 30. (J) Frequency of Env+ IgG+ BPC in BM at week 37. (K and L) Correlation between AUC of Env-binding IgG antibodies at week 12 (K) or week 30 (L) and frequency of Env+ IgG+ BPC. Error bars in B–D represent mean with SEM. Horizontal black lines in E–H and J indicate geometric mean and median, respectively. The dotted black line in J indicates the LOD and was used to calculate percent responders. Statistical significance (B–D and J) was assessed using the Kruskal-Wallis test, followed by Dunn’s multiple-comparison test; and in E–H was assessed using an unpaired 2-tailed Mann-Whitney U test. Data in I, K, and L were analyzed using Spearman’s correlation test. *P ≤ 0.05 and **P < 0.01. All data represent n = 6 animals/group.