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 3

Robust longitudinal Env-binding BMem are detected with high QS-21 SMNP doses.

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Robust longitudinal Env-binding BMem are detected with high QS-21 SMNP d...
(A) Representative flow cytometry plots of Env-binding BMem (Env-BV421+Env-AF647+) and Env bKO-binding BMem (bKO-PE+) in PBMCs at weeks 10 and 12. (B) Env-binding BMem as a percentage of total B cells (medians per group) in PBMCs at different time points after immunization. Black triangles indicate times of immunizations. The LOD for Env-binding BMem was 0.0006%. (C and D) Frequency of Env-binding BMem in PBMCs at week 12 (C) and week 26 (D). (E and F) Frequency of bKO-binding BMem in PBMCs at week 12 (E) and week 26 (F). (G) bKO-binding BMem as a percentage of Env-binding BMem. (H) Representative flow cytometry plots of total BGC (CD71+CD38–) and Env-binding BGC (Env-BV421+Env-AF647+) in ipsilateral LN FNAs at weeks 6 and 13. (I) Frequency of total BGC in ipsilateral LN FNAs at weeks 6 and 13. (J) Representative flow cytometry plots of GC-TFH (PD-1hiCXCR5+) in ipsilateral LN FNAs at weeks 6 and 13. (K) Frequency of GC-TFH in ipsilateral LN FNAs at weeks 6 and 13. (L) Frequency of Env-binding BGC in ipsilateral LN FNAs at weeks 6 and 13. (M) Frequency of Env-binding BMem in ipsilateral LN FNAs at weeks 6 and 13. (N) Frequency of Env-binding BMem compared across 3 different tissues (PBMCs, ipsilateral LN, and contralateral LN). (O) Frequency of Env-binding BMem in contralateral LN FNAs at week 13. Bars represent the median per group. Gray area in L, M, and O indicates the LOD. Statistical significance was assessed using the Kruskal-Wallis test, followed by Dunn’s multiple-comparison test. *P ≤ 0.05 and **P < 0.01. All data represent n = 6 animals/group unless the exclusion criteria described in Methods apply.