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NIH grant 1R01AI198218-01: Dissecting mechanisms of action of next-generation saponin combination adjuvants.
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Darrell J Irvine. Award: $865432.
Start: 2026-07-23T00:00:00.
Project Summary / Abstract
Saponins, triterpene glycosides originally isolated from the Chilean soapbark tree Quillaja saponaria, have potent
adjuvant activity in humans and animal models and are used as adjuvants in several licensed vaccines. Recently,
we discovered a combination adjuvant based on the self-assembly of saponins with the Toll like receptor-4
agonist monophosphoryl lipid A (MPLA) with lipids and cholesterol, forming cage-like nanoparticles that we
termed SMNP (Saponin/Mpla NanoParticles), which outperformed diverse clinical and experimental adjuvants
in promoting humoral immunity to protein vaccines in both small and large animal models. The efficacy of SMNP
in preclinical models led to a recent first-in-humans clinical trial of SMNP (clinicaltrials.gov: NCT06033209), and
early data from this study indicates SMNP is safe and very potent for promoting multiple elements of the immune
response in humans. Importantly, we have retained the IP rights for SMNP to make it available for non-
profit/academic clinical trials, to help solve an important bottleneck in the availability of safe and effective clinical
adjuvants. Despite these exciting findings, the mechanisms of action of SMNP, in particular, and saponins, in
general, remain poorly understood. In this proposal, we aim to dissect the mechanisms of action governing the
potency of SMNP and explore how its structure and composition govern its function in both traditional and novel
dosing schemes of relevance to human vaccination. We will carry out these studies using humanized mouse
models developed by the Batista lab that model the complexity of protective vs. non-protective B cell recruitment
to germinal centers following vaccination, and genetic reporters allowing the fate of GC B cells toward memory
or plasma cell fates to be followed. In addition, we will apply the computational modeling expertise of the Einav
lab to make in silico predictions of optimal dosing regimens. Our aims are to (1) Dissect pathways controlling
SMNP effects on lymph flow; (2) Define mechanisms underlying potent germinal center (GC) reactions and
boosting effects of SMNP; (3) Explore novel ISCOM compositions to gain insights into how SMNP and related
adjuvants boost GCs, memory, and plasma cell development; and (4) Understand mechanisms underlying the
efficacy of “escalating-dose” immunization with SMNP. These studies will provide important new insights into the
function of saponin-based combination adjuvants and may identify even more effective and safe novel saponin
adjuvants.document fetched 2026-08-02 08:24