# NIH grant: Mechanism of Action of MPL-QS21 Adjuvant Combination (1R01AI198258-01) — retained record

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NIH grant 1R01AI198258-01: Mechanism of Action of MPL-QS21 Adjuvant Combination
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Anthony  Cunningham. Award: $736873.
Start: 2026-07-10T00:00:00.
PROJECT ABSTRACT/SUMMARY
Adjuvants boost specific immune responses to vaccine antigens. Optimal matching of adjuvants to vaccine
antigens is an unmet medical challenge in the long, expensive pre-clinical and clinical stages of the vaccine
translational pipeline. The Impact of this proposal will be to assist this match-making and speed future vaccine
design while maintaining safety, by improving our understanding of adjuvant mechanisms of action (MOA) and
possibly toxicity. Adjuvants are especially important as recombinant antigens are favored over whole live or
whole or split inactivated vaccines. Use of adjuvants with protein vaccines, such as recombinant zoster vaccine
(RZV, ShingrixTM) and the adjuvanted influenza vaccine (FluadTM) have improved efficacy, especially in the aging
and immune compromised. In particular, RZV has remarkable and durable efficacy in recipients aged >70, with
90% and 82% efficacy at 1 and 11 years. Modelling suggests efficacy for 20 years. The combination of two
adjuvants monophosphoryl lipid A (MPL), a TLR4 agonist, and QS21, a saponin, into cholesterol-containing
liposomes as AS01 are responsible for the RZV immunogenicity, which also persists and plateaus over >10
years. No vaccines in clinical use utilize MPL or QS21 singly. The MPL-QS21 combination has shown synergy
in innate immune and effector cell functions in mouse models and in our human lymph node (LN) explant model.
In this response to RFA-AI-25-006: Molecular Mechanisms of Combination Adjuvants (MMCA), we propose
detailed human and murine investigations of the MOA of MPL and QS21 alone and in combination. AS01
liposomes are taken up into LN sinus-lining macrophages and results in a cascade of interacting innate and
adaptive immune cell events leading to stimulation of naïve and memory IFNγ/IL-2 polyfunctional CD4 T cells
and durable nAb. The efficacy of AS01 is dependent on cell-to-cell interactions within the intact lymph node,
informing our Approach. Our Preliminary Data indicate key roles for macrophages and inflammasome
components followed by macrophage pyroptosis and liberation of IL1β and IL18. In Aim 1 we compare primary
LN human explants and genetically defined mice treated with AS01 single and combination components to
further define MOA synergy, using single cell, spatial, and pathway inhibitor Approaches. Aim 2 centers on a
Novel study design of explanted human draining LN after RZV administration that retains immune cell
interactions in the LN structure. We probe the initiating MOA and the progression to gE-specific acquired
immunity with: 24-48 hour LN specimens examining AS01 action on interacting macrophages, DCs and NK cells;
4–6 day post-vaccine specimens focusing on DC stimulated antigen-specific effector CD4 T cell activation
(including polyfunctional T cells and TFH), defined by T cell receptor (TCR) matching to known vaccine-specific
CD4 T cells. Aim 3 defines the phenotype of the remarkably durable and effective RZV CD4 T cell population in
PBMC of long-term vaccinees using an existing biobank and single cell technologies to determine the
biosignature of effective, adjuvant-enabled immunity.
```



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