Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants
Melissa C. Hanson, Monica P. Crespo, Wuhbet Abraham, Kelly D. Moynihan, Gregory L. Szeto, Stephanie H. Chen, Mariane B. Melo, Stefanie Mueller, Darrell J. Irvine
Melissa C. Hanson, Monica P. Crespo, Wuhbet Abraham, Kelly D. Moynihan, Gregory L. Szeto, Stephanie H. Chen, Mariane B. Melo, Stefanie Mueller, Darrell J. Irvine
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Technical Advance Immunology

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

Abstract

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.

Authors

Melissa C. Hanson, Monica P. Crespo, Wuhbet Abraham, Kelly D. Moynihan, Gregory L. Szeto, Stephanie H. Chen, Mariane B. Melo, Stefanie Mueller, Darrell J. Irvine

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Figure 4

NP-cdGMP promotes antigen-specific CD4+ T cell expansion.

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NP-cdGMP promotes antigen-specific CD4+ T cell expansion. (A–D) C57BL/6 ...
(A–D) C57BL/6 mice (n = 4 per group) received adoptive transfer of 105 CD90.1+ OT-II CD4 T cells and were immunized 24 hours later with NP-MPER with or without the OT-II helper epitope and with or without addition of cdGMP or NP-cdGMP. One week later, OT-II T cell responses were characterized via flow cytometry. (A and C) Representative flow cytometry plots and (B and D) total cell counts of total CD90.1+ OT-II T cells and CXCR5+PD-1+ OT-II cells, respectively. Data are combined from two independent experiments (in total n = 8 mice per group). (E) C57BL/6 mice (n = 3 per group) without OT-II adoptive transfer were immunized were immunized as in A on days 0, 21, and 42, and on day 49 splenocytes were restimulated for 48 hours with OT-II peptide or media only, and supernatants were assessed for cytokines by bead-based ELISA. *P < 0.05; **P < 0.01; ***P < 0.001, ANOVA followed by Tukey’s multiple comparison test (B and D) and Bonferroni’s multiple comparison test (E).