The following interview was conducted by Signals+ Editor Maialen Sebastian-delaCruz, Ph.D.
A recent study by Emily Aunins, Anthony Phan et. al. from the Hunter Lab at University of Pennsylvania School of Veterinary Medicine published in Science Immunology, “An Il12 mRNA-LNP adjuvant enhances mRNA vaccine induced CD8 T cell responses” showed that incorporation of an mRNA encoding for interleukin 12 (IL-12) in mRNA vaccination enhances CD8 T cell expansion, function and memory responses, and that this enhanced response translated to better protection against Listeria Monoctyogenes and B16F0 melanoma upon challenge, as stated by first co-author Emily Aunins. This work demonstrates that cytokine-adjuvanted mRNA-LNPs represent a strategy to tailor the magnitude of the immune response to vaccination, as highlighted by editor Hannah Isles.
ABSTRACT
Optimizing vaccine design to induce CD8 T cell responses has been challenging, but lipid nanoparticle (LNP)–encapsulated mRNA vaccines effectively generate CD8 T cell memory. Interleukin-12 (IL-12) supports CD8 T cell expansion and acquisition of effector function, but the role of IL-12 in the generation of CD8 T responses to mRNA vaccination is unclear. Here, we determine that endogenous IL-12 is not required for CD8 T cell responses to mRNA-LNP vaccination. We assessed the adjuvant activity of an mRNA-LNP encapsulating a codon-optimized mRNA that encodes both subunits of IL-12 (LNP–IL-12). Coadministration of LNP–IL-12 with ovalbumin (OVA) mRNA-LNPs enhanced CD8 T cell expansion and effector function and expanded circulating, effector, and tissue-resident memory CD8 T cells. LNP–IL-12 increased CD8 T cell responses against SARS-CoV-2 and influenza virus antigens and improved protection against Listeria monocytogenes–OVA and B16F0-OVA melanoma. Thus, modification of mRNA-LNP formulations to include a cytokine mRNA provides a strategy to enhance CD8 T cell–mediated protection.
Emily Aunins is a fourth-year Ph.D. student in Cell and Molecular Biology: Microbiology, Virology, and Parasitology program at the University of Pennsylvania, and Dr. Anthony Phan is an associate researcher in the Hunter Lab; and both are ICIS members. Prof. Christopher Hunter is the Mindy Halikman Heyer Distinguished Professor of Pathobiology at the University of Pennsylvania School of Veterinary Medicine, and the Past-President of ICIS. We have interviewed them about their latest article in which they are the first co-authors and the senior author of this work, respectively.
What was the key question you addressed with this paper, and what led you to ask it?
The SARS-CoV2 mRNA vaccines are uniquely capable at eliciting SARS-CoV2-specific CD8+ T cell responses, despite not being a live or attenuated virus. We started with the goal to understand what signals mRNA-LNP vaccines induced that allow the generation of T cell responses, and from that we asked whether providing additional signals that the mRNA-LNPs don’t normally induce via delivery of cytokine-encoding mRNA could augment the capabilities of the current mRNA-LNP formulations.
Which of your findings was the most unexpected and/or exciting to you?
The most surprising aspect is the magnitude of the difference in the CD8+ T cell response following addition of IL-12 mRNA-LNPs. While we were hopeful that providing IL-12 could improve the CD8+ T cell response, we didn’t expect the change to be quite so dramatic. The most exciting aspect of this is how relatively easy it was to tweak the response to the mRNA-LNP vaccines, and we think this lays the groundwork for a lot of exciting future approaches that may improve the efficacy and usefulness of mRNA-LNP therapies.
Could you tell us how the initial idea and/or observation led to the major discovery?
Our initial data suggesting that IL-12 wasn’t induced by mRNA-LNP vaccination led us to have conversations with our collaborators on this paper, Mohamad-Gabriel Alameh and Drew Weissman, to see how easy it could be to co-deliver cytokine encoding mRNAs. The planning and generation of the IL-12 mRNA-LNPs was instrumental in allowing us to perform the studies that show the massive impact that providing an additional cytokine signal can have in promoting and altering CD8+ T cell response to mRNA vaccines.
If people take away only three things from this paper, what do you want them to be?
- Current mRNA-LNP vaccine formulations do not induce significant levels of IL-12 following vaccination.
- IL-12 encoding mRNA co-delivery during vaccination with mRNA-LNPs is a potent strategy for expanding the antigen-specific CD8+ T cell response following mRNA-LNP vaccination.
- The modularity of the mRNA-LNP platform holds significant potential for creative application of insights on cytokine biology. Adding other cytokines or mixes of them to these formulations may allow future vaccines to be tailored to specific pathogens/use cases.
Why is this discovery of particular significance to the Cytokines community?
We believe the findings described in this paper really open the door to leveraging the wealth of knowledge that exists on cytokine biology and complements an existing literature on the use of cytokine adjuvants via other approaches like DNA vaccination. We look forward to seeing how others make use of the flexibility of the platform to generate novel strategies for prophylactic and therapeutic use of mRNA-LNPs.
Citation of the article:
Emily A. Aunins et al., An Il12 mRNA-LNP adjuvant enhances mRNA vaccine–induced CD8 T cell responses, Sci. Immunol. 10, eads1328 (2025). DOI: 10.1126/sciimmunol.ads1328
Link (open access): https://www.science.org/doi/epdf/10.1126/sciimmunol.ads1328