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Rational Vaccinology: A revolutionary new approach to cancer vaccine design

In a recent paper published in Nature Biomedical Engineering, researchers from Northwestern University have developed a new way to increase the potency of almost any cancer vaccine. The researchers used spherical nucleic acid nanoparticles to investigate how the spatial distribution and placement of antigens and adjuvants affect the immune response.

How do cancer vaccines work?

Cancer vaccines have been touted as a promising method to combat cancers that express targetable antigens. For example, in melanoma, many attempts have been made to create vaccines to target specific proteins expressed by tumour cells. These vaccines work by primarily activating cytotoxic (killer) T-cells which target melanoma cells. However, this approach can be inadequate as tumours are very heterogenous and have a high mutational burden that allows the tumour cells to evade the immune response. Therefore, there is still a need to develop vaccines that elicit a multi-faceted immune response.

Recent approaches to activate a more robust immune response include administering long peptides which cover multiple epitopes, in order to activate both cytotoxic and helper T cells, or multiple minimal peptide antigens which target specific T-cell subclasses. However, these approaches often involve pools of peptides, sometimes with or without an adjuvant (a substance that enhances the immune system’s response), delivered in saline as a mixture. While extensive research has already explored the importance of antigens and adjuvants in cancer vaccines, the importance of how they are presented and the structure of the vaccine itself have not been explored.

“Rational vaccinology”

In this study, Mirkan and his team investigated how the spatial distribution of multiple antigens and adjuvants affect the efficacy of a vaccine using the “spherical nucleic acid (SNA) platform” to change the structure of vaccines on a nanoscale. The SNA is comprised of a nanoparticle core (such as a liposome) with a dense and radially arranged surface of oligonucleotides. These SNAs are biocompatible, can rapidly enter cells in high quantities, and are very modular, which allows for defined nanoscale placements of different components (such as antigens or adjuvants).

Figure 1 ¦ Illustration of two dual-antigen SNA (DA-SNA) vaccines that were synthesized to allow researchers to alter the placement of different antigens (orange and green)

The findings of the study showed that differences in the structure of SNA vaccines greatly influenced the activation of the immune system. Changing the position of the antigens within the SNA altered dendritic cell processing, changed the regulation of immune-cell pathways at the transcriptome level, affected the production and secretion of cytokines and memory markers at the cellular level, and slowed tumour growth in multiple animal models. This concept of strategically structuring vaccines has been coined “rational vaccinology” by Chad Mirkan, one of the authors of the study, who explained “Where and how we position the antigens and adjuvant within a single architecture [of the vaccine] markedly changes how the immune system recognizes and processes it.”

Designing better vaccines

Previous vaccine development has almost solely focussed on the composition, number and type of antigens. This study is one of the first to investigate how the structure of a vaccine, and the way in which antigens and adjuvants are presented to the immune system, can drastically affect its efficacy. As the researchers point out in their paper, “For vaccine efficacy, antigen placement may be as critical as antigen choice.” Michell Teplensky, another author of this study said, “The collective importance of this work is that it lays the foundation for developing the most effective forms of vaccine for almost any type of cancer. It is about redefining how we develop vaccines across the board.”

More on these topics

Cancer / Cancer Research / Vaccine