Spherical Nucleic Acids Upend Vaccine Design

Northwestern University researchers report that they have developed a new way to increase the potency of almost any vaccine. The novel approach, which systematically controls antigen and adjuvant locations within modular vaccine architectures, is called rational vaccinology.

“The work shows that vaccine structure and not just the components is a critical factor in determining vaccine efficacy,” explains Chad A. Mirkin, senior author on the paper published in Nature Biomedical Engineering today. “Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognizes and processes it. 

“A challenge with conventional vaccines is that out of that blended mish mosh, an immune cell might pick up 50 antigens and one adjuvant or one antigen and 50 adjuvants,” adds Michelle Teplensky, first author of the paper. “But there must be an optimum ratio of each that would maximize the vaccine’s effectiveness.”

Enter SNAs (spherical nucleic acids), which are the structural platform used in this new class of modular vaccines. SNAs allow scientists to pinpoint exactly how many antigens and adjuvants are being delivered to cells. SNAs also enable scientists to tailor how these vaccine components are presented, and the rate at which they are processed.

This approach to systematically control antigen and adjuvant locations within modular vaccine architectures was created by Mirkin, who coined the term rational vaccinology to describe it. It is based on the concept that the structural presentation of vaccine components is as important as the components themselves in driving efficacy.  

“Vaccines developed through rational vaccinology deliver the precise dose of antigen and adjuvant to every immune cell, so they are all equally primed to attack cancer cells,” notes Mirkin. “If your immune cells are soldiers, a traditional vaccine leaves some unarmed; our vaccine arms them all with a powerful weapon with which to kill cancer. Which immune cell ‘soldiers’ do you want to attack your cancer cells?” Mirkin asked rhetorically.  

The team developed a cancer vaccine that doubled the number of cancer antigen-specific T cells and increased the activation of these cells by 30% by reconfiguring the architecture of the vaccine to contain multiple targets to help the immune system find tumor cells. 

The team investigated differences in how well two antigens were recognized by the immune system depending on their placement—on the core or perimeter—of the SNA structure. For an SNA with optimum placement, they could increase the immune response and how quickly the nanovaccine triggered cytokine production to boost T cells attacking the cancer cells. The scientists also studied how the different placements affected the immune system’s ability to remember the invader, and whether the memory was long-term. 

“Where and how we position the antigens and adjuvant within a single architecture markedly changes how the immune system recognizes and processes it,” Mirkin said. The study data show that attaching two different antigens to an SNA comprising a shell of adjuvant was the most potent approach for a cancer vaccine structure. It led to a 30% increase in antigen-specific T-cell activation and doubled the number of proliferating T cells compared to a structure in which the same two antigens were attached to two separate SNAs.  

These engineered SNA nanostructures stalled tumor growth in multiple animal models.  “It is remarkable,” Mirkin said. “When altering the placement of antigens in two vaccines that are nearly identical from a compositional standpoint, the treatment benefit against tumors is dramatically changed. One vaccine is potent and useful, while the other is much less effective.”