Cornell University researchers have made a synthetic immune organoid system that can quickly predict how well conjugate vaccines will work and speed up the process of finding antigen-specific antibodies. By sidestepping animal immunization, this immune organoid-based approach enabled antibody discovery on a time scale that was significantly shorter than for conventional immunization-based workflows.

The article, “Profiling Germinal Center-like B Cell Responses to Conjugate Vaccines Using Synthetic Immune Organoids,” was published in ACS Central Science.

Bacteria have garnered increased interest in recent years as a platform for the biosynthesis of a variety of glycomolecules, such as soluble oligosaccharides, surface-exposed carbohydrates, and glycoproteins. These glycoengineering bacteria have emerged as a cost-effective platform for rapid and controllable biosynthesis of designer conjugate vaccines. These types of glycoconjugates are used in the Haemophilus influenzae, pneumococcal, and meningococcal type B vaccines that are currently approved. However, little is known about the engagement of such conjugates with naive B cells to induce the formation of germinal centers—a sub-anatomical microenvironment that converts naive B cells into their antibody-secreting form.

With the use of biomaterials in tissue engineering growing over the past decade, new, interesting ways have emerged to study how B cells activate and mature. By putting B cells, costimulatory signals, and cytokines in a hydrogel matrix, immune tissues create a 3D cell culture architecture that is more like conditions in the body than traditional methods of stimulating and differentiating B cells in the lab.

Lead authors Tyler D. Moeller and Shivem B. Shah worked with researchers from Cornell University to set up a methodology for testing glycoconjugate vaccine candidates made from glycoengineered E. coli for their immune effects using hydrogel-based immune organoids to mimic in vivo testing. Supported by senior authors Zhe Zhong and David Redmond, the research team developed a three-dimensional biomaterials-based B-cell follicular organoid system to show that conjugates triggered key features of germinal cell structures that are needed for B-cell antibody production. These features include B cell receptor clustering, intracellular signaling, and somatic hypermutation. The researchers took advantage of the fact that these things happen in a much shorter amount of time than usual animal immunization-based workflows to find high-affinity antibodies against parts of the conjugate.

Importantly, the ex vivo responses of germinal cell structures correlated with the humoral responses in vivo. Immune organoid culture systems not only give a realistic microenvironment for immune tissue to model how B cells behave, but they also have a high throughput. One mouse spleen is enough to make more than 800 organoids. These organoids can be arranged in 96-well plates for high-throughput experiments and analyzed after four days of incubation, while animal immunization work usually takes weeks or months. Collectively, these findings highlight the potential of synthetic organoids for rapidly predicting conjugate vaccine efficacy as well as expediting antigen-specific antibody discovery.

Most of the time, a small subset of vaccine candidates is chosen to study for immune responses. This is done instead of screening large libraries of candidates that cover every possible design configuration. With the recent advances in glycoengineering, such coverage is possible. And with this ex vivo system, the authors think it will be possible to cut down on the number of animals, costs, and time by using organoid-based prescreening of these large conjugate libraries to find interesting candidates for further study.

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