Improved Humanized Mice Enhance Vaccine Development

 Every animal model of disease comes with its own unique set of drawbacks. Yet, scientists continually push to improve the quality of animal models to recapitulate the physiological and molecular signatures of disease states. For decades, researchers have turned to mice whose immune systems have been “humanized” to respond in a manner similar to humans. Infectious diseases kill millions of people each year, but the search for treatments is hampered by the fact that laboratory mice are not susceptible to some human viruses.

However now, a team at Princeton University has developed a comprehensive way to evaluate how immune responses of humanized mice measure up to actual humans. In the current study, the research team looked at the mouse and human immune responses to one of the strongest vaccines known, a yellow fever vaccine called YFV-17D. The comparison of these “vaccine signatures” showed that a newly developed humanized mouse developed at Princeton shares significant immune-system responses with humans. Findings from the new study were published recently in Nature Communications through an article titled “Selective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses.”

“Understanding immune responses to human pathogens and potential vaccines remains challenging due to differences in the way our human immune system responds to stimuli, as compared to, for example, that of conventional mice, rats, or other animals,” explained senior study investigator Alexander Ploss, Ph.D., associate professor of molecular biology at Princeton University. “Until now a rigorous method for testing the functionality of the human immune system in such a model has been missing. Our study highlights an experimental paradigm to address this gap.”

Humanized mice have been used in infectious disease research since the late 1980s. Yet without rigorous comparisons, researchers know little about how well the mice predict human responses such as the production of infection-fighting cells and antibodies.

To address this issue, researchers exposed the mice to the YFV-17D vaccine, which is made from a weakened, or attenuated, living yellow fever virus. Vaccines protect against future infection by provoking the production of antibodies and immune-system cells.

“By taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we provided an in-depth comparison of immune responses in human vaccines, conventional humanized mice, and second-generation humanized mice,” the authors wrote. “We demonstrated that selective expansion of human myeloid and natural killer cells promotes transcriptomic responses akin to those of human vaccines. These enhanced transcriptomic profiles correlate with the development of an antigen-specific cellular and humoral response to YFV-17D.”

In previous work, the researchers explored the effect of YFV-17D on conventional humanized mice. However, the research team found that the mice responded only weakly. This led them to develop a mouse with responses that are more similar to those of humans.

By introducing additional human genes for immune system components – such as molecules that detect foreign invaders and chemical messengers called cytokines – the Princeton team was able to ensure the complexity of the engrafted human immune system reflected that of humans. Additionally, the researchers found that the new mice have responses to YFV-17D that are very similar to the responses seen in humans. For example, the pattern of gene expression that occurs in response to YFV-17D in the mice shared significant similarities to that of humans. This signature gene expression pattern, reflected in the “transcriptome,” or total readout of all the genes of the organism, translated into better control of the yellow fever virus infection and to immune responses that were more specific to yellow fever.

“Many vaccines have been generated empirically without profound knowledge of how they induce immunity,” noted lead study investigator Florian Douam, Ph.D., a postdoctoral researcher in Dr. Ploss’ laboratory. “The next generation of mouse models, such as the one we introduced in our study, offer unprecedented opportunities for investigating the fundamental mechanisms that define the protective immunity induced by live-attenuated vaccines.”

“Our study highlights the importance of human biological signatures for guiding the development of mouse models of disease,” concluded Dr. Ploss. “It also highlights a path toward developing better models for human immune responses.”