Development of a next-generation human immune system mice for the study of vaccines against high containment viruses

Project summary/abstract Immunologists use animal models to test vaccine immunogenicity and efficacy. Mice are commonly used in early vaccine efficacy tests due to their low cost, ease of genetic manipulation, and ability to dissect mechanisms of vaccine protection. Although mice share many genes and cell types with humans, differences in cell subtypes, population lifespans, cytokine response, and other factors can lead to variations in vaccine response and susceptibility to infectious diseases. One example of divergent susceptibility is seen with viruses from the Filoviridae family, including Ebola, Sudan, and Marburg viruses. While these viruses cause highly lethal hemorrhagic fever in humans, mice are resistant. Although this resistance can be overcome with mouse-adapted Filoviruses, it is not ideal because adapted viruses may not interact with the mouse immune system as clinical isolates do. Therefore, vaccine efficacy studies have relied on non-human primate models, creating significant ethical and cost barriers to testing candidate filovirus vaccines. To address the divergence between the mouse and human immune systems, immunologists, oncologists, and infectious disease researchers have utilized human immune system (HIS) mouse models. Studies with Filoviruses showed that HIS mice were permissive to the native isolates. However, deficiencies in critical target cell populations, including B cells, render them unsuitable as models for use in filovirus vaccine studies. Recently, several new HIS mouse models have been reported that show improved myeloid and lymphoid cell line engraftment. A separate breakthrough has resulted in sustained high levels of engraftment and mature B cell responses. We are combining these advances into a single new mouse model. In this project, we will define the new model's ability to engraft human immune cells. We will then vaccinate the mice with a VSV-Ebola vaccine and evaluate T and B cell responses, including the ability of B cells to undergo class-switching and somatic hypermutation. We will then determine if the new HIS mouse can be used as a model of Ebola virus disease. If successful, this exploratory proposal will have identified a new HIS mouse model that shows high engraftment of myeloid and lymphoid lineages, including fully mature B cell responses. Importantly, the model may minimize the need to use non-human primates for vaccine efficacy studies. If we are successful in developing a new Ebola virus disease model, it will greatly increase the number of vaccines that can be evaluated for efficacy and more easily allow for direct comparisons of vaccine types and regimens. The model may also allow future studies to dissect the mechanisms by which viruses such as HIV and Ebola target the immune system and cause disease. Thus, a successful outcome of this exploratory proposal has the potential for a significant impact on vaccinology, immunology, oncology, and infectious diseases.