Targeted genetic engineering of B cells to induce protective antibody responses to pathogens

PROJECT SUMMARY / ABSTRACT In the United States alone, respiratory viral pathogenic infections such as influenza cause millions of provider visits and tens of thousands of work days lost, hundreds of thousands of hospitalizations and deaths. According to the World Health Organization, the number of viral pathogenic infections continues to rise with higher mortalities in resource limited countries. While a successful vaccine strategy is highly desirable, this approach relies on the induction of B cells to produce protective antibodies that either prevent viruses from entering cells or target infected cells for destruction. Unfortunately, successful vaccines for many viruses are not yet available after decades of research such a respiratory syncytial virus (RSV). In this proposal, we leverage a novel approach developed by Dr. Justin Taylor’s laboratory to genetically engineer B cells to express antibodies protective against respiratory viruses including RSV and influenza. This strategy has already been shown to result in the production of protective antibodies against influenza, RSV, and human immunodeficiency virus infection [Moffett et al., Science Immunology, 2019]. While this approach can ensure protective antibody production, the genetic engineering process required 10 days of complicated ex vivo manufacturing and is not broadly distributable. To overcome these barriers, we will co-opt a novel, synthetic nanoparticle that was developed in Dr. Jennifer Adair’s laboratory to deliver genetic engineering in a single, passive step [Shahbazi et al., Nature Materials, 2019]. We show that this nanoparticle can be assembled to genetically engineer primary human blood cells in less than 2 days, and can be modified to specifically interact with target blood cell types in vivo. Here we will develop this scalable nanoformulation as a vaccine-like in vivo delivery system to direct immune responses against respiratory viruses such as RSV. We will use these nanoparticles to directly genetically engineer the most protective primary B cell subtypes, and hematopoietic stem and progenitor cells, which can provide lifelong replenishment of protective B cells and antibodies. This research will not only develop a unique tool set against viral pathogens, but will provide transformative advances in equitable distribution of gene editing therapies.