Research

Major research directions

mRNA vaccine development for human and animal pathogens
We have extensive experience making mRNA vaccines using methods pioneered by Weissman, Karikó, Pardi, and colleagues, which uses nucleoside-modified mRNA encapsulated in lipid nanoparticles. We published the first preclinical efficacy study of this platform in animal models of Zika virus infection in 2017. Now we're interested in leveraging this technology to tackle some of the most challenging diseases of our time, including chronic infections and cancer, and we are working to extend the benefits of mRNA vaccines into veterinary, agricultural, and wildlife applications.
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Immunological mechanisms of mRNA vaccines
We are deeply interested in the innate immune mechanisms that drive protective immune responses vs. adverse reactions to mRNA vaccines, and whether these two outcomes are dissociable. By understanding how mRNA and lipid nanoparticles are sensed by our cells, we hope to uncover approaches to make next-generation mRNA vaccines that are even more effective but with milder side effects and adverse events. 
 
Non-classical T cell immunity
CD8+ or killer T cells are conventionally known to recognize microbial peptides presented on classical MHC class I molecules (e.g. HLA-A, B, and C in humans). But in recent years, it has become apparent that effective CD8+ T cell responses can also be generated against peptides presented on MHC-E, a family of non-classical MHC molecules that includes HLA-E in humans and Qa-1 in mice. Excitingly, these CD8+ T cells have shown a remarkable level of protection against simian immunodeficiency virus (SIV), a relative of HIV, in monkeys, although the properties distinguishing these protective CD8+ T cells from classical CD8+ T cells are not understood. We recently discovered an MHC-E-restricted CD8+ T cell response to influenza virus infection in mice, which offers a tractable model system in which to elucidate this biology. Now, a major focus of our lab is to develop mRNA vaccine-based methods to elicit MHC-E-restricted T cell responses against viruses, especially HIV and cancer, where they have the greatest potential for clinical benefit.

Antibody/T cell collaboration
While many scientists cite the potential of T cells to protect from viral infections that escape neutralizing antibody responses, surprisingly little is known about the actual protective effects of T cells in a variety of acute viral infections. We hope to shed light in this area by studying a poorly understood phenomenon of antibody/T cell collaboration: intriguingly, neither CD8+ T cells nor non-neutralizing antibodies protect mice from influenza infection on their own, but they are highly protective when combined, although it is unclear how this works! Unlocking this mystery may guide future vaccine design for influenza and other diseases. For early work on this topic, see Laidlaw et al., PLoS Pathogens (2013).​