A promising platform for rapid vaccine and therapeutic development involves the use of packaged messenger RNAs (mRNAs) that can be delivered to a patient, whose own cellular machinery then produces the antigenic protein or biotherapeutic drug from the mRNA sequence. In principle, such vaccines and biotherapeutics can be quickly adapted to new disease organisms simply by substituting a new mRNA sequence, making them ideal tools for combatting emerging epidemics. The development of mRNA vaccines and biotherapeutics has increased dramatically as past problems, such as instability from cellular degradation, immunogenic responses, and delivery problems, have been greatly ameliorated by recent technological advances. These have included the introduction of modified nucleosides, engineering of the untranslated regions (UTR), and development of lipid nanoparticle (LNP) encapsulation. However, the impact of mRNA structure in the context of different UTRs, open reading frames and lipid formulation on the safety and efficacy of these vaccines remains an open question. In addition, the interchangeability of different mRNA sequences with respect to the structure of the LNP has not been fully demonstrated. To address these issues, a multi-modal approach will be taken, in which cryogenic electron microscopy (CryoEM) and scattering techniques (SAXS and SANS) will be combined with other biophysical and chemical footprinting approaches (e.g., SHAPE), in an effort to establish and harmonize methods for structural profiling of mRNA vaccines. These methods will be taken together to determine ‘best practices’ to meet the rigorous assessment and quality assurance required by the pharmaceutical industry.

key words

mRNA; platform; structure profiling; vaccines; biotherapeutics; lipid nanoparticle; cryoEM; SAXS; SANS; chemical foot-printing; SHAPE

Citizenship:  Open to U.S. citizens

Level:  Open to Postdoctoral applicants