Controlling Vaccine Kinetics with Small Molecule Drugs

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PROJECT SUMMARY Infectious diseases such as HIV, malaria, tuberculosis, and seasonal influenza epidemics and emergence of new pandemics remain major global health problems highlighting the need for innovative approaches in vaccine design. The precise kinetics of antigen exposure relative to inflammatory cues is known to play a critical role in shaping a coordinated cellular and humoral immunity and thereby enhancing the vaccine immunogenicity and efficacy. Current vaccination strategies, however, do not include mechanisms for the temporal control of antigen and adjuvant exposure to lymphoid tissues. Here, we propose incorporating synthetic biology approaches to create nucleic acid-based vaccines where the kinetics of vaccine (antigen and adjuvant) exposure can be controlled using orally-available FDA-approved small molecule drugs. This strategy is enabled using self-replicating RNAs termed replicons that encode antigens and cytokine molecular adjuvants and encompass regulatory mechanisms governed by the FDA-approved small molecule drug, trimethoprim (TMP). This strategy allows the delivery of replicons encoding antigens and cytokines in vivo with a single bolus injection and then controlling the amplitude and duration of antigen and cytokine expression by oral administration of TMP. Using the RNA replicon platform provides several advantages: (i) it allows antigens and cytokines to be produced in their native conformation; (ii) it self-replicates and therefore persists inside the cells longer than mRNA and sustains a steady supply of “fresh” antigen and adjuvant; (iii) unlike DNA therapeutics, it does not harbor the risk of genome integration and also does not require delivery to the nucleus for transgene expression. An HIV envelope immunogen, known as the engineered outer domain (eOD-GT8), will be used as the model antigen, and interleukine-2 and interleukine-12 will be used as the cytokine molecular adjuvants. The Specific Aims of this project are: (1) Generate small molecule-responsive RNA replicon vaccines enabling control over the dynamics of antigen and adjuvant expression. (2) Identify optimal temporal patterns of antigen and adjuvant exposure maximizing the protective immunity elicited by replicon vaccines. Results from this project will establish a vaccine platform that allows modulating and promoting the magnitude and quality of T cell and antibody responses following immunization by taking a drug available as an oral pill, as a simple and clinically- translatable strategy to enhance vaccine-induced immunity. In addition, elucidating the optimal cytokine and antigen exposure patterns that confer protection will provide critical information and insights for use in conceiving better vaccine design strategies.