Development of an RNA based vaccine against Mycobacterium tuberculosis
Led by Affiliate Prof Rhea Coler (Center for Global Infectious Disease Research, Seattle Children's Research Institute, USA), with Prof Helen Fletcher (LSHTM, UK)
Tuberculosis (TB) now ranks as the leading infectious killer worldwide, surpassing HIV/AIDS and malaria for the last several years in a row. The bacterium that causes TB disease, Mycobacterium tuberculosis (Mtb), is typically transmitted by inhaling the bacteria from infected people. These bacteria infect one-quarter of the world’s population, causing disease in ~10.4 million people and resulting in ~1.6 million deaths each year. Therefore, new TB vaccines represent a critical, unmet global public health need.
A new vaccine technology, based on the delivery of self-replicating RNA molecules, has gained attention worldwide but there has been limited exploration of this vaccine technology in protection against TB. IDRI has adapted their ID93 vaccine antigen into a self-replicating RNA molecule formulated in a state-of-the-art nanostructured lipid carrier. This enables the RNA vaccine candidate to be compared head-to-head with the classical ID93 protein with adjuvant vaccine, currently in phase 2b trials. Comparison of the nucleic acid based ID93 with the classical protein adjuvant formulation of ID93 will accelerate the development of the RNA based vaccine and provide insight into the breadth and magnitude of immune response induced by nucleic acid versus protein based vaccines.
We will evaluate ability of these vaccine candidates to reduce bacterial burden in the mouse model along with the accompanying immune responses. Recent clinical trial data have uncovered sets of host biomarkers that identify people who are more likely to advance to active disease states. This proposal aims to evaluate these clinically defined host markers (post-Mtb challenge) in a preclinical model of TB and to determine if immunization with two different types of vaccine candidates influences these host risk signatures. Successful completion of this proposal would significantly advance the TB vaccine pipeline and has the potential to streamline efforts and resources for the most promising candidates.
A new vaccine technology, based on the delivery of RNA molecules, has gained attention worldwide but there has been limited exploration of this vaccine technology in protection against tuberculosis (TB). We have designed TB vaccine candidate antigens into self-replicating RNA moleculs with a state of the art delivery formulation. This enabled the RNA vaccine candidates to be compared head-to-head with the classical protein with adjuvant vaccines of the same antigenic composition. In this work we observed the lung-based mycobacterial growth inhibition assay (MGIA) corresponded well with traditional in vivo challenge studies examining efficacy by plating organ homogenates. By both efficacy measures we observed homologous prime-boost regimens afford greater protection from Mycobacterium tuberculosis (Mtb) challenge than heterologous regimens, albeit these studies are preliminary. We did not observe safety signals following prime or boost RNA immunizations, and consider this RNA platform and delivery formulation well tolerated in the preclinical mouse model. Due to challenges outside of our control, we were unable to in tandem assess immunogenicity induced by the two vaccine platforms as homologous or heterologous prime-boost strategies nor evaluate RNA host correlate of risk (COR) signatures. Fortunately, these preliminary studies have led to follow-on funding which we are leveraging to complete the full suite of efficacy, immunology and biomarker endpoints for our down selected protein + adjuvant and RNA-based vaccine candidates. Specifically, we will characterize the safety, immunogenicity and protective efficacy of the RNA vaccine expressing Mtb candidate antigens, complexed with Lipid InOrganic Nanoparticle (LION) formulations in a preclinical animal model of Mtb infection. We will also assess the ability of human COR signatures to predict disease burden in animals challenged with Mtb after these prophylactic vaccine strategies. Successfully continuing this work would significantly advance the TB vaccine pipeline and has the potential to streamline efforts and resources for the most promising candidates.