The ID IRG is structured around three pillars, designed to advance the state-of-the-art in critical areas:
The major long-term goal of the Dengue Program is to develop vaccines that can prevent dengue infection and/or prevent disease development following infection. The ID IRG will approach this challenge by synergistically combining its expertise in life sciences, physical sciences and engineering. In the short term, the ID IRG aims to develop 1) a universal vaccine that is effective against all four serotypes for clinical evaluation in four years, and 2) a set of general principles for vaccine development, including antigen selection, expression, delivery, immunological, efficacy and safety characterization.
To reach our goals, the ID IRG will focus on the several key and inter-related areas. Firstly, we have developed the full suite of omics tools to interrogate the host response to infection and vaccination. This would guide the development of vaccine candidates and choice of adjuvants to maximise immune response to vaccination. Secondly, we will exploit the power of novel bioinformatic approaches to identify epitopes that elicit the best protective responses. Thirdly, we will develop novel methods to deliver the vaccine that takes advantage of the natural innate immune responses. Finally, we will also develop animal models that would enable us to glean maximal information on the human immune responses to vaccination.
- Dengue Vaccine Design and Dengue Antibody-based Therapeutics
- Dengue Vaccine Formulation and Delivery
- Dengue Vaccine Evaluation
- Biomarkers of Dengue Infection
Eradication of malaria is the long term goal of the global research effort studying this globally important infectious disease. Key prerequisites for a successful campaign are highly sensitive, cheap and reliable diagnostic tools, a panel of effective drugs as well as a vaccine that is capable to significantly reduce transmission in malaria endemic countries. To date there are challenges and limitations in relation to all these. The malaria research effort at the SMART Infectious disease IRG aims to develop novel approaches that combine state of the art technologies in biology and engineering to provide new solutions
- Systemic Identification of Effective Vaccine Targets and Humanized Mouse Model of Malaria Infection
- Mechanobiology of Malaria Pathogenesis
- RNA-based Mechanisms of Malaria Pathogenesis
Bacterial Pathogens Program
To complete the full spectrum of infectious diseases, the ID IRG has a major research thrust addressing bacterial pathogens, which represent a major cause of morbidity and mortality globally. The emergence of drug-resistance in virtually every major bacterial pathogen, such as extreme drug-resistant Pseudomonas aeruginosa in Singaporean hospitals and drug resistant strains of Mycobacterium tuberculosis (Mtb) in Southeast Asia and Singapore, is outpacing the development of new antibiotics. The scale of this problem is illustrated by the fact that over one-third of the world’s population is infected with Mtb, with the majority of infections existing in a poorly understood asymptomatic latent or persistent form that both escapes detection by the immune system and confers significant drug resistance to the Mtb organisms.
To deal with these challenges, a team of MIT, NUS and NTU researchers has embarked on a translational program to discover fundamental mechanisms of bacterial adaptation, survival and persistence in the host and then to exploit these mechanisms as targets for antibiotic development. This approach is illustrated by the poorly understood phenomenon of persistence and latency in Mtb infections, in which the bacterium enters a non-replicative and drug resistance state for decades-long survival in the host. Using innovative convergent technologies, ID IRG researchers have discovered a novel molecular mechanism that mycobacteria use to enter this latent state, in which the cells reprogram a system of tRNA modifications that controls selective translation of critical latency-inducing proteins.
To facilitate development of new antibiotics that target this and other critical survival pathways in Mtb, ID IRG researchers are also developing novel fluorescence-based phenotypic screening tools to search for drug candidates that are both capable of passing through the uniquely impermeable cell wall of Mtb and of reacting with the target proteins. ID IRG researchers have discovered that these survival and response pathways are common to all bacterial pathogens, which has led to a pipeline of both drug screening and structure-based drug design efforts. Researchers continue this innovative infectious disease research with discoveries made in other bacterial survival and host response pathways.
- Whole Cell Phenotypic Screening Tools for Mycobacterial Antibiotic Development
- Mechanisms of Mycobacterial Persistence in Tuberculosis
- Antibiotic Development Based on Translational Control Mechanisms in Bacteria
- Bacterial PK/PD problems in drug resistance and drug discovery