Omics for Faster Drug and Vaccine Development
By Iva Fedorka
The path of drug development — from initial discovery to final medication — is a lengthy and expensive process. Today, genomics, proteomics, and other new technologies are helping to make drug development faster and more efficient.
Currently, many research-based pharmaceutical companies, other pharmaceutical companies, biotech companies, and research institutions are engaged in producing drugs and vaccines effective against COVID-19. Developers are trying to work quickly, even though it is difficult to conduct clinical trials during a pandemic. Their efforts include the creation of new drugs and the repurposing of drugs already approved for other diseases. Vaccines must be proven safe and efficient, and strict limits apply to pre-approval testing before they can be administered to healthy people.
In the United States, it may take more than 10 years and hundreds of millions of dollars to bring a single new drug to market. Detailed protocols and administrative requirements contribute to a high failure rate for most new drug candidates. As an example, of 5,000 compounds that undergo pre-clinical testing, only five may actually be tested in human clinical trials and only one ultimately approved for therapeutic use.1
In the U.S., the Food and Drug Administration (FDA) has the primary responsibility for overseeing drugs, biological products, and vaccines. Therapeutic product and vaccine developers must get approval from the FDA before they can investigate or market these substances.
Before testing in humans can start, significant pre-clinical data must be collected, and toxic doses determined to ensure human safety. Toxicology, pharmacology, metabolic, and pharmaceutical sciences comprise the core of pre-clinical development.
New drug development has multiple phases:
- New compound synthesis and extraction
- Biological screening and pharmacological testing
- Dosage formulation and stability testing
- Toxicology and safety testing (in vivo)
- Clinical evaluation (Phases I, II, and III)
- Manufacturing process and quality control
- Bioavailability studies
- Post-approval research
The widespread availability of genomic sequencing has shifted vaccine and therapeutics development from microbiologically based to sequence-based methods. Genomics, transcriptomics, metabolomics, structural genomics, proteomics, and immunomics can help to identify targets, design new vaccines and drugs, and better predict the effects for patients. Human genomics also provides insights into the host biology that is important in infectious disease.
DNA microarray analyses have already become standard tools for studying transcription levels and patterns in cells, and advances in two-dimensional gel electrophoresis and mass spectrometry provide insights into the function of specific gene products. A full understanding of the proteome must consider the post-translational modifications of proteins that determine intracellular location, stability, activity, and function.
Exclusive reliance on mRNA levels to measure protein function can be misleading; information about protein levels and modifications, signaling pathways, and metabolite concentrations and distribution are also needed.
Functional genomics, a combination of proteomics and transcriptomics, offers a systematic way to identify biological pathways and processes in normal and abnormal physiological states. High-throughput, large-scale methodologies, and statistical and computational analyses can expand investigations beyond single genes and proteins to thousands of genes and gene products. With the biological functions of about 30 percent of the human genome still unknown, scientists are moving from genome mapping and sequencing toward functional genomic approaches to gain new insights into biological systems.
Functional genomics combined with combinatorial chemistry and information from emerging proteomics methods are helping to identify new drug targets. Some companies are virtually screening libraries of existing compounds for in silico predictions: unique combinations of biochemical assays, X-ray crystallography, informatics, and chemical and compound library screening can accelerate the drug discovery process.
Vaccines are a great public health success for eradicating diseases like smallpox and polio. But we still don’t fully understand how genes and vaccine-induced proteins contribute to either innate and adaptive protective immune responses.
Proteomics can help identify potentially new antigens with greater speed and sensitivity; as a complement to transcriptomic approaches, systems vaccinology helps us understand the immune response following vaccination. Biotechnology and molecular immunology advances have provided new insights for vaccine manufacturers.
For example, serum antibody concentrations are one measure of whether a vaccine has elicited the intended immunogenic response. Range doses and several administration routes are typically evaluated to decide the final dose and dosing regimen. Initial assessment of post-vaccination immune responses occurs in Phase I and II trials; Phase III trials assess efficacy after preliminary results about vaccine safety and immunogenicity are available.
The quantitative biological data available from the human genome project, along with innovations in instrumentation, reagents, methodologies, bioinformatics, and software are transforming drug discovery and development. High-throughput genomic, proteomic, metabolomic, and other drug discovery methods will make for faster development, and safer, more effective, and better-targeted therapeutics.
1. Sandra Kraljevic, Peter J. Stambrook, and Kresimir Pavelic, Accelerating drug discovery, EMBO Reports, 2004 Sep; 5(9): 837–842.