How has genomics guided therapeutic design?

Therapeutics are required for individuals who become sick following COVID-19 infection, especially those who experience severe disease and are hospitalised. Severity of the disease can depend on several factors: previous COVID-19 vaccination, strength of the immune system and factors yet to be discovered. As information evolves, the World Health Organisation has provided living guidelines about therapeutics, which are updated by experts as studies emerge and new drugs are brought to the market. Genomics can help us monitor the effectiveness of therapeutics as the pandemic progresses.

By using genomics, we can detect whether there are changes in the viral genome that can influence how the virus behaves in a human body. There may be certain variants which can impact human health, increasing the severity of disease or the likelihood of someone being infected. Genomics can help us to understand why some medications may work better in some people than others and how we can we make therapeutics more effective.

The use of genomics has provided a database of information that can be used to improve and monitor therapeutic use. Openly shared international databases such as GISAID provide information on viral genomes across the world. This shared data has enabled the design and manufacture of therapeutics that target regions of the SARS-CoV-2 viral genome. Most of them target the Spike protein, the region in the virus associated with entry into cells. The databases are regularly updated so that researchers and healthcare professionals across the world can be informed if variants emerge that can alter the effectiveness of a therapeutic option.

Once therapeutics are available to treat patients, we can use genetic sequencing to detect mutations in the SARS-CoV-2 genome in the individual sequences which may alter therapeutic effectiveness. Treatment of individual patients with medications can be paired with genomic testing, and this information updates researchers to allow for therapeutic options to be updated.

Genomic seqeuncing can detect variations in the human genome which can affect how the immune system works to fight off COVID-19 infection. Because all humans have a genetic code that is unique to them, a particular therapy might be more effective in one person compared to another. Studies such as [The Genetics Of Mortality in Critical Care (GENOMICC)] (https://genomicc.org/results/) has identified genes involved in antiviral immunity and lung inflammation that can make people susceptible to life-threatening COVID-19. This study identified mechanisms that are amenable to targeted treatment with existing drugs.

The COG-UK mutation explorer platform can be used to identify important changes in the SARS-CoV-2 genome and provides information on mutations of potential or known importance (Figure 1). This can enable studies that recognise the impact of the immune system against therapeutics.

Figure 1 – Bar plot demonstrating the emergence of SARS-CoV-2 variants over time in the United Kingdom. Source: COG-UK/Mutation Explorer

Monoclonal antibodies (mAb) are proteins produced in a laboratory that use similar processes as the human immune system to combat pathogens including viruses. Ronapreve is a combination of two human antibodies (casirivimab and imdevimab) which bind to the SARS-CoV-2 spike protein, preventing entry into human cells. The COG-UK mutation explorer has presented genomic pairing with monoclonal antibody performance, outlining the frequency of SARS-CoV-2 mutations emerging which affect the Ronapreve monoclonal antibody response.

It is essential that we increase the level of rapid international genomic surveillance to keep therapeutic options available and successful as the SARS-CoV-2 virus mutates and new variants emerge. International collaboration is crucial for future therapeutic design.

Explore the COG-UK/Mutation Explorer tool and cite in the comments examples of how you could use these resources, for instance in your own research.