The rapid development, approval and roll out of multiple vaccines against SARS-CoV-2, the virus that causes COVID-19, is an impressive achievement for science and healthcare. The virus genome was sequenced and shared publicly in early January 2020, within months of the virus first being identified, meaning researchers and manufacturers could begin developing vaccines against SARS-CoV-2 in record time. Genomic surveillance - where the genome of the virus is sequenced and monitored for changes - is essential for identifying mutations that could undermine disease control measures, including vaccine effectiveness. Viral genome sequencing will be vital during vaccine roll out to ensure they are still effective in the face of ongoing genetic changes to the virus.
Mutations and genomic surveillance
The genes of viruses, as with the genes of all organisms, accumulate mutations over time. These mutations are spontaneous and can have negative, positive or neutral effects on the organism, in this case, the virus. Negative mutations will reach an evolutionary dead end and eventually die out. But mutations that have neutral or positive impacts on viral biology will stay in the gene pool, causing the virus population to diversify as it is transmitted from person to person.
Genomic sequencing allows researchers to monitor how SARS-CoV-2 is mutating as it spreads from person to person and from place to place. The systematic sequencing of virus genomes within a defined population (e.g. within a country) is called genomic surveillance. Coupling genomic surveillance data with other epidemiological and clinical datasets (e.g. number of cases or disease outcomes) is proving invaluable to creating a complete picture of how the pandemic might evolve.
Essential to exploring viral genetic variation is the construction of genetic family trees. These trees are developed to visualise the relationships between circulating and historical versions of the virus and when new variants have evolved, forming a new branch of the family tree. The term variant means that one or more mutations have accumulated creating a genetically distinct subgroup of the virus. Each variant therefore, carries a specific set of mutations that define it.
Why mutation matters for vaccine effectiveness
COVID-19 vaccines work by introducing the human immune system to specific parts of the virus. This introduction teaches the immune system to recognise SARS-CoV-2, so if it is exposed to the virus at a later date, it can fight it off more efficiently than if it had never seen it before. Importantly, the immune system learns to recognise only very precise parts of the virus.
The Spike protein is known to be one of the most immunogenic (i.e. able to provoke an immune response) proteins of SARS-CoV-2. This protein exists on the outside of every particle of a virus, allowing it to enter host (e.g. human) cells. It is the first part of the virus that the immune system comes into contact with, even before it has infected human cells.
The vaccines being rolled out are based on the version of the virus identified in late 2019. But as we know, the virus has since evolved – we need to find out if the new mutations change the physical or chemical structure of proteins, particularly those in the gene coding for Spike. Over the past several months genomic surveillance has identified mutations in the Spike gene that are cause for concern. Some of these are thought to enable the virus to evade recognition by the immune system.
What we know about the impact of identified mutations on vaccine effectiveness is updating daily. So far researchers are fairly confident that although the effectiveness of some vaccines appears to be decreased, they should still offer protection against infection and severe disease. The fact that there are so many different vaccines, each with its own way of working to prime the immune system means there are multiple options if some become ineffective against current variants.
Continuing genomic surveillance is essential
With two vaccines now being rolled out in the UK, and more likely on the way, we are at turning point in the pandemic. However, whilst some countries are steaming ahead with their vaccination programmes, others have limited vaccine supply and/ or a lack of infrastructure and resources to vaccinate a large proportion of their population. Unless the virus can be eliminated everywhere, the potential for new variants of concern to emerge remains. Indeed, vaccination itself could put a selection pressure on the virus. For example, if a variant has mutations that enables it to escape recognition by the immune system, that variant will survive and continue to spread – i.e. adaptation.
While this might sound alarming, vaccine developers are already adapting vaccines to account for the genetic changes so far identified. Regulators, meanwhile, have issued guidance on fast tracking the approval process when updates to vaccines are made. Both of these will facilitate a fast and versatile response to the virus mutating.
The role of genomic surveillance is clear. It provides invaluable information about which variants are circulating, what mutations they have and flagging the variants that may make vaccines less effective. Over the next few months it will be important to genetically characterise variants that are able to cause infection in individuals who have been vaccinated.
Our work on pathogen genome sequencing
At PHG Foundation, we have been exploring the use of sequencing in infectious disease management for some years. In 2015, we released a report on the implementation of pathogen genome sequencing in the UK health system. The report sets out a roadmap supported by multiple recommendations for embedding pathogen sequencing into public health and clinical laboratories. With developments of genomic surveillance advancing rapidly, the report goes beyond surveillance to explore the range of applications where pathogen genomic sequencing could help in the fight against infectious disease.
More recently, we have been investigating the use of genomic sequencing during the pandemic with the Foundation for Innovative New Diagnostics (FIND). Our recent report expands on the impact of identifying SARS-CoV-2 variants of concern and the role of genomic surveillance for informing public health and policy.