While COVID-19 has fallen from the spotlight of media attention, the pandemic is far from over. Through a process referred to as immune evasion – or antibody escape – the virus has endured and continues to spread throughout the globe. With winter fast approaching, we could soon expect another wave.
The hallmark waves of the pandemic have characterised COVID-19. Immune evasion has played a role in this. The World Health Organization (WHO) identified variants of concern (VOCs) throughout the pandemic. The most well known of these were the Delta variant, and the Omicron variant.
Fresh waves of COVID-19 typically corresponded with the emergence of a new strain. New strains such as Omicron have demonstrated the capacity to infect those who have previously been infected with the disease, or even those who have been vaccinated. This is due to the process of immune evasion allowing these strains to effectively bypass the immune system.
A recent study has analysed immune responses to yet another COVID-19 variant, a sub-strain of the Omicron variant.
In order to understand the process of immune evasion – and the implications for the future of COVID-19 – we must first understand how the immune system operates, and how vaccines play a role in this.
Through natural infection with the virus, the body produces antibodies. These cells are able to detect a specific antigen, in a form of lock and key mechanism that allows the body to detect and destroy invading pathogens if exposed to them a second time. In the case of viruses such as COVID-19, the spike protein is the focus of discussions of immunity and virality. The spike protein is a membrane protein on the viral surface that forms a protrusion. The purpose of the spike protein is to facilitate interaction, and, importantly, the capacity of the virus to interact with cell surface receptors located on the host cells to facilitate viral entry and therefore, infection.
Vaccines use these easily recognisable domains of pathogens as a means of introducing the immune system to the targeted antigen without exposure to the pathogen. Some vaccines use artificially weakened strains of a virus, some use dead strains with no capacity for reduced effects of the vaccine. In either case, the human body detects the antigens of the viral strain and begins to produce antibodies. Should the person be exposed to the real thing, the immune system has already been trained to recognise and respond to the viral threat.
mRNA vaccines, while not a new technology, have been brought into the media spotlight during the COVID-19 pandemic. While only sparsely utilised beforehand, the two mRNA COVID-19 vaccines produced by Pfizer and Moderna may have advanced research in the area by decades.
mRNA vaccines differ from conventional vaccines in that they are entirely synthetic. Whereas a typical vaccine will use actual pathogenic material to provoke recognition within the body’s immune system, mRNA vaccines do not use any pathogenic material. Instead, mRNA vaccines operate by teaching cells within our body to produce a protein, or even part of a protein. RNA is the intermediary step between DNA and the production of proteins. While DNA acts as genetic storage, RNA is used in the process of translation in order to create proteins from the genetic information. mRNA vaccines operate by entering cells in the body following injection. The mRNA provides instructions to the cells to produce copies of some of the components found in the spike protein, allowing recognition of the virus should the real thing invade the body.
While vaccines are an important tool in averting disease instances, as well as in reducing the severity of disease where it does still occur, the process of immune evasion allows diseases to avoid eradication. Some pathogens are prone to mutation. Typically, such as with conditions like influenza, these diseases are airborne, and spread rapidly. With so many hosts infected, each and every viral replication holds the potential for a mutation – a change in the genetic code. This can allow for a pathogen to evade the host’s previously accumulated immune response.
Not all mutations create such a situation. The changes made are a result of replication errors and so are entirely random. Some changes may do nothing at all, some may cause a change in a membrane protein that causes enough of a structural change that it renders the viral particle unviable. Others, however, such as those found in the currently circulating strains of COVID-19, have caused structural changes within the spike protein.
This can result in changes that are potentially beneficial to the replication cycle of the virus. One characteristic of the Delta strain was the mutation to the spike protein that, it was theorised, allowed for the virus to more readily bind to human cell surface receptors. This in turn made the virus far more transmissible, at the time allowing it to become the predominant circulating strain.
Omicron mutations have been associated instead with immune evasion. A critical finding has been that many cases of Omicron have occurred in people who have either previously been infected with COVID-19, or have been immunised. This has suggested that mutations are present that have caused a change in the structure of the antigen domain that make it more difficult for previously generated antibodies to detect and destroy the virus.
The study, published in Cell Host & Microbe, has analysed the immune response to a number of Omicron variants compared to the formerly dominant Alpha variant (D614G mutation strain).
The study primarily investigated BA.2.75, a strain predominantly circulating in South East Asia. The experiments involved the use of neutralising antibodies (nAbs) in serum samples taken from either healthcare workers vaccinated with mRNA vaccines, either primary or booster doses, as well as patients hospitalised during the Omicron surge. Viral samples were added to the serum samples and the results monitored the capacity for the antibodies within the samples to neutralise the viral strains.
Concerningly, BA.2.75 was found to have increased neutralisation resistance even when compared to the BA.2 strain of Omicron that it recently branched out from. Both of these variants showed a considerable level of resistance when compared to the ancestral D614G strain.
Moderate to severe previous infection with the Omicron strain was found to provide less protection against the new strain when compared to vaccination alongside a single booster dose. However, while a booster dose of vaccination was found to restore a degree of neutralising capacity against Omicron strains, it would appear that the effects of a booster are reduced the further a strain has mutated since its ancestral variant. Compared to the original D614G strain, boosters had a five-fold weaker effect against BA.2.75, and a four-fold weaker effect against BA.2 and BA.2.12.1. Other recent strains showed even more resistance to antibodies, with the BA.4 and BA.5 variants of Omicron having a 10-fold resistance compared to D614G.
The BA.2.75 was identified as having nine mutations in the spike protein region compared to the ancestral strain, with three of these differentiating it from its closest BA.2 relative. The researchers marked the G446S and N460K mutations, as well as the reversion mutation R493Q as notable within the strain.
The implications of the study are not a new conclusion. As viruses spread and replicate they run the risk of becoming more extensively mutated and resistant to current vaccines and treatments. This is true of not just COVID-19, but is mirrored in other diseases such as tuberculosis, with strains now circulating that are resistant to multiple lines of treatment. It is for this reason that any declaration of the pandemic being over, may be preemptive.
For as long as COVID-19 is in circulation – and, with an estimated 200,000 to 600,000 cases a day worldwide, it is very much still in circulation – there lies the possibility that a mutation occurs that makes the disease more transmissible, more lethal, and ever more difficult to deal with.