Mutations, mutations, mutations

08 Feb 2021

Jimmy Muchechetere Dr. CFA

Senior Equity Analyst

Virus mutations are a fact of life and while we do not know when mutations will occur, we do know that they will. Dr. Jimmy Muchechetere explains exactly why and how mutations happen, and what can be done about them.

How do mutations work?

Mutations are a fact of life. Many cells divide regularly and in the process of replicating, errors may occur, and it is these errors we call mutations. Some changes may not be errors but deliberate changes to adapt to a new environment – an evolutionary process of sorts. Viruses are typically made up of a string of amino acid bases that contain instructions on how to multiply.
 
Upon entering a cell, viruses use the machinery of the cell to make more viruses. If the instructions are misread, what are called transcription errors, the new virus churned out by the cell will be slightly different i.e. a mutant variant1. It must be said that these errors are completely random.
 
And so it follows, the more chances a virus has of multiplying, the higher the chances of a mutation. The more a virus spreads in a community, a high viral burden, the more chances it has of multiplying and mutating. So there is no magic in mutations or antigenic drift as it is known du jargon médical, it is a game of numbers.

How has Covid-19 mutated?

We had been warned but not that went unheeded. In March and April last year, a variant called D416G emerged in Europe2. This was found to be ten times more transmissible than the wildtype variant first identified in Wuhan. This new mutation quickly spread across Europe, causing the scenes we saw in Lombardy and the rapid increase in cases in the UK3.
While we do not know when mutations will occur, we do know that they will. But here is the important point, mutations are not made equal. Many mutations are inconsequential. Indeed many deleterious mutations lead to death of the virus and we never know of them.
Others result in a strong bond between virus and human cell receptor, binding affinity, which often results in increased transmissibility. This seems to be the situation with the B.1.1.7 variant, first identified in Kent. 
 
Still, other mutations result in immune-escaping variants. The B.1.351 variant first identified in South Africa, according to early data, seems to partially evade immunity, resulting in a weaker immune response for those infected with it, and for those who have natural or vaccine-induced immunity, escape in about 50% of people4
To date, we have had four key mutations. The first was D416G which increased transmissibility but had little effect on virulence. The N501Y mutation, found in the B.1.1.7 variant, has a higher binding affinity to the ACE-2 receptor, increasing transmissibility. Thus far there is no data to conclude on its virulence but we know it does not cause immune escape.
 
The B.1.351 variant carries the K417N and E484K mutations that are showing, in early data, some ability to escape immunity, ergo, reduce vaccine efficacy. Some data from Public Health England in January suggested that the E484K mutation had been found in some B.1.1.7 variants5  – a cause for concern but also a reminder that we are in a race against time.

What might happen next?

The data are early and still evolving so we watch for developments with great interest. If the raison d’etre for a virus is to multiply and spread, then killing its host is not the desired outcome, ergo, a more deadly mutant is defeatist as far as the virus is concerned. Rather, a more transmissible variant, needing fewer particles and taking less time to spread, is the ideal outcome. There is no a priori reason that the virus will not exhaust its mutational avenues, many viruses do.
 
Although mutations occur randomly, the rate of mutation of viruses differs greatly. Some viruses mutate rapidly. It has been demonstrated that the human immunodeficiency virus (HIV), can in a single day, mutate to confer drug resistance hence necessitating a multi-drug approach. Other virus rarely mutate. The measles vaccine which was developed in the 1980’s, is still effective today.
 
Many other viruses mutate at a rate that falls in between these two6. Sars-CoV-2, the virus that causes Covid-19, does not replicate fast enough to evade being cleared by the immune system, as most people recover within a few days and viral replication peaks 2-3 days before onset of symptoms. It has been shown that viral replication can continue for those who are immunosuppressed. This is a small minority and so natural and vaccine-induced immunity ought to be significant in controlling the spread of the virus.

What is the worst-case scenario?

A mutant that completely escapes immunity, both natural and vaccine-induced, which would leave us back as square one. While this is theoretically possible, it remains unlikely with Sars-Cov-2. This virus is a simple mRNA virus that uses one spike protein to attach to the ACE-2 receptor on human cells. This means mutations on the virus other than the spike protein do not cause escape immunity as vaccines are designed to target that spike protein.
 
Variations in the spike protein are the subject of the mutations hitting the headlines. If too extreme, the virus may lose its ability to bind and enter human cells. If too similar to the original, then there is little impact on immunity, this is what we think applies to the B.1.1.7 variant. Mutations in the middle therefore need to balance retaining the ability to enter cells while different enough to evade immune mechanisms.
In dealing with mutations, natural immunity differs somewhat from vaccine-induced immunity.  Vaccines are designed to produce specific proteins which then stimulates the immune system. If a mutation occurs and the specific proteins are substantially different to the ones carried by the new variants of the virus, the vaccine-induced immunity is thus watered down at the least, and rendered useless at the most.
The former situation is what we think has happened with the B.1.351 variant and quite possible the 501Y.V3 variant first identified in Brazil. Natural immunity though is more robust on two accounts. First, the immune system recognises more than just the spike protein as it gets a look at the whole virus. Secondly, the immune system evolves as it continuously in surveillance mode and forming antibodies to match new mutations.
 
As the Sars-Cov-2 virus stops replicating after about 5-7 days, the immune system tends to be primed only for the original variant, explaining why one can get re-infected by a mutant strain. Nevertheless, recognition of other parts of the virus speeds up the immune response, relative to someone naïve to Sars-CoV-2, and tends to result in asymptomatic or less severe disease the second time round.

What can be done about mutations?

The first line of defence is constantly searching and seeking out deadlier variants. In this respect, the UK is a world-leader and so should provide for an early warning system. There is a global effort to sequence and share viral RNA to help track mutations, all collated on GISAID7. Secondly, scientists have already identified what could be troublesome mutations –D796H, Y453F, and ΔH69/ΔV70 which if they do occur are likely spell trouble8,9, the prospective mapping and surveillance is already underway.
 
Thirdly, pharmaceutical companies can and will adapt their vaccines to account for the mutations. Fourth, pharmaceutical companies are designing multivalent vaccines, targeting multiple points of the spike protein, which would require many more mutations to occur simultaneously to afford escape. Finally, there is work around vaccination regimes to mix and match traditional vaccines with mRNA vaccines to elicit as broad an immune response as possible (humoral and cell-mediated). 
 
In the long term, eradication of Covid-19 will largely depend on immunity, natural or vaccine-mediated, lasting long. In the meantime, the biggest weapon against mutations remains preventing infection and reducing the burden of disease. So while highly efficacious vaccines may dig us out of the hole we are in, vaccine effectiveness relies on non-pharmaceutical interventions (physical distancing and case isolation) to keep infections down, break the chains of transmission and reduce the possibility of mutations.