Coronavirus: mutations

Mutations are normal

The emergence of new virus variants is nothing unusual: Viruses – including the Sars-CoV-2 pathogen – repeatedly randomly change their genetic makeup during replication. Most of such mutations are meaningless. But some are beneficial to the virus and prevail.

In this way, viruses can quickly adapt to the environment and their host. This is part of their evolutionary strategy.

In the meantime, however, so-called “Variants of Concern” (VoC) have emerged with Sars-CoV-2 – that is, variants that are of concern to experts. What they have in common is that they are more contagious than the original form of Sars-CoV-2.

These are the following four variants:

• Alpha: The line, also known as B.1.1.7, spread from the UK.
• Beta: The line, also known as B.1.351, spread from South Africa.
• Gamma: The line, also known as P.1, spread from Brazil.
• Delta: The line, also known as B.1.617, spread from India.

Virus variations are grouped into so-called clades or lines – researchers create a kind of “family tree of the coronavirus”. Each variant is characterized according to its genetic make-up and given a combination of letters and numbers. Whether a certain virus strain is more dangerous or not cannot be determined from this designation – it is only used for systematic recording and documentation.

The World Health Organization (WHO) recently suggested introducing new names for the most important Sars-CoV-2 variants. According to the WHO, individual virus variants are now to be named in ascending order according to the Greek alphabet.

This new, simpler and, above all, neutral description is intended to prevent new virus variants from being equated with the location of their first detection. This is to prevent unjustified and scientifically unfounded stigmata, discrimination and prejudice against individual countries in the public debate.

How is the coronavirus changing?

In principle, there are two ways for the coronavirus to “successfully” develop further: It changes so that it can get better into the human cell, thereby becoming more contagious, or it tries to “escape” our immune system by adapting:

Improved cell entry: This is particularly the case when beneficial changes develop within the so-called receptor binding domain (RBD) of the spike protein (for the virus): The spike protein is the “door opener” for human cells. The stronger the interaction with the ACE2 receptor of the human cell, the easier it is for a virus particle to get inside the cell – and the more contagious and dangerous the respective virus variant is.

Escape mutation: These are changes that enable the coronavirus to “escape” the immune system. The virus then changes its external shape in such a way that the (already formed) antibodies of an initial infection or vaccination are now less able to “recognize” and neutralize it. One also speaks of “escape mutations” or “immune escape”. This could make secondary infections more likely.

The longer the pandemic lasts, the more virus variants?

Yes. The longer the pandemic lasts, the more infections, the more variations and mutations of the coronavirus. The corona pandemic has been going on for a good year and a half: As of June 9, 2021, the Johns Hopkins Coronavirus Resource Center (CRC) is now reporting around 174 million cases of infection worldwide.

Opportunity enough for the coronavirus to accumulate diverse changes (variations) in the genetic make-up.

Since not every country in the world can offer comprehensive medical care or has the same test and documentation capacities, one can assume a high number of unreported cases worldwide.

These enormous numbers of cases – and the associated genetic changes in Sars-CoV-2 – are reflected in the now widespread spread of a large number of new virus variants:

Alpha: The B.1.1.7 line

The coronavirus variant Alpha (B.1.1.7) was detected for the first time in the UK. B.1.1.7 has increasingly spread to the European continent from the south-east of England since autumn 2020.

With 17 mutations, the B 1.1.7 line has a noticeably high number of genetic changes. Several of these mutations affect the spike protein. The N501Y mutation is very important.

Experts assume that B.1.1.7 is around 35 percent more contagious than the wild type of Sars-CoV-2. According to a study by the Universities of Exeter and Bristol, the observed death rate from infection with the UK virus variant is 4.1 people per 1,000 cases.

Infection with B.1.1.7 without prior vaccination therefore carries a 64 percent higher risk of fatal outcome – compared to the original virus variant. However, it is not yet possible to assess whether people with certain pre-existing conditions (diabetes, high blood pressure, etc.) are particularly at risk. This research was conducted prior to the widespread use of coronavirus vaccines in the UK. Preliminary data suggest that the Pfizer-BioNTech and AstraZeneca vaccines are highly effective against the B.1.1.7 line.

Beta: The B.1.351 line

The B.1.351 line (501Y.V2) – also called Beta according to the new WHO nomenclature – first spread in South Africa. In addition to N501Y, there are other mutations (E484K, K417N) of the spike protein.

The mutant very likely developed as a result of a high level of infection with the virus in the South African population. South Africa already recorded large-scale coronavirus outbreaks in the summer of 2020. In the townships in particular, the virus found ideal conditions in which to spread by leaps and bounds.

This means very many people were already immune to the original form of Sars-CoV-2 – the virus had to change. Researchers refer to such a situation as evolutionary pressure. Therefore, a new virus variant has gained acceptance that was superior to the original form because, among other things, it is more contagious.

Experts consider the additional mutation E484K to be a possible escape mutation: in other words, an “escape adaptation” of the coronavirus to the human immune system. This could mean that antibodies that the immune system developed against the original form of Sars-CoV-2 could no longer fully recognize B.1.351. Those affected could be infected a second time.

Preliminary data suggest that the Pfizer-BioNTech vaccine is also highly effective against the B.1351 line. The AstraZeneca vaccine, on the other hand, could, according to a preliminary statement by the authors Madhi et al. have a reduced effectiveness.

Gamma: The P.1 line

A new circulating variant called P.1 – previously known as B.1.1.28.1, now called Gamma – was first discovered in northern Brazil in December 2020. Like the alpha variant (B.1.1.7) and the Beta variant (B.1.351), P.1 also has the important N501Y mutation. This P.1 virus strain is also highly contagious.

It originally developed and spread in the Amazon region. The spread of the variant goes hand in hand with the sudden increase in Covid-19-related hospital admissions in this region in mid-December 2020.

In Brazil, too, the virus was able to reproduce ideally for a long time. This resulted in a high level of contamination among the population. As in South Africa, this could have been the reason for the correspondingly high pressure to adapt to the virus. Here, too, the virus had to “fight” the human immune system over a longer period of time. A unique combination of specific mutations that is beneficial for the virus has established itself.

Experts are also concerned because P.1 – among others – also has the mutation E484K. The Brazilian virus could also infect people who were already infected with Sars-CoV-2 again. There are increasing reports from the badly affected Amazon region that P.1 has been shown to reinfect Covid-19 patients who have already recovered.

Delta: The B.1.617.2 line

The Delta variant of Sars-CoV-2 is now also spreading in Europe. Although the proportion of infected people is currently 6.2 percent (as of June 17, 2021), it had almost doubled within a week. Experts assume that the variant will also prevail in Europe and also on other continents.

The situation in the UK, where more than 90 percent of those infected with Delta, shows that this virus has the potential to spread among and through people who have only received one vaccination. The good news is that the second immunization can also effectively limit this virus.

How much more contagious is Delta?

A person infected with delta is 60 percent more likely to infect household members than those infected with the alpha variant. And this was already significantly more contagious than an infection with the original variant of Sars-CoV-2.

Is Delta More Dangerous Than Original Virus?

Most likely. A study from Scotland published in the prestigious journal The Lancet shows that the risk of hospital treatment for an infection with Delta is twice as high as with the original variant.

Do the vaccinations protect against the Delta variant?

Yes. However, at least the protection after just one AstraZeneca vaccination, which otherwise worked even better than a syringe from Pfizer-BioNTech, is significantly weaker than against the original virus form and other, already known variants. Even after the second injection, the protection seems to be reduced.

Pfizer- BioNTech protects 79 percent against illness against Delta after the second vaccination dose compared to 92 percent against the Alpha variant, which was initially detected in the UK. After vaccination with AstraZeneca, the protection after the second vaccination dose is 60 percent compared to 73 percent.

However, these numbers also relate to mild and moderate symptomatic courses. How well the vaccinations protect against severe disease and death is not taken into account, but it is precisely here that the protection rating could be significantly better.

Delta Virus – Immunological Facts

The delta variant of the coronavirus (B.1.617) was first found in India. It shows three sub-variants and combines several characteristic changes. Such a bundling was demonstrated for the first time in a virus variant.

On the one hand, these are changes in the spike protein, which is considered the “key” for the human cell. On the other hand, B.1.617 also shows changes that are discussed as a (possible) escape mutation.

Specifically, B.1.617 combines the following mutations:

• The D614G mutation: it can make the coronavirus more contagious. Initial modelling indicates that B.1.617 is transmitted at least as easily as the very contagious Alpha variant (B.1.1.7).
• The mutation E484K: Was also found in the Beta variant (B.1.351) and the Gamma variant (P.1). It is suspected of making the virus less sensitive to neutralizing antibodies that have already been formed.
• The L452R mutation: It is also being discussed as a possible escape mutation. Coronavirus strains with the L452R mutation were partially resistant to certain antibodies in laboratory experiments.

Other known virus variants

In addition, additional Sars-CoV-2 virus variants developed that differ from the wild type – but experts do not currently count them as VOCs. These virus strains are called “Variants of Interest” (VOI) – that is, variants of particular interest.

It is not yet clear what impact these emerging VOI could have on the pandemic. Should they hold their own against strains of viruses that are already in circulation, they too could be upgraded to corresponding VOCs.

Variants of particular interest

According to the European Center for Disease Prevention and Control (ECDC), these VOI currently include:

• Epsilon: First discovered in California ( B.1.427 and B.1.429 )
• Zeta: First discovered in Brazil ( P.2 )
• Eta: proven in many countries ( B.1.525 )
• Theta: First discovered in the Philippines ( P.3 )
• Iota: first discovered in the USA in the New York area ( B.1.526 )
• Kappa: first discovered in India ( B.1.617.1 )

There are also other VOI that are not yet described according to the new WHO nomenclature:

• B. 1.616 first discovered in France.
• B. 1,620 of unknown origin.
• B. 1,621 first discovered in Colombia.

Variants under observation

The so-called “Variants under monitoring” (VUM) are also in the expanded focus – however, there is still no reliable, systematic data on these. Usually there is only evidence of their bare existence. They include sporadically occurring variants or “modified” – or better said further developed – descendants of already known mutations.

According to the ECDC, these rare VUM currently include:

• Variants of unknown origin: B.1.214.2, A.27 , A.28 , C.16 and B.1.1.318
• Other variants that were first detected in South Africa: B.1.351 + E516Q and B.1.351 + P384L
• Other variants that were first detected in UK: B.1.1.7 + L452R and B.1.1.7 + S494P, A.23.1 + E484K
• Other variants that were first detected in the USA: B.1.526.1, B.1.526.2
• Variant that was first detected in Russia: AT.1
• Variant that was first detected in Egypt: C.36 + L452R
• Variant that was first detected in Peru: C.37

Although a great number of new virus variants are now known, this does not automatically mean a greater threat. A risk assessment is not yet possible at this point in time. The influence of this VUM on the (global) infection process cannot be foreseen either. So whether some virus variants are relevant or dangerous can only be clarified by further observations.

How dangerous are coronavirus mutations?

The coronavirus mutations officially classified as “Variants of Concern” are, according to the current state of knowledge, more dangerous than the wild type of the coronavirus. They are highly contagious, and their appropriated changes (escape mutations) could promote secondary infections.

However, a general assessment of whether other coronavirus mutations are more dangerous than the original Sars-CoV-2 pathogen is not easily possible. There is a lack of experience and a solid database, especially with the new variants.

What does the higher contagious power mean?

If the Sars-CoV-2 becomes more contagious, it will also be more difficult to stop its spread. Measures that have so far successfully contained the spread may then no longer suffice.

If, for example, it is possible to lower the replication value R for the wild form of the virus to 0.8 and thus gradually reduce the number of infected people, a virus that is around 35 percent more contagious would spread further and set chains of infection in motion if the same measures were taken.

What does this mean for the vaccines?

There is no general answer to this. A possible reduced protective effect of the newly developed vaccines is lively discussed in specialist circles. So far, the vaccine manufacturers and preliminary investigations have given the all-clear in this regard.

In initial studies, for example, Pfizer-BioNTech shows comparable effectiveness against the Alpha variant (B.1.1.7) and Beta variant (B.1.351). AstraZeneca also seems to give good protection in B.1.1.7, but the effectiveness against the B.1.351 line could be reduced.

To what extent the other vaccines from Moderna and Johnson & Johnson will hold their own against the modified virus variants has not yet been conclusively clarified.

As the virus progresses, vaccine adjustments may be necessary. However, due to the progress in vaccine development, this can be done in a short period of time. However, all vaccines approved in the European Union still provide effective and adequate protection – especially against severe and fatal courses of Covid-19.

Further information on the subject of coronavirus vaccines can be found here.

How quickly does Sars-CoV-2 mutate?

In the future, Sars-CoV-2 will continue to adapt to the human immune system and to a (partially) vaccinated population through mutations. How quickly this happens depends largely on the size of the actively infected population.

The more cases of infection – regional, national and international – the more the coronavirus multiplies – and the more frequently mutations occur.

Compared to other viruses, however, the coronavirus mutates relatively slowly. With a total length of the Sars-CoV-2 genome of around 30,000 base pairs, experts assume one to two mutations per month. For comparison: Influenza viruses mutate two to four times as often in the same period.

How can I protect myself from coronavirus mutations?

You cannot specifically protect yourself against individual coronavirus mutations – the only option is not to become infected.

As a general rule, adhere to the rules of hygiene, keep your distance and wear your FFP2 mask in public. If you get vaccinated, you will also enjoy a good basic immunity against severe courses.

How are coronavirus mutations discovered?

Germany has a close-knit reporting system to monitor circulating Sars-CoV-2 viruses – it is called an “integrated molecular surveillance system”. To this end, the relevant health authorities, the Robert Koch Institute (RKI), specialized diagnostic laboratories and the consulting laboratory for coronaviruses at the Berlin Charité work closely together.

How does the reporting system work if a mutation is suspected?

First of all, every professionally carried out positive coronavirus test is required to be reported to the responsible health authority. This includes coronavirus tests that have been carried out in a test center, at your doctor, in your pharmacy or at government facilities – such as schools. However, private self-tests are excluded from this.

If the result is positive, doctors send the corresponding patient sample to a specialized diagnostic laboratory, which confirms the result using a PCR test. If the PCR test is also positive – the sample can also be sent to a sequencing laboratory where it can be further examined (sequencing genome analysis).

The RKI then compares the reporting data and the result of the sequence analysis in a pseudonymized manner. Pseudonymized means that it is not possible to draw any conclusions about a single person. However, this information forms the data basis for scientists and stakeholders in the health care system in order to obtain a precise overview of the current pandemic situation. This enables the best possible assessment of the situation in order to (if necessary) derive political measures.

What is a sequencing genome analysis?

A sequencing genome analysis is a detailed genetic analysis. She examines the exact sequence of the individual RNA components within the viral genome. This means that the Sars-CoV-2 genome, comprising around 30,000 base pairs, is deciphered and can then be compared with that of the coronavirus wild type.

Only in this way can the individual mutations be recognized at the molecular level – and an assignment within the “coronavirus family tree” possible.

Genome sequencing is a time-consuming and costly process with (very) limited capacities. So not every positive sample can be routinely sequenced. Experts make a preselection – so they take a sample.

This also makes it clear that not every country in the world is able to track the exact spread of certain coronavirus variants in detail. It is therefore likely that there is a certain lack of clarity in the available reporting data.