New SARS-CoV-2 monster on the block

Recently, we all have heard about the new UK strain of SARS-CoV-2 that is touted as more transmissible (i.e., the ability of the virus to be passed from one person to another, or the “infectiousness” of the virus) - resulting in numerous countries banning flights from the UK, an introduction to new lockdown measures; and closely tracking the spread of this new strain on a global scale as a potential threat to our collective measures to fight COVID-19. But what is the actual evidence to suggest that this new strain is indeed of a greater threat than the previous strains?

Surprisingly very little can be found in the media. So little in fact, that we wonder why such drastic measures and the spread of fear-mongering took place without proper evidence. Increased surveillance, yes, increased vigilance, yes, but dramatic steps prior to establishing the scientific validity of this new strain’s behaviour is highly inappropriate as we can potentially impact thousands of lives negatively.

We decided to dig for some facts and it was exciting to see the first scientific analysis emerge. We wanted to go over this carefully as sometimes science can be used ingeniously in how it gets to a point, and let’s you discover a proper background on a new threat, especially if we are to be subjugated to the increased fear of a new hazard (that should not be dismissed lightly). Let’s try to get to know our new monster that we have to face.

But above all, this is a story about how rapid data capture and scientific analysis can be used for the incredible surveillance of SARS-CoV-2 in order to protect the global population to the best of our abilities (even if at times misguided). Only time will tell (and judge) the current response we are taking to the COVID-19 pandemic, but this story of a UK new SARS-CoV-2 strain exemplifies how rapidly the leaders are willing to respond to maintain the general safety of the population, and how the work of thousands of people around the clock is used to monitor the evolution of the virus and the pandemic. How the decision was made to proclaim the emergence of this new threatening strain is not discussed in the media and very few have actually probed for its scientific merit. We simply all got the announcement. But are you curious, where did it come from? Very few people get to peak behind the curtains. So, sit back, relax and enjoy this complicated but very fascinating ride of how apparently a more infectious strain of SARS-CoV-2 was caught in its early tracks and an instant global alarm was raised.

What happened to start all of this?

UK breaks the scary news to the world

The news of the new UK SARS-CoV-2 virus strain was first announced on December 19 in a statement by Prime Minister Boris Johnson. It was this communication that proposed the unsubstantiated claim that the new strain was 70% more transmissible with a reproductive number (R value) of 0.4 higher than the original strain (R value changing from 1.1 to 1.5, meaning that of 100 infected people, they are expected to infect 150 other people instead of 110 people). That communique did mention that this is a big “maybe” though.

This is what the world originally saw and then responded to immediately.

The following day, on December 20, the European Union Centre for Disease Prevention and Control (ECDC) published information warning of the new UK SARS-CoV-2 strain labelled as VUI 202012/01 (and currently labelled as B.1.1.7) where again no supporting data was provided to confirm the estimated transmissibility of the virus, but at least it was mentioned that these conclusions were arrived at based on modelling using existing information.

But what exactly was this based on?

The statement of the British Prime Minister was based on the findings of a specially designed advisory group on New and Emerging Respiratory Virus Threats (NERVTAG). Basically, it seems like the UK assembled some of the smartest people in the nation to warn them about virus threats. They met on December 18 to review the data and make recommendations. It seems that it was the minutes of this meeting that resulted in an immediate announcement to the nation by the Prime Minister, and these NERVTAG meeting minutes are publicly available. They are a truly fascinating detective story. A two-hour long meeting that changed the world!

What did those folks look at? How was this new threat discovered? It appears they had two sets of data: the PCR test results and genomic data of the virus (we are talking about decoding the RNA genome of SARS-CoV-2 samples collected throughout the country) although no actual data was presented in the notes. The data appears to have been modelled multiple different ways to come to all conclusions.

The geographical area of southern UK and London indicated higher rates of infection than the rest of UK. Along with the fact that UK has one of the best programs for tracking the genomic sequences of the SARS-CoV-2 virus. Together these allowed them to identify a new strain B.1.1.7 that was significantly different than the original SARS-CoV-2. Check out the progression mapped on Twitter.

How new variant B.1.1.7 spread across England and London pic.twitter.com/JMSVfgSobm

— Theo Sanderson (@theosanderson) January 9, 2021

Furthermore, the genomic data allowed them to not only decode the sequence of the new strain, but also estimate the amount of the virus in the studied samples. It appears that at least 1000 samples were studied. The more virus present in the sample, the more of its genome is available for sequencing. This allowed them to estimate that the new UK virus strain grows approximately 71% faster than the previous strains. This is not the same as increased transmissibility, but rather it means that once within bodies, the virus production cycle is faster. In other words, infected person becomes infectious to others faster. That lag time between becoming infected and being infectious to others is shorter. This of course should correlate with an increased ability of the virus to infect new hosts (increased transmissibility), but the December 18 NERVTAG notes did not in fact mention anything about specific increased transmissibility number. So we wonder if the Prime Minister’s statement got the information confused when it announced increased transmissibility by combining two separate statements together? If so, that would be kind of a cute mistake on the part of the leader, but the point is that the Prime Minister took this warning to heart and acted immediately. From the outside, that looks like instant desire to protect UK people (and by extension, the rest of the world). The UK did not try to hide the facts under the pretext of further investigation. It took immediate action to protect the rest of the world. When China did its very first lockdown in Wuhan, while perhaps it was not as fast in delivering data - that lockdown was also meant to protect its people and the rest of the world (and they were going in blind with a first of its kind pandemic lockdown). In some ways, the pandemic exposes our actions on a level of global responsibility and that is very beautiful and extremely mature of our collective humanity. While wars will continue between people, a pandemic makes all humanity a common victim and this is uniting all of us in that we are all the same in the end in this battle.

The increased viral load as observed from increased amount of viral genome available for sequencing was also supported by the fact that those infected with the new UK virus strain also were more easily detected with the COVID-19 PCR test with corresponding lower Ct values. Ct refers to cycle threshold, or how many times a virus genetic information in the PCR test has to be copied before it can be accurately detected. The lower the Ct value of the PCR test, the more starting viral material was available in the samples. The take home message is that those infected with the new UK virus strain appear to have more of the virus in their samples.

Tracking the genomics sequences of samples throughout the country also allowed them to estimate the R value between 0.39 to 0.93. The Prime Minister reported the lower estimate. The higher estimate is a scary number though because if that were true, if we understand this correctly, basically it would nearly double the infection rate. We do not want to see that so let’s hope the on the ground reality will bear out the lower value.

In addition, based on the fact that this strain showed up during a time of already high infection rates in the country (meaning, different viruses have to compete against many compromised hosts who already exhibit some form of immunity – so fewer and fewer people to infect), and also during the present existing stringent lockdown then these facts taken together could indicate that the mutations observed in the new UK virus strain have a very distinct advantage in propagation from person to person over prior strains.

Thus, the conclusion of the meeting was summarized as follows:

“NERVTAG has moderate confidence that VUI-202012/01 demonstrates a substantial increase in transmissibility compared to other variants.”

And that kicked off the storm of warnings, vigilance and whatever measures we could employ to protect people from this virus.

What we still do not know about this new UK SARS-CoV-2 strain

There were other very important statements in the NERVTAG meeting notes we should examine.

What NERVTAG could not estimate:

• How is the increased infectiousness of the virus between people actually achieved? In other words, how do the mutations in the virus allow it to take enhanced advantage of its environment to spread faster between people? There are just so many steps in the life cycle of the virus. What actually improved the virus so that we can then begin to fight it?
• Does age affect a person’s infection susceptibility?
• How does the virus affect COVID-19 disease severity? Of around 1000 studied cases, 4 people died. This is not a sufficient number to draw conclusions, yet.
• Whether the strain’s mutations provide an antigenic escape. Antigen is a word to describe any molecule that is targeted by antibodies. If the antibody is the lock, the antigen is the key that goes into that lock. Antibodies are built to recognize different three-dimensional surface areas of the virus. As a consequence not all antibodies are created equal as we discussed in previous post. Furthermore, if the three-dimensional surface area of the virus that is supposed to be recognized by the antibodies changes significantly, then these antibodies run the risk of not working or work less efficiently at recognizing the new UK virus strain. This is referred to as antigenic escape. But what this means is that those who previously been infected by SARS-CoV-2 and currently sport immunity, well, that immunity might not work against the new strain and such person could be infected again. As the NERVTAG concluded: “Four probable reinfections have been identified amongst 915 subjects with this variant but further work is needed to compare this reinfection rate with comparable data sets.” To us that sounds like a lot because we thought reinfection was a very rare event. This is why there is a fear that the current vaccines might not work, and so this premise is now being tested. It is this exact reason, plus other risks, that some used to argue against the current mRNA vaccine design and instead recommended using only part of the spike protein for the final antigen produced from the template provided by the mRNA vaccines (for review of this please see our last post).

Thus, there are still some big unknowns.

In addition to that, the meeting notes mentioned that a group of scientists from the London School of Hygiene and Tropical Medicine built a model using additional parameters. Their data suggested that this new UK virus strain could be 56% more transmissible (with a 95% statistical confidence of accuracy that could include transmissibility anywhere between 50-74%. So Boris was still within the right window of statistical probabilities).

Now that we analyzed the transmissibility to death, let’s mention that increased transmissibility does not necessarily mean a greater severity of the COVID-19 disease. This might sound counter-intuitive as you would automatically assume that a greater rate of infection between people would result in a greater chance of observing the development of COVID-19 disease but that is the whole point - virus infection does not have to mean that a person will actually develop COVID-19, and that is the topic we previously mentioned about the potential problem with PCR testing in terms of diagnosing COVID-19. Does the PCR test used actually diagnose the disease or does it diagnose an infection? The point is that SARS-CoV-2 infection does not have to result in COVID-19. Many people who seemingly get infected do not develop any disease symptoms (although that also does not mean that they are not ravaged from inside without any symptoms showing up immediately or acutely as opposed to later on). Thus, even though the new UK SARS-CoV-2 could be more infectious, the same mutations that could have helped the process of transmissibility could underpower it from being able to lead to COVID-19 and as a consequence the virus could be more easily dealt with by the body. At the moment we simply do not know. We are taking precautions due to the chance that the increased transmissibility could lead to greater chance of COVID-19. Which is smart, but we do not have evidence yet to suggest that this strain is certainly an increased threat to our health.

Thus, the December 21 NERVTAG meeting notes concluded:

“The committee therefore has high confidence that B.1.1.7 can spread faster than other SARS-CoV-2 virus variants currently circulating in the UK.”

Only 5 days later, on December 26, data indicating how the estimates of increased transmissibility of the new UK SARS-CoV-2 strain estimates of increased transmissibility of the new UK SARS-CoV-2 strain preprint publication (meaning it has not been peer reviewed). Currently this is the only scientific information available to us to support the potential new threat of this new strain.

We will dive into that in more detail as this is one fascinating virus strain.

How is the new UK virus strain unique?

What is unique about this new UK virus that seemingly appeared out of nowhere, is the new strain showed up with 17 new mutations within the virus genome. The ECDC suggested that this new strain was unlikely to have arrived from gradual accumulation of these mutations because of the very high surveillance in the UK of the SARS-CoV-2 genome using DNA sequencing so basically this build up would have been observed before.

What is super interesting is that ECDC proposed that “One possible explanation for the emergence of the variant is prolonged SARS-CoV-2 infection in a single patient, potentially with reduced immunocompetence ” (meaning, their immune system was not strong enough to wipe out the virus allowing the virus to mutate and adapt to the hostile environment). Why is that super interesting? Because this is the same theory that has been previously proposed for the potential emergence of SARS-CoV-2 virus in the first place through infections of Chinese miners in 2012 with a related bat virus which we previously covered in another post. It is interesting that this theory has never been given any merit but is also used by a reputable organization to explain an emergence of a novel and substantially different strain of SARS- CoV-2 virus. Perhaps there are nuances that we just do not fully understand as to why in one case the theory can be accepted and in another it cannot be. As the ECDC stated “Such prolonged infection can lead to accumulation of immune escape mutations at an elevated rate” which is exactly what was proposed to have potentially taken place with the Chinese miners in 2012 who suddenly came down with mysterious respiratory illness reminiscent of current COVID-19 symptoms.

First, let’s take a look at these genetic changes.

Of the 17 new mutations in the SARS-CoV-2 genome in the new UK strain, 8 are in the spike protein, the protein used by the virus to contact and invade our cells via ACE2 receptor found on the surface of our cells. It is especially the spike protein mutations that are of concern and could explain why we see the increased rates of infection with this new strain. The top three spike protein mutations that are expected to have biological significance are:

• N501Y mutation where the number indicates the position of amino acid in the spike protein that is affected by the mutation while the letters are a shorthand description of which original amino acid is substituted by another as a consequence of the mutation in the viral genetic code. Remember, amino acids are the building blocks of proteins, which are the molecular robots that execute the majority of activity within cells to create an illusion that a cell is alive (it is simply an exquisitely coordinated random movement of inanimate molecules that together make a cell appear to be alive but we are only talking about chemical reactions to specific stimuli). Amino acids are strung together and eventually this snake of amino acids can start folding onto itself (due to chemical bonding between different amino acids) to form very specific three-dimensional shapes. The code for how amino acids are supposed to be put together into this continuous string is encoded in the genomic code of the SARS-CoV-2 virus. So, if the genome mutates, a mutation can result in a substitution of one specific amino acid for another. This is exactly what took place in this case, and this happens to be a very important spot for the final three-dimensional structure of the spike protein - this particular spot is needed for interaction with our own human ACE2 receptors. Thus, you can appreciate its importance. It is also this alteration that was tracked with genomic sequencing to follow the new UK virus strain.
  Finally, this N501Y mutation was just confirmed not to reduce effect of the current mRNA vaccines. This is important because that is important antibody target area. Antibodies targeting that specific area of the spike protein where the mutation changes the protein make up might stop recognizing the area affected by the mutation. Luckily, that does not seem to be the case although this was based only on 20 vaccinated individuals. Incredible how rapidly that data was generated!
• P681H mutation, the function of which is unclear, but it is located immediately adjacent to the furin cleavage site in a spike protein. The furin cleavage site is the unusual feature that makes SARS-CoV-2 especially prone to infecting our cells, and it is still unknown how it showed up in this virus as none of the closely related viruses have such a feature. This unusual presence of a furin cleavage site in the SARS-CoV-2 spike protein has been used by some to suggest that SARS-CoV-2 has been synthesized rather than originated in nature but you should not be surprised that no actual solid proof of such has ever been presented.

• And the mutation that we found the most fascinating is a deletion of two amino acids at positions 69-70 of the spike protein. This particular mutation has been observed in multiple independent strains of SARS-CoV-2, and has been proposed that it allows the virus to escape the immune system’s detection in immunocompromised patients. Also, this same deletion is the site used for SARS-CoV-2 detection in several commercial diagnostic PCR tests, thus it is this very deletion that leads to failure of such test to detect the spike protein gene we mentioned above. This is one of the reasons why PCR tests have to look for SARS-CoV-2 detection by targeting multiple SARS-CoV-2 genes at the same time. Ever since strains with such a deletion emerged, leading to spike protein gene detection failure, this phenomenon of failing to detect the spike protein gene has been referred to as “S gene drop-out”. Cute, right? At that point, the only way to confirm which strain of virus we are dealing with is through sequencing of the virus genome, and sequencing confirmed that nearly all virus strains that exhibit this S gene drop out in PCR tests in the UK are the new B.1.1.7 strain.

Your movement in a pandemic and models of pandemic

What we also found fascinating is how the authors of the preprint proved that the observed greater infection rate in southern UK and London was likely due to the new virus strain and not some unusual circumstance like increased exposure of people with one another. The authors used Google phone data to show that mobility of people between southern UK and London and the rest of the country was very similar. Interesting that this type of data (that most people would agree they would prefer NOT to be collected unless they specifically consented to it), was actually used in a scientific analysis of SARS-CoV-2. It is also a powerful reminder of how much information is potentially gathered on every single individual, and that such data collection can be used either for good or bad purposes, depending on the choices made by those entrusted with the information storage. Once again, probably many would agree that use of such information for improving one’s health is a good idea. After all, most of us want to live longer healthier lives.

Adapted from doi: https://doi.org/10.1101/2020.12.24.20248822 preprint

The authors concluded nicely: “This apparent decoupling between social contacts and transmission during November and December could therefore indicate a change in characteristics of the virus.” Scientific language can be so polite. Would you like some cream with that?

The authors tested different models of what could be the contributing factor to the increased prevalence of the new UK virus strain. The good news is that the model based on a primary assumption that the increase is because prior COVID-19 survivors can be reinfected with the new strain did not pan out and the real-life data did not fit that model pattern and this suggests that the increased infection seen with this new virus is not because of that. The model that best fit the real-life observations was a model where the primary driver is the increase in transmissibility (each person infected with SARS-CoV-2 can now infect more people than before).

Shorter generations of the virus was also not good model design in comparison to real-life data because in that model lockdowns would be expected to reduce the number of infected people with the new UK virus strain, whereas in real life there was an increase. In fact, it was one of the least effective models, and therefore the least effective driver behind the increased rates of detection of the new B.1.1.7 strain in the UK population.

The authors then projected what could be expected in 2021 under lockdown measures. Basically, the current lockdowns appear to have a limited impact on the Covid-19 and therefore any increased transmissibility is expected to increase the number of infections and deaths and thus we could be seeing even worse numbers in 2021 compared to what we have seen in 2020. The only saviour in this picture would be a roll out of an extremely effective vaccine (their modelling was very generous in how effective the vaccine would be). The best performance, in terms of expected deaths, was observed with a complete national lockdown, schools closed and 2 million vaccinations per week! Sounds intense. But even then, according to their models, the worst hit regions would observe approximately 400 deaths/day in moderate lockdowns versus approximately 50 in the most extreme lockdown case scenario. The authors acknowledged that the strain could also affect the efficacy of vaccines though and so that will require testing. The model is based on the assumption that vaccines will work.

Time will tell. We have previously been duped with modelling because models always oversimplify the complex reality of the world. It is similar to the over-reliance on climate change models that subsequently do not come close to the future reality they attempted to predict. The world was expected to see how many catastrophic events based on these types of models?

But being cautious and prepared is definitely smart.

The authors’ sobering conclusion was, “without strengthened controls, there is a clear risk that future epidemic waves may be larger – and hence associated with greater burden – than previous waves.”

There you have it, all the science we could find so far on the new UK SARS-CoV-2 virus strain and what it can mean for us. It means potentially a new threat which may or may not impact the effectiveness of the vaccines. The virus is mutating and it appears to be adapting to be an even bigger pain by becoming more infectious.

Another such more infectious strain also just recently emerged in South Africa, again with numerous mutations affecting the spike protein. One of these is the N501Y mutations discussed above.

This shows the versatility of the problem and the continued difficulty of how we might have to fight this pandemic and that the SARS-CoV-2 virus might not be taken down so easily.

Let us hope that the vaccines will be effective.

But in the meantime, happy 2021 everyone!

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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