Why the U.K. Coronavirus Strain Just Got (Slightly) Deadlier, To Our Surprise

Wasn’t SARS-CoV-2 supposed to become less deadly as it evolves? After all, a dead host is a dead-end for viruses.

Shin Jie Yong
Mar 15 · 9 min read
Image by rawpixel.com

Author’s note: A few clarifications have been added at the end of this article.

About a week post-publication, about 250 news outlets have covered the new study showing that people infected with the B.1.1.7 coronavirus (SARS-CoV-2) strain — first discovered in the U.K. around Sept 2020 and has now spread to over 90 countries — are 64% more likely to die than those infected with prior strains or variants.

This probably comes as a surprise since many of us thought that SARS-CoV-2 would become milder over time. After all, as viruses couldn’t live without a host, a dead host is a dead-end for viruses. So, what’s the point of killing the host quicker? This article will explain why this assumption is not necessarily true and why SARS-CoV-2 just got deadlier.

Although there’s debate on the term usage between strains and variants, this article defines a strain as a viral variant that has evolved a different biological property.

The new study that confirms what we don’t want

The study, “Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study,” published in the British Medical Journal (BMJ), is authored by researchers in renowned institutions in the U.K.

The study used PCR to differentiate between strains by the S (spike protein) gene. If the PCR detected other SARS-CoV-2 genes — such as the N or ORF1ab genes — except the S gene, it means that the person has been exposed to the B.1.1.7 strain whose spike protein is distinct from the older strains. Likewise, if the PCR detected the S gene, it means that it’s the prior SARS-CoV-2 strain with the older spike protein. A cycle threshold (Ct) value of <30 is considered as a positive result, a reasonable number.

The study then matched 54,906 persons with positive S gene (older strain) with 54,906 persons with negative S gene (B.1.1.7 strain) — ensuring that age, sex, ethnicity, income, and geographical distribution are almost equal in both groups. This ensures that the results obtained won’t be a result of these factors (e.g., age, sex, etc.), which we call confounders.

Only PCR results from 1 Oct 2020 to 29 Jan 2021 were analyzed, minimizing possible biases from different pandemic circumstances.

So, yes, the B.1.1.7 strain is more virulent now, but not drastically so, at least not in this study. Still, it’s not a piece of good news as it could mean that SARS-CoV-2 may become deadlier over time.

The 28-day mortality was then measured. In the older strain group, 141 (0.3%) deaths occurred. In the newer strain group, the number was 227 (0.4%). This translates to a hazard ratio of 1.64, which means that persons exposed to the B.1.1.7 strain were 64% more likely to die than those exposed to the older strains.

But ratio alone doesn’t inform much about personal risk. For instance, a 3% to 1% rate reduction means a 300% relative reduction (3%/1% = 3-fold), but only a 2% absolute reduction (3%–1% = 2%).

Therefore, in terms of absolute risk, the B.1.1.7 strain increases one’s risk of Covid-19 death from 0.3% (141 per 54,906 persons) to 0.4% (227 per 54,906 persons). As the authors wrote, “The absolute risk of death in this group of community identified participants, however, remains relatively low, increasing from 2.5 to 4.1 deaths per 1000 cases.”

One notable limitation of this study is that 88% of participants were 30–59 years old from the community, not hospitals. So, the death rate might have been higher if the at-risk elderly populations were not underrepresented.

So, yes, the B.1.1.7 strain is more virulent now, but not drastically so, at least not in this study. Still, it’s not a piece of good news as it could mean that SARS-CoV-2 may become deadlier over time.

Why it’s deadlier?

In the BMJ study, the researchers also found that those infected with the B.1.1.7 strain had higher viral loads — as indicated by lower Ct values —on average than those infected with the older strains. A higher viral load means increased viral replication, which might result in more severe disease.

In PCR, specifically RT-PCR, Ct values refer to the number of amplification cycles needed to detect the gene of interest. So, the higher the gene’s initial abundance is, the lower applications are required — thus, lower Ct values.

After adjusting for the Ct values as a confounder, however, the higher death rate in the B.1.1.7 strain group remains significant but with a lower hazard ratio at 1.37. This means that, after standardizing viral load, those infected with the B.1.1.7 strain were still 37% more likely to die.

So, viral load is only part of the reason behind the increased lethality of the B.1.1.7 strain. There’s something else that makes it deadlier, but the paper did not mention what that could be.

Overall, the B.1.1.7 strain may be deadlier because of its increased cell infectivity and antibody evasiveness from the N510Y and E484K mutation, respectively. And these two mutations really complement each other.

One possible reason could be an immune escape ability, which would lead to a more aberrant inflammation from failing to eliminate the virus as quickly as it should be.

Initially, the B.1.1.7 strain in the U.K. is characterized by the N501Y mutation that increases the virus’s ability to bind to the ACE2 receptor on human cells. This increases the viral infectivity and transmissibility, which may explain the higher viral load the B.1.1.7 strain produces.

However, on 1 Feb 2021, the U.K. Public Health England announced that the E484K mutation was already present in some circulating B.1.1.7 strains. The E484K mutation — first discovered in South Africa — endows SARS-CoV-2 the ability to evade antibodies, at least in lab settings.

Even the AstraZeneca/Oxford’s adenoviral vaccine is no longer effective against the SARS-CoV-2 strain carrying the E484K mutation in the real-wold. The Novavax and Johnson & Johnson vaccines are less effective against the E484K mutation in humans. Based on lab settings (not confirmed in humans yet), the Pfizer-BioNTech and Moderna mRNA vaccines may also be less effective at fending off this strain.

Overall, the B.1.1.7 strain may be deadlier because of its increased cell infectivity and antibody evasiveness from the N510Y and E484K mutation, respectively. And these two mutations really complement each other.

A more infectious SARS-CoV-2 has to ‘open’ its spike protein more often. And an opened spike protein makes the virus more vulnerable to the immune system’s antibody attacks. So, by evolving an antibody evasion mutation, the virus can be both infectious and deadlier at the same time.

Why didn't it evolve to be milder?

“After all, the seductive logic goes, from an evolutionary perspective it makes no sense for a pathogen to harm the host on which it depends for its survival,” Ed Feil, microbial evolution professor, and Christian Yates, mathematical biology senior lecturer, wrote for The Conversation. But “this comfortable chain of reasoning was rudely broken by the announcement,” they added, of a more transmissible and lethal B.1.1.7 SARS-CoV-2 strain.

How and why did this happen?

In the 19th Century, Theobald Smith, MD, introduced the “law of declining virulence” based on his observations that cattle exposed to a tick-borne disease multiple times had less severe disease than cattle with first-time exposure. Of course, this phenomenon may have been just immunity at work.

However, later in 1859, Australia introduced the lethal myxoma virus to control the rapidly growing European rabbit population. By the 1950s, the myxoma virus’s death rate decreased from 99.5% to 90%. This led to the wide acceptance of Smith’s law.

Ultimately, the law isn’t absolute. It sometimes applies but not always.

Ancient diseases such as tuberculosis, gonorrhea, and dengue never got weaker or less deadly, Prof. Feil and Dr. Yates mentioned. After a decade, there’s some evidence that HIV is getting a bit weaker in Southern Africa, but remains the same or even slightly deadlier in the U.S. and Europe. Even the myxoma virus did not support Smith’s law to the very end, with some reports showing that it may have regained some of its lethality among rabbits.

There’s no reason why a lethal microbe can’t spread quickly, virologists have mentioned, cautioning against the assumption that evolution would favor Smith’s law. A notorious example is HIV that causes AIDS, which has spread and killed widely.

Prof. Feil and Dr. Yates then highlighted a more robust evolutionary model of microbial virulence called the “trade-off” that two professors, Robert May and Roy Anderson, put forward in the late 1970s.

“May and Anderson proposed that the optimal level of virulence for any given pathogen will be determined by a range of factors, such as the availability of susceptible hosts, and the length of time between infection and symptom onset,” Prof. Feil and Dr. Yates explained. “It emphasises that each host-pathogen combination must be considered individually. There is no general evolutionary law for predicting how these relationships will pan out, and certainly no justification for evoking the inevitability of decreased virulence.”

So, either way, SARS-CoV-2 could benefit from being a milder (silent spreader, but perhaps slower) or more severe (faster spreader, but perhaps louder) disease-causing virus.

So, why did we even think that SARS-CoV-2 will get milder over time?

A modeling study published last month in Science predicted that SARS-CoV-2 might weaken to an endemic level in the future, akin to the common cold, because SARS-CoV-2 isn’t lethal in children. So, as subsequent generations progress, there may be less vulnerable populations due to immunity retained from childhood into adulthood.

Indeed, certain coronaviruses (229E, NL63, OC43, and HKU1) might have caused serious epidemics or pandemics in the past, but evolution might have attenuated their virulence over time into the mere common cold they are now. However, other coronaviruses — namely the 2003 SARS-1 and 2012 MERS — were successfully contained, so we never get to see how their evolution turned out to be. Thus, we can’t really conclude that Smith’s law of declining virulence has applied to every pathogenic coronavirus.

The “trade-off” model, on the other hand, states that each pathogen-host interaction and evolution trajectory is unique.

The next SARS-CoV-2 strain might evolve an ability to increase its replication rates, producing higher viral loads that would facilitate both transmission and disease progression. This is similar to what has happened now with the B.1.1.7 strain first discovered in the U.K.

Nevertheless, a SARS-CoV-2 strain that causes a more serious disease would enable contact tracing and isolation easier because symptoms will be more obvious. Such strain might thus be easily contained. So, it’s also reasonable to speculate that the next SARS-CoV-2 strain might evolve the ability to spread silently by causing more asymptomatic infections.

So, either way, SARS-CoV-2 could benefit from being a milder (silent spreader, but perhaps slower) or more severe (faster spreader, but perhaps louder) disease-causing virus.

The better scenario for us, however, is to perform global-scale vaccination to achieve herd immunity faster so that fewer vulnerable hosts are available for SARS-CoV-2 to infect. This way, we can slow down the SARS-CoV-2 evolution and minimize the uncertainty about how the next strain would turn out.

17 March 2021: A commenter has pointed out something I had overlooked. The BMJ study identified the U.K. B.1.1.7 strain via the negative S gene PCR result. But the B.1.1.7 strain is not the only strain with a distinct S gene from the previous strains or variants.

The South African B.1.351 (105 cases as of Feb 2021) and Brazillian P.1 (6 cases as of Mar 2021) strains have also been found in the U.K., including England, where this study was conducted. But since these two strains are not the dominant ones circulating in the U.K., the authors mentioned that the negative S gene cases in their study are “highly likely to be” the B.1.1.7 strain.

18 March 2021: As a commenter has pointed out, certain pathogens like the Ebola virus, tuberculosis-causing bacterium, and blood-borne viruses can remain infectious in a dead body for some time. After all, all cells do not immediately die following death. For SARS-CoV-2, however, the research is scarce on how it survives in a dead body. So, a dead host may not be a dead-end just yet. But at least a dead host can’t go around spreading the pathogen.

31 March 2021: A recent similar study published in Nature has also found that those with negative S gene status (most likely the B.1.1.7 strain) were 55% more likely to succumb to Covid-19 — after adjusting for age, sex, ethnicity, income, residence, and test date. While the absolute increased risk of death is small — from 0.6% to 0.9% among males aged 55–69 years within 28 days of testing positive for SARS-CoV-2 in the general community — it should be noted that it may be different for hospitalized patients.

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