Biology of N501Y, A Novel U.K. Coronavirus Strain, Explained In Detail
By: Shin Jie Yong
Tags: Health, Life, Science, Public Health, Covid 19

Biology of N501Y, A Novel U.K. Coronavirus Strain, Explained In Detail

Image by torstensimon from Pixabay

A new SARS-CoV-2 strain called N501Y has been spreading widely in London and south-east England. “The spread is being driven by the new variant of the virus,” the U.K. Prime Minister, Boris Johnson, said in a press conference. “It appears to spread more easily and may be up to 70% more transmissable than the earlier strain.” This new strain caused about 60% of SARS-CoV-2 infections in London, reported Chris Whitty, England's chief medical officer. As a result, the country was initiating a lockdown yesterday. Many other countries have also restricted travel from the U.K.

Anyways, let’s see what the scientific literature has to say on this newly emerged SARS-CoV-2 strain.

Its evolution

Scientists believe that the N501Y strain evolved in single or a few individuals, rather than mutations accumulating slowly over iterations of virus infections in many different people. In those fighting Covid-19 for an extended duration, SARS-CoV-2 may have mutated at a high rate to keep up with the on-going onslaught by the host immune system.

Indeed, sequencing SARS-CoV-2 genomes revealed a higher mutation rate from patients who did not recover early from Covid-19 and were later treated with remdesivir and convalescent plasma. This may have resulted from a sequence of events that experts in the U.K have proposed, although they cautioned that further verifications are still required:

First, selection from natural immune responses in immune-deficient/suppressed patients will be weak or absent. Second, the selection arising from antibody therapy may be strong due to high antibody concentrations. Third, if antibody therapy is administered after many weeks of chronic infection, the virus population may be unusually large and genetically diverse at the time that antibody-mediated selective pressure is applied, creating suitable circumstances for the rapid fixation of multiple virus genetic changes through direct selection and genetic hitchhiking.

Its emergence

There’s no evidence that the N501Y strain was imported from elsewhere, so it has most likely evolved independently in the U.K. around September 2020, the British Medical Journal (BMJ) reported. The BMJ also named this strain VUI-202012/01, which stands for the first “Variant Under Investigation” in December 2020. Another preliminary analysis has classified this strain under the B.1.1.7 lineage. So, overall, it goes by three names for now.

A similar strain has also arisen independently in South Africa, where it’s also spreading much faster, according to Tulio De Oliveira, a virologist associate professor at the University of KwaZulu Natal. He has also done work on this new strain that first notified the U.K. about the emergence of N501Y. In South Africa, this strain is called 501Y.V2.

The WHO has also reported that SARS-CoV-2 with N501Y mutation in the U.K. and South Africa have evolved independently of each other. Differences between the U.K. and South Africa strains were detailed in the preliminary data that Assoc. Prof. Oliveira posted on Twitter:

Credit: Assoc. Prof. Tulio De Oliveira tweet. As stated in the summary, South Africa’s 501Y.V2 coronavirus strain has 15 mutations — of which 8 occurred in the spike protein — and one deletion. In contrast, the U.K.’s B.1.1.7 (also called N501Y or VUI-202012/01) has 14 mutations (of which six occurred in the spike protein) and 3 deletions (of which 1 occurred in the spike protein). More details on the mutations are discussed below.

There are also records of this new SARS-CoV-2 strain in Spain, where it was initially believed to increase Covid-19 mortality by 50%. But later, scientists realized that the data was flawed, and the new strain is not any more lethal. Evidence also exists that this new strain emerged in the Netherlands, Denmark, Australia, Italy, Iceland, and maybe other countries lacking robust SARS-CoV-2 genomic monitoring system.

1st Jan 2021 update: The new SARS-CoV-2 strain has been detected in 20 countries. A few countries reported that the strain was imported from the U.K., and others remain unsure of its origin.

Its mutations

N501Y means that the amino acid N (asparagine) at position 501 of the virus’s genome mutated to Y (tyrosine). However, the so-called N501Y strain in the U.K. is actually distinguished by a set of 17 mutations, of which N501Y is the defining one as it occurs in the coronavirus’s spike protein.

For more information on strain vs. variant, kindly see here:

In a preliminary report, titled “Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations” and researchers at the Covid-19 Genomics U.K. Consortium and other top universities have analyzed the genetic features of this move strain. And they found several mutations that may alter the coronavirus’s functions.

N501Y mutation in the spike protein’s receptor-binding domain (RBD) may alter its binding capacity to the ACE2 receptor on human cells.

69–70del mutation means loss of two amino acids at positions 69 and 70 in the spike protein, which may increase the coronavirus’s ability to evade the immune system.

P681H mutation near the spike protein’s furin cleavage site with unknown consequences. Since the furin cleavage site mediates cell infection, this mutation is suspected to be important.

Presumably less important: 5 mutations in ORF1ab (C913T, C5986T, C14676T, C15279T, C16176T), and 1 mutation in M gene (T26801C).

Its virulence

Presently, only a few studies have provided hints on the biological properties of the new coronavirus N501Y strain (or VUI-202012/01 or B.1.1.7).

Three separate reports have found that mutations changing N (asparagine) at position 501 to other amino acids increase the binding capacity of SARS-CoV-2 to the human ACE2 receptor, according to bioinformatics modeling and cell culture studies. To reiterate, N501Y means that the amino acid at position 501 changed from N (asparagine) to Y (tyrosine).

A study published in the top-ranking journal, Science, titled “Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy,” can tell us more. Herein, researchers in China did an innovative experiment to repeatedly passage SARS-CoV-2 in mice over many generations to emulate natural evolution. Briefly, a dose of SARS-CoV-2 was inoculated into the mice's nose. After a few days, the infected mice were sacrificed to isolate the viruses from their lungs, which were re-inoculated into another mice’s nose.

At subsequent mice generations, the coronavirus became more virulent with increased symptom severity, viral replication in the respiratory tract, and viral dissemination to other organs. They called this mice-adapted SARS-CoV-2 the coronavirus MASCp6.

Sequencing its genome, the study discovered five key mutations, with one of them being the N501Y. More advanced data analyses showed that N501Y is responsible for increasing both the coronavirus’s binding efficiency to the ACE2 receptor and disease lethality. As the authors wrote, “the increased virulence of SARS-CoV-2 MASCp6 in mice was likely attributed to the rapid emergence of N501Y substitution in the RBD [receptor-binding domain] of SARS-CoV-2 S [spike] protein.” But thankfully, vaccinating mice with one of the Covid-19 candidate vaccines — the recombinant subunit RBD-Fc vaccine — prevented MASCp6 from causing severe disease.

While this seems alarming, it should be noted that MASCp6 is not exactly similar to the new SARS-CoV-2 strains in the U.K. (i.e., N501Y, VUI-202012/01, or B.1.1.7) or South Africa (501Y.V2). Thus, MASCp6’s virulence in mice may not translate to these other strains circulating in human populations. Plus, MASCp6 evolved in mice in experimental settings and not in humans.

However, clinicians in South Africa have said that they noticed a shift in Covid-19 epidemiology, where an increasing proportion of young people without medical comorbidities are getting hospitalized, said Zweli Mkhize, the minister of Health. But these are anecdotes and might be a coincidence. So, more research is definitely needed to determine the virulence of these newly emerged strains.

1st Jan 2021 update: Fortunately, preliminary data from the Public Health England (PHE) found no significant differences in the death rate among 1,769 people infected with the new strain versus the older strain. Importantly, these two groups of people were matched in terms of age, sex, location, and time of testing.

Its transmissibility

As mentioned initially, the U.K. primer minister said that the new SARS-CoV-2 strain is 70% more transmissible. According to the European CDC, this number was derived from mathematical modeling showing that the reproductive number (R-naught) of SARS-CoV-2 has increased by at least 0.4.

Again, whether this increased R-naught is coincidence or causation remains uncertain. Mathematical modeling can sometimes be wrong. Others have argued that it’s more likely an association rather than causation, meaning that N501Y tagged along with certain superspreader events rather than directly increasing the coronavirus’s infectivity.

However, the European CDC has also reported that the D614G mutation is present in the new N501Y (or VUI-202012/01 or B.1.1.7) strain in the U.K. In contrast to N501Y, the increased transmissibility of D614G in animals and cultured cells have been demonstrated. Hence, if the new U.K. SARS-CoV-2 strain is causing an increase in infectivity or transmissibility, it’s more likely the job of D614G or D614G-N501Y synergism.

1st Jan 2021 update: A pre-print study from Center for Mathematical Modeling of Infectious Diseases at the London School of Hygiene and Tropical Medicine estimated that the new strain is 56% more transmissible with a possible range of 50–76%. This modelling study found no evidence that the new strain is related to more severe Covid-19, consistent with data from PHE above.

Its prospects

Health authorities have warned of possible Covid-19 re-infection from the new SARS-CoV-2 strain in the U.K. Indeed, true cases of re-infections have occurred many times, which are usually caused by two sufficiently distinct SARS-CoV-2 strains or variants —such as the D614G vs. Wuhan strains.

If Covid-19 re-infection is suspected, then the coronavirus’s genome should be sequenced and checked for any N501Y or other mutations. The re-infected person should also be followed closely to monitor any development of resistance to monoclonal antibody, convalescent plasma, or vaccine.

Future research also needs to study the biological functions of the newly emerged strains. We still don’t know much about its virulence, transmissibility, and vaccine susceptibility. Notably, these things should not be looked at as a yes/no answer. For instance, its virulence may increase, but how much is the increase is the more relevant question. The good news is that little changes in the virus’s genome — as with the case of the N501Y strain — don’t usually lead to massive changes in its biological behaviors.

Currently, “With this variant, there is no evidence that it will evade the vaccination or a human immune response,” said Sharon Peacock, a professor of public health and microbiology and director of Covid-19 Genomics UK. “But if there is an instance of vaccine failure or reinfection, then that case should be treated as high priority for genetic sequencing.”

This emergence of another SARS-CoV-2 strain also tells us why letting the coronavirus mutates can be problematic. Although the SARS-CoV-2 mutation rate is much lower than influenza or other nasty viruses, it can happen with time and numbers of coronaviruses circulating among humans. Also, even though SARS-CoV-2 has a slow mutation rate, its pandemic scale works in its favor. Vaccines, physical distancing, masking, and handwashing are some of the effective methods that we can use to mitigate SARS-CoV-2 mutations.