Evolution of N501Y

Researchers suggest that the N501Y variant likely evolved from a single individual or a small group, rather than through gradual mutations across numerous infections. In patients with prolonged COVID-19, the virus may mutate rapidly to adapt to the host's immune response.

Genomic sequencing of SARS-CoV-2 from patients who did not recover quickly revealed a higher mutation rate, particularly in those treated with remdesivir and convalescent plasma. UK experts have proposed a sequence of events that might explain this, although they emphasize the need for further validation:

1. In patients with immune deficiencies, natural immune selection may be weak or absent.
2. Antibody treatments could exert strong selective pressure due to high concentrations of antibodies.
3. If administered after extended infections, a diverse viral population may be present, creating conditions conducive to rapid genetic changes.

Emergence of the Variant

There is no evidence to suggest that the N501Y strain was imported; it likely developed independently in the U.K. around September 2020, as reported by the British Medical Journal (BMJ). This strain has been designated as VUI-202012/01, marking it as the first “Variant Under Investigation” in December 2020. Other analyses have categorized it under the B.1.1.7 lineage, giving it three different names.

A related variant has also emerged independently in South Africa, where it spreads rapidly, according to virologist Tulio De Oliveira. This strain is referred to as 501Y.V2 in South Africa. The World Health Organization (WHO) has noted that the N501Y mutations in the U.K. and South Africa likely evolved separately. Preliminary data shared by De Oliveira highlights distinctions between these variants:

Records of this new strain have also surfaced in Spain, initially thought to increase COVID-19 mortality by 50%. However, later reviews indicated that the data was flawed and that the variant is not more lethal. Evidence shows its presence in the Netherlands, Denmark, Australia, Italy, Iceland, and potentially other countries lacking robust genomic monitoring.

As of January 1, 2021, the new strain has been detected in 20 countries, with some reporting importation from the U.K., while others remain uncertain of its origins.

Mutational Characteristics

The name N501Y indicates that the amino acid asparagine (N) at position 501 of the virus's genome has mutated to tyrosine (Y). However, the U.K.'s N501Y strain is characterized by a total of 17 mutations, with N501Y being the most significant as it occurs in the spike protein.

For further insights regarding strains vs. variants, refer to:

Many Strains of Coronavirus Are Out There, but Only One Is Important Scientists analyzed functions of over 100 distinct SARS-CoV-2 variants — how many strains did they find? medium.com

In a preliminary study titled “Preliminary genomic characterization of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations,” researchers from the COVID-19 Genomics U.K. Consortium and top universities have examined the genetic properties of this new strain, revealing several mutations that may alter the virus's behavior:

• The N501Y mutation in the spike protein’s receptor-binding domain (RBD) may affect its binding affinity to the ACE2 receptor on human cells.
• The 69–70 deletion mutation results in the loss of two amino acids, potentially enhancing the virus's ability to evade the immune response.
• The P681H mutation, located near the spike protein’s furin cleavage site, may have unknown implications for infection.
• Additional mutations in ORF1ab and the M gene are considered less critical.

Virulence Assessment

Currently, only a limited number of studies have provided insights into the biological characteristics of the N501Y strain. Three independent reports suggest that mutations replacing asparagine at position 501 with other amino acids enhance the binding capacity of SARS-CoV-2 to the human ACE2 receptor.

A notable study published in the journal Science titled “Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy” presents valuable insights. Researchers conducted an innovative experiment involving repeated passages of SARS-CoV-2 in mice over several generations to mimic natural evolution. The study found that the virus became more virulent, with increased symptom severity and viral replication.

Through genome sequencing, five key mutations were identified, including N501Y. Advanced data analyses indicated that N501Y is responsible for enhancing both the virus's binding efficiency to the ACE2 receptor and its lethality. The authors noted, “The increased virulence of SARS-CoV-2 MASCp6 in mice was likely attributed to the rapid emergence of the N501Y substitution.” Fortunately, the recombinant subunit RBD-Fc vaccine prevented severe disease caused by MASCp6.

Although this might seem concerning, it's important to note that MASCp6 is not identical to the N501Y strains circulating in the U.K. or South Africa. Thus, its virulence in mice may not translate to human strains. Clinicians in South Africa have observed a shift in COVID-19 demographics, with more young individuals without underlying health issues being hospitalized, as noted by Health Minister Zweli Mkhize. However, these observations are anecdotal, necessitating further research to ascertain the true virulence of these new variants.

As of January 1, 2021, preliminary data from Public Health England (PHE) indicated no significant differences in mortality rates between individuals infected with the new strain and those with earlier strains, with both groups matched for age, sex, location, and testing time.

Transmissibility Insights

As previously mentioned, the U.K. Prime Minister stated that the new SARS-CoV-2 strain is 70% more transmissible. According to the European CDC, this figure is based on mathematical modeling, which shows that the reproductive number (R-naught) has increased by at least 0.4.

The question remains whether this increase is coincidental or causal. Mathematical models can sometimes be inaccurate. Some researchers argue that this increase is more likely an association with specific superspreader events rather than a direct increase in infectivity due to N501Y.

Moreover, the European CDC has noted that the D614G mutation is present in the new N501Y strain. Unlike N501Y, D614G has been shown to enhance transmissibility in both animal models and cell cultures. Therefore, if the new U.K. strain is indeed more transmissible, it may be largely due to D614G or a combination of D614G and N501Y.

What the D614G Mutation Means for Covid-19 Spread, Fatality, Treatment, and Vaccine Real-life implications of the global shift of D614 to G614 variant. medium.com

As of January 1, 2021, a preprint study from the Center for Mathematical Modeling of Infectious Diseases at the London School of Hygiene and Tropical Medicine estimated the new strain is 56% more transmissible, with a range of 50–76%. This study found no evidence linking the new strain to more severe COVID-19, aligning with PHE's findings.

Future Considerations

Health officials have expressed concerns regarding potential COVID-19 reinfections linked to the new SARS-CoV-2 strain. Documented cases of reinfection have occurred, typically involving sufficiently distinct strains.

If reinfection is suspected, sequencing the virus's genome is essential to check for N501Y or other mutations. Close monitoring of the reinfected individual is crucial to observe any developments related to resistance to treatments like monoclonal antibodies or vaccines.

Further studies are needed to explore the biological functions of these newly emerged strains. We currently lack comprehensive knowledge about their virulence, transmissibility, and vaccine susceptibility. It is essential to recognize that these factors do not have binary answers; understanding the degree of change in virulence is critical. Fortunately, minor genomic changes, like those seen with the N501Y strain, typically do not lead to significant alterations in biological behavior.

Presently, “With this variant, there is no evidence that it will evade the vaccination or human immune response,” stated Sharon Peacock, a professor of public health and microbiology and director of Covid-19 Genomics UK. “However, if vaccine failure or reinfection occurs, it should be prioritized for genetic sequencing.”

This emergence of a new SARS-CoV-2 strain underscores the challenges posed by allowing the virus to mutate. Although its mutation rate is lower than that of influenza or other viruses, the cumulative effect of time and the number of circulating coronaviruses among humans can lead to significant changes. Vaccines, social distancing, masking, and hand hygiene are effective strategies to limit SARS-CoV-2 mutations.

Genetic Diversity of SARS-CoV-2 Vs. Other Nasty Viruses A universal vaccine is nearly impossible for HIV, influenza, or hepatitis viruses. How about the novel coronavirus? medium.com