What to Know

• Mutations of the virus have given rise to thousands of variants, only a few of which currently appear as a major threat due to increased infectivity, lethality, or vaccine resistance.
• In the US, the current major variant is the so-called “UK” variant (officially “B.1.1.7”), which is about 35-50% more infectious or transmissible, and can give rise to a rather more lethal form of COVID-19.
• The doubling time of the “UK” variant in the US, where it is expected to become the dominant form of the virus by March 2021, is estimated to be 9.8 days.
• The other major variants, the “South Africa” and “Brazil,” are less widespread but considered more of a threat, especially with respect to vaccine resistance.
• Vaccine manufacturers are rushing to develop second-generation booster shots designed to combat these variants.
• The US currently lags far behind much of the world in systematic genomic sequencing of samples from confirmed cases of COVID-19, which is the only effective way to track the development and spread of variants.
• A bill currently before Congress would attempt to correct that lag with additional funding for the CDC.
• Viruses need human hosts in order to mutate, so the fewer the cases, the lower the opportunity for mutation and the formation of vaccine-resistant variants.
• Therefore, continuation of established precautions during the current vaccine roll-out – “hands, face, space, vax” – is essential.

Mutations and Variants

Mutations refer to errors in the RNA-based genetic code of the novel coronavirus (SARS-CoV-2) that occur naturally as the virus replicates within a human host. Although other RNA viruses (e.g., influenza) typically have higher rates of mutation than DNA viruses (e.g., papillomavirus, smallpox), coronaviruses mutate less frequently than other RNA viruses because they encode an enzyme that can correct some of the errors made during replication (Luring and Hodcroft, JAMA, Feb. 9, 2021). Mutations are subject to the basic evolutionary concept of “survival of the fittest”: those that confer some sort of benefit on the virus such as increased transmission rates or infectivity tend to spread faster, while those that are detrimental to the virus tend to disappear.

A single mutation in the spike protein of the novel coronavirus – the target of most current vaccines – refers to a single change in its amino acid sequence caused, in turn, by a replication error in the RNA sequence of the viral genome that encodes it. The term “variant” is generally used to refer to a form of the virus differing from the original or “wild” type and containing one or more (sometimes many more) mutations, which together may confer some significant change in its properties. One of the earliest reported mutations occurred in several parts of China in January 2020 and was designated “D614G.” This simply means that the amino acid aspartate (abbreviated as “D”) had been replaced by the amino acid glycine (“G”) at position 614 on the half of the spike protein S (called the subunit S1) that binds to the ACE-2 receptor on the surface of the human host cell. This mutation had spread to global dominance by April 2020; it was later shown to be transmitted more efficiently and therefore able to spread faster than the original form of the virus, which it quickly supplanted.

It is estimated that the novel coronavirus undergoes a mutation about once every two weeks, or about half the rate observed with influenza (Callaway, Nature, September 10, 2020). However, this process may be leap-frogged in individuals with severe and prolonged cases of COVID-19, primarily those who are immunosuppressed or immunocompromised. For example, in one case study reported in the New England Journal of Medicine (NEJM) in December 2020, a patient receiving multiple immunosuppressants for a long-standing, severe autoimmune disease was admitted to a Boston hospital on day 0, diagnosed with COVID-19, put on a course of remdesivir and discharged on day 5. He was readmitted on day 68, but after several courses of treatment died on day 154, after a total of 5 months. Genetic sequencing of the virus showed multiple mutations, especially in the spike protein, that accumulated over time during the course of his disease. (Choi et al.) In another recent case from the UK, an elderly immunosuppressed individual was treated with two courses of remdesivir and then convalescent plasma, and his virus sequenced at 23 time points spanning 101 days. Little change in the virus was observed during the remdesivir treatment, but mutations on the spike protein appeared after the convalescent plasma therapy, one of which showed two-fold higher infectivity than the “wild type” virus. (Kemp et al., Nature on-line, Feb. 5, 2021.) One of the lead authors of the NEJM letter has recently opined that immunocompromised individuals should be prioritized for vaccination, both for their own safety and also for the benefit of the population in general, to help retard the development of potentially more serious variants of the virus. (US Chamber of Commerce Foundation on-line presentation: “COVID-19 Variants: What You Need to Know,” February 17, 2021.)

Major variants have been reported in the United Kingdom, South Africa, and Brazil. Although these may not necessarily be the countries where the variants first emerged, they are where they were first detected, and that is how they have been unofficially identified: the “UK” variant, the “South African” variant, and the “Brazil” variant. However, it is important that countries first detecting and reporting variants not be stigmatized as the sources, since it is in everyone’s best interests that countries are encouraged to report variants of concern as soon as they are detected. In addition to these unofficial names, there are at least two different official variant naming systems in use, which adds to the confusion. (Callaway, Nature, 21 January 2021.)

The UK variant is now spreading rapidly throughout the United States and appears to be both more transmissible and more lethal than the existing version of the coronavirus. The South African and Brazil variants are also present in the United States but are currently at much lower levels than the UK variant. However, they appear to be significantly more resistant to at least some of the first generation of COVID-19 vaccines, and a second generation of booster shots is being rapidly developed to address them. A summary of these and other significant variants is provided in the Appendix to this Alert.

The Need for Increased Genomic Surveillance

On the basis of the old adage “forewarned is forearmed,” it is clearly imperative that the world be alerted to new and potentially more infectious or lethal variants of the novel coronavirus as soon as possible after they initially emerge. That can only be achieved by widespread and consistent use and sharing of the genetic sequencing of virus samples from as many confirmed COVID-19 cases as possible. To that end, genetic sequences of novel coronavirus samples from confirmed cases across the globe are maintained in a database by GISAID (originally the “Global Initiative on Sharing Avian Influenza Data”) located in Geneva, Switzerland, which makes the data freely available. Unfortunately, contributions to this database vary enormously from one country to another and are not necessarily reflective of a nation’s prosperity, technical prowess, or population size. The UK, with its centralized COVID-19 Genomics UK Consortium, has already contributed 280,000, or close to 50%, of the genome sequences in the database, representing almost 5% of its confirmed cases, while Denmark has contributed data from 12% of its cases (7% of the database) and Australia almost 60% of its cases. Even South Africa, which lacks the resources for such large-scale sequencing, has been able to establish a Network for Genomic Surveillance that can sequence a random 50-100 samples per week, and this has been vital in tracking the progress of the South African variant. The US, on the other hand, with its fragmented genomic surveillance system, has contributed data from only about 0.3% of its cases. A new US variant would probably be rapidly detected in states such as New York that have plenty of sequencing capacity, but much more slowly in other states that lack that capacity. As noted in a recent article, this is a problematic situation, because the longer a virus circulates, the greater is the opportunity for it to mutate undetected (Cyranowski, Nature, January 21, 2021).

As a result of this country’s major lag in genomic surveillance, Senator Tammy Baldwin and Representative Scott Peters introduced legislation, the Tracking COVID-19 Variants Act, into Congress on February 4, 2021. It would provide $2 billion to the CDC to support a “robust, national sequence-based surveillance program that is vital to protecting public health and combatting the next phase of the COVID-19 pandemic while preparing for emerging threats.” One of the goals of the proposed legislation is to sequence at least 15% of confirmed cases of COVID-19.

The Bottom Line

A virus can only mutate to new and potentially more infectious, lethal or vaccine-resistant variants when it is circulating through the human population. Consequently, the more that transmission and infection can be reduced, the lower the opportunity for the formation of such variants. The experts are therefore stressing how essential it is to continue to maintain the well-established precautions of hand-washing, face-masks and social distancing even as a greater and greater percentage of the population receive the first-generation COVID-19 vaccines – “hands, face, space, vax.”

Appendix

SIGNIFICANT VARIANTS OF THE NOVEL CORONAVIRUS

The “UK” or “Kent” Variant

This variant was first detected in September 2020 in the county of Kent in southeastern England, from where it spread rapidly in a devastating wave across the UK that resulted in significant lock-downs. Officially it is designated variant B.1.1.7 or 20I/501Y.V1. It has accumulated over 20 mutations (at least 8 of which are in the spike protein), which suggests that it may have originated from a chronically infected individual. The spike protein mutations include N501Y, which is shared with variants from South Africa and Brazil, discussed below. Originally it was merely one of the hundreds of different variants detected in the UK, which currently has the world’s most advanced coronavirus sequencing program.[1] However, by the end of 2020, it accounted for approximately 28% of cases in England, and that figure has now risen to about 90%. The variant has already spread to 82 countries, including the United States, where it is thought to have been first introduced in late November 2020 on multiple independent occasions, primarily in Florida and California and then Georgia and Michigan, presumably as the result of international travel followed by domestic travel over the holiday season. It has now spread to 44 US states with 1661 total cases as of February 21, 2021 (CDC). Washington et al. have recently estimated its average doubling time in the US to be 9.8 days (medRxiv preprint, posted February 7, 2021); these authors have confirmed CDC’s earlier modeling estimate that the variant is likely to be the dominant form of the novel coronavirus in the US by March 2021, although confirmation will be hindered by the lack of a national genetic sequencing surveillance program.

The UK variant has been shown to be about 35-45% more infectious or transmissible than the original form due to its increased ability to attach to human cells, and this may be partly due to the N501Y mutation. A UK government report issued on February 11, 2021, indicates that it is also associated with an increased disease lethality, estimated to be about 35%. In addition, at least one PCR-based COVID-19 test has failed to detect it on account of the multiple mutations. Nevertheless, the current crop of vaccines for which there are Phase 3 clinical trial results, including those already authorized by the US, UK, or WHO, appear to be encouragingly effective against this variant, albeit at a somewhat reduced level compared to the earlier form of the virus. For example, Novavax recently announced the results of the UK trial of its genetically engineered NVX-CoV2373 vaccine; they showed an efficacy of 95.6% against the original strain and 85.6% against the UK variant.

One recent observation of concern, however, is the appearance of an additional mutation, designated E484K (known colloquially as “Eeek”), in the UK variant in small clusters of cases (11 in Bristol, 32 in Liverpool); the E484K mutation is already present in the more threatening South African and Brazil variants.

The “South African” Variant

This variant was first detected in a fast-growing epidemic in Eastern Cape Province in late 2020. Its official designations are B.1.351 or 20H/501Y.V2, and it now accounts for over 95% of new cases in South Africa, having almost completely supplanted earlier versions of the virus. It is estimated to be 50% more transmissible than the earlier versions and is currently considered by many experts to be the most troubling of the major variants. It has spread to at least 41 countries, including 10 US states with 22 total cases (CDC, February 21, 2021). It carries multiple mutations in the spike protein, including some linked to weakened antibody activity against the virus. Investigators tested convalescent plasma from patients who had recovered from COVID-19 caused by earlier versions of the virus against those earlier versions and against this variant and found that the neutralizing effect of the antibodies in the plasma was much weaker against the variant. This raises the possibility of reinfection by the variant virus of individuals who have already recovered from earlier forms of COVID-19. However, most vaccines that have already been authorized or that are in advanced stages of development elicit high levels of antibodies that target a variety of regions of the spike protein, giving them the potential to block the variants; other aspects of the immune response from vaccines, including T cells, may also provide continued efficacy against this variant. In its recent Phase 3 clinical trial press release, Johnson and Johnson reported that its adenovirus-based vaccine showed efficacy against moderate to severe disease of 57% in South Africa compared to 72% in the United States. Similarly, Novavax reported that its vaccine had an overall efficacy in South Africa of 60% in HIV-negative subjects and 49.4% in HIV-positive subjects compared to an overall efficacy of 89.3% in the UK. South Africa recently paused the rollout of AstraZeneca’s adenovirus-based vaccine because a local university study had shown a low level of efficacy against the variant compared to 75% against the original virus, but that study had significant limitations, including too few participants to be statistically reliable, an emphasis on young, healthy individuals (median age 31), and a lack of data on severe cases. Regardless, AstraZeneca plans to have a second-generation version of the vaccine that is effective against the South African and other variants available later this year, while Pfizer, Moderna, and Johnson & Johnson are all rapidly developing third-shot boosters designed to counteract these variants.

The “Brazil” variant

This variant was first detected in Manaus, in the state of Amazonas. It is officially designated P.1, B.1.1.248, or 20J/501Y.V3. It may have been responsible for a second wave of infections in Manaus in January 2021 that strained the local health system and led to oxygen shortages, and also for some recently reported cases of reinfection. It has similarities to both the South African and the UK variants and, like the South African variant, contains the E484K mutation. It is thought to be more transmissible, and to elicit a reduced immune response, compared to the earlier form of the virus circulating in that region of Brazil. Currently, it has spread to at least 9 other countries, including 4 US states with 5 total cases (CDC, February 21, 2021).

Other Notable Variants

The Southern California Variant

This variant, designated CAL.20C, has been described by Zhang et al. in a recent letter to JAMA (published online February 11, 2021). It has evolved from just 4 cases in Southern California in October 2020, to 30 cases in Northern California and cases in 5 other states in November, to detection in 26 states and other countries by January 22, 2021. It has three mutations in the spike protein, one of which is associated with resistance to certain monoclonal antibodies.

The “Bird” Variants

This refers to a collection of seven variants currently circulating in the United States that all contain mutations at the same location (677) on the spike protein. First reported in a preprint in medRxiv posted online on February 14, 2021 (Hodcroft et al.), the variants have been named after birds to make them more readily identifiable. The mutations are thought to allow escape from neutralizing antibodies or to show enhanced transmission. “Robin 1” has been found in over 30 states, especially in the Midwest, while “Robin 2” and “Yellowhammer” appear mainly in the southeast, “Quail” mainly in the southwest and northeast, “Bluebird” also in the northeast, and “Mockingbird” mainly in the south-central US and east coast; “Pelican,” first seen in Oregon, now appears in 12 other states and four other countries.

Mink Farm Variants

Outbreaks of COVID-19 began to appear on mink farms in Denmark and the Netherlands towards the middle of 2020; one investigation showed human-to-mink, mink-to-mink, and mink-to-human transmission. Genetic sequencing of the virus showed the frequent appearance of a common mutation in the spike protein (Y453F), which may represent an enhanced affinity for the virus to bind to the ACE-2 receptor on mink cells. Although the Danish authorities reported just 214 cases of human COVID-19 associated with mink farms, the outbreaks were of concern because of the potential risk that ongoing viral mutations in such an animal reservoir could lead to new strains of novel coronavirus that could transfer to humans and possibly other mammals. As a precaution, some countries performed large-scale culls of farmed mink, while others instituted increased surveillance.

[1] The UK program is run by the COVID-19 Genomics UK Consortium, a joint government-academia collaboration that started work early in the pandemic, on April 1, 2020. It currently accounts for close to 50% of global coronavirus genetic sequencing reported to the GISAID database. Although it currently shares with GISAID the coronavirus sequencing from about 5% of the UK’s confirmed cases, its intention is to increase this to at least 10% and preferably 20%