L strain of SARS-CoV-2?

L strain of SARS-CoV-2?

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Early in the epidemic, Chinese researchers (Jian Lu, et al,) reported in the National Science Review earlier this month that there was an aggressive more virulent L strain compared to the older S strain of the virus. Of the 103 viral genomes they scoured, 70% were of the L-type variant using phylodynamic analysis of samples taken during the earliest phase of the outbreak that began in Wuhan late last year. But subsequent later samples taken later in the course of the epidemic were mostly of the S strain. Peer review by researchers at other institutions have recently called this study into question.

Does anyone know where this stands currently? Has an aggressive L strain been confirmed? Do current rRT-PCR tests make any distinctions between L and S strains?

The six strains of SARS-CoV-2

Worldwide distribution of the SARS-CoV-2 six strains. Credit: Frontiers in Microbiology

The virus causing the COVID-19 pandemic, SARS-CoV-2, presents at least six strains. Despite its mutations, the virus shows little variability, and this is good news for the researchers working on a viable vaccine.

These are the results of the most extensive study ever carried out on SARS-CoV-2 sequencing. Researchers at the University of Bologna drew from the analysis of 48,635 coronavirus genomes, which were isolated by researchers in labs all over the world. This study was published in the journal Frontiers in Microbiology. It was then possible for researchers to map the spread and the mutations of the virus during its journey to all continents.

The first results are encouraging. The coronavirus presents little variability, approximately seven mutations per sample. Common influenza has a variability rate that is more than double.

"The SARS-CoV-2 coronavirus is presumably already optimized to affect human beings, and this explains its low evolutionary change," explains Federico Giorgi, a researcher at Unibo and coordinator of the study. "This means that the treatments we are developing, including a vaccine, might be effective against all the virus strains."

Currently, there are six strains of coronavirus. The original one is the L strain, that appeared in Wuhan in December 2019. Its first mutation—the S strain—appeared at the beginning of 2020, while, since mid-January 2020, we have had strains V and G. To date strain G is the most widespread: it mutated into strains GR and GH at the end of February 2020.

"Strain G and its related strains GR and GH are by far the most widespread, representing 74% of all gene sequences we analyzed," says Giorgi. "They present four mutations, two of which are able to change the sequence of the RNA polymerase and Spike proteins of the virus. This characteristic probably facilitates the spread of the virus."

If we look at the coronavirus map, we can see that strains G and GR are the most frequent across Europe and Italy. According to the available data, GH strain seems close to non-existence in Italy, while it occurs more frequently in France and Germany. This seems to confirm the effectiveness of last months' containment methods.

In North America, the most widespread strain is GH, while in South America we find the GR strain more frequently. In Asia, where the Wuhan L strain initially appeared, the spread of strains G, GH and GR is increasing. These strains landed in Asia only at the beginning of March, more than a month after their spread in Europe.

Globally, strains G, GH and GR are constantly increasing. Strain S can be found in some restricted areas in the U.S. and Spain. The L and V strains are gradually disappearing.

Besides these six main coronavirus strains, researchers identified some infrequent mutations, that, at the moment, are not worrying but should nevertheless be monitored.

"Rare genomic mutations are less than 1% of all sequenced genomes," confirms Giorgi. "However, it is fundamental that we study and analyze them so that we can identify their function and monitor their spread. All countries should contribute to the cause by giving access to data about the virus genome sequences."

This study was published in the journal Frontiers in Microbiology, titled "Geographic and Genomic Distribution of SARS-CoV-2 Mutations."

SARS Cov-2 original strain slowly disappearing

Hyderabad: The first strain of the SARS Cov-2 virus &mdash the so-called L strain &mdash which initially caused Covid-19 is slowly disappearing according to 48,653 genomes that were studied by researchers and published in the journal Frontiers of Microbiology.

The L strain, which was widespread in Wuhan, has mutated during its journey to different continents and five different strains have been produced.

The L strain from Wuhan emerged in December 2019 and the first mutation was the S strain that appeared in the beginning of 2020. After that, there were strains G and V which have been produced in mid-January 2020 as they spread to different parts.

The G strain is most widespread till date and it has mutated to GR and GH strains in February 2020. In India, earlier there was L strain and then G and GH strains have been dominant. According to the Centre for Cellular and Molecular Biology (CCMB), there has also been Clade A 3i which has been found to be very virulent in India. These were found in Maharashtra, Tamil Nadu and Delhi and also parts of Telangana.

There are different samples which are being collected from states and the genomic studies are being carried out.

The genomic study of the virus is important for development of drugs for the disease and also checking use of old molecules on the virus. Presently, CCMB has got more than 20 different molecules for testing on whether it will work on the virus. The scientists are looking at the different strains and the impact of medicines on them to understand how treatment can be further improved.

Meanwhile the biggest worry was whether like the influenza virus, the coronavirus will be variable but it has been found that, despite mutations, variability will be limited. This means that despite the different strains due to mutations, the virus structure has remained the same.

A scientist at CCMB explained, &ldquoLess variability means that even if there is a mutation the vaccine will work for all the strains of coronavirus. This is positive news. The disappearing strain L also shows that due to constant mutations there are chances that other strains will slowly disappear and there may be new ones or they may not be. Or it could also mean that there is immunity developing for some strains.&rdquo

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Structural features of SARS-CoV-2

SARS-CoV-2 is a new member of the family Coronaviridae, order Nidovirales, and comprise of two sub-families, Coronavirinae and Torovirinae [ Reference Fehr 11] it is the seventh coronavirus known to infect humans [ Reference Andersen 12]. SARS-CoV-2 is relatively large in size (0.12 μm) and characterised by the presence of highly glycosylated spikes on the protein membrane in a crown-like arrangement, hence the name, Corona (Fig. 1). It has a single-stranded positive-sense RNA genome of 29 891 nucleotides. The glycosylated spike protein binds to the host angiotensin converting enzyme-2 (ACE-2) protein which serves as a functional receptor for entry into host respiratory cells. This receptor also binds the earlier SARS-CoV but with 10–20 times less affinity than for SARS-CoV-2 spike protein [ Reference Daniel 13, Reference Lu 14].

Fig. 1. Binding of SARS-CoV-2 to ACE-2 receptor.

SARS-CoV-2 genome analysis of strains in Pakistan reveals GH, S and L clade strains at the start of the pandemic

Objectives Pakistan has a high infectious disease burden with about 265,000 reported cases of COVID-19. We investigated the genomic diversity of SARS-CoV-2 strains and present the first data on viruses circulating in the country.

Methods We performed whole-genome sequencing and data analysis of SARS-CoV-2 eleven strains isolated in March and May.

Results Strains from travelers clustered with those from China, Saudi Arabia, India, USA and Australia. Five of eight SARS-CoV-2 strains were GH clade with Spike glycoprotein D614G, Ns3 gene Q57H, and RNA dependent RNA polymerase (RdRp) P4715L mutations. Two were S (ORF8 L84S and N S202N) and three were L clade and one was an I clade strain. One GH and one L strain each displayed Orf1ab L3606F indicating further evolutionary transitions.

Conclusions This data reveals SARS-CoV-2 strains of L, G, S and I have been circulating in Pakistan from March, at the start of the pandemic. It indicates viral diversity regarding infection in this populous region. Continuing molecular genomic surveillance of SARS-CoV-2 in the context of disease severity will be important to understand virus transmission patterns and host related determinants of COVID-19 in Pakistan.

Description of the tables

Category: variant of concern (VOC), variant of interest (VOI), or variant under monitoring (see definition above each table).

WHO label: As of 31st May 2021, WHO proposed labels for global SARS-CoV-2 variants of concern and variants of interest to be used alongside the scientific nomenclature in communications about variants to the public. This list includes variants on WHO’s global list of VOC and VOI, and is updated as WHO’s list changes.

Lineage and additional mutations: the variant designation specified by one or more Pango lineages and any additional characteristic spike protein changes. An alternate description may be used if the variant is not easy to describe using this nomenclature. For updated information on Pango lineages and definition of lineages and for instructions on how to suggest new lineages, visit the Pango lineages website.

Country first detected: only present if there is moderate confidence in the evidence relating to the first country of detection.

Spike mutations of interest: not all spike protein amino acid changes are included – this is not a full reference for assignment of the variants. It includes changes to spike protein residues 319-541 (receptor binding domain) and 613-705 (the S1 part of the S1/S2 junction and a small stretch on the S2 side), and any additional unusual changes specific to the variant.

Year and month first detected: as reported in the GISAID EpiCoV database. This can be adjusted backwards in time if new retrospective detections are made

Evidence concerning properties in three different categories:

The evidence is annotated to indicate whether it is derived from the variant itself (v) or from mutations associated with the variant (m). For the immunity category, the evidence is also annotated to indicate whether it is measured using neutralising antibodies (neutralisation), or in terms of vaccine efficacy or efficiency (escape). Evidence that is deemed “low confidence” is annotated to indicate that it is unclear. An empty field means that we have not yet found and evaluated any scientific evidence for the category, while “no” indicates evidence that there is no change associated with the property. The comparator virus assumed (“wild-type’” is B.1 (with D614G and no other spike protein changes).

Transmission in the EU/EEA: categorised as dominant, community, outbreak(s), and sporadic/travel. The categories are qualitative, and the assessment is based on surveillance data collected in TESSy, GISAID EpiCoV data, epidemic intelligence data, and direct communications with the affected countries.

‘No evidence’ of coronavirus mutating into more dangerous strains

Scientists at the University of Glasgow analysed samples of SARS-CoV-2, the virus that causes COVID-19.

Published: 06th May, 2020 at 11:15

The virus that causes COVID-19 has not mutated into different types, according to new analysis.

Recent research had suggested more than one type of SARS-CoV-2, the virus that causes COVID-19, is now circulating, with one strain being more aggressive and causing more serious illness than the other.

However using analysis of SARS-CoV-2 virus samples, scientists from the Medical Research Council-University of Glasgow Centre for Virus Research (CVR) have found only one type of the virus.

Viruses, including the one causing COVID-19, naturally accumulate mutations – or changes – in their genetic sequence as they spread through populations.

Scientists said most of these changes will have no effect on the biology of the coronavirus or the aggressiveness of the disease they cause.

Read the latest coronavirus news:

Dr Oscar MacLean, from the CVR, said: “By analysing the extensive genetic sequence variation present in the genomes of the SARS-CoV-2 virus, the evolutionary analysis shows why these claims that multiple types of the virus are currently circulating are unfounded.

“It is important people are not concerned about virus mutations – these are normal and expected as a virus passes through a population.

“However, these mutations can be useful as they allow us to track transmission history and understand the historic pattern of global spread.”

It was reported earlier this year that scientists had found two or three strains of SARS-CoV-2 circulating in the population, evidenced by certain mutations that had been detected.

However extensive analysis by the team found these detected mutations are unlikely to have any functional significance, and, importantly, do not represent different virus types.

. There's no evidence #SARSCoV2, the virus that causes #COVID19, has mutated into different types. New research in @Virus_Evolution by @CVRinfo finds there is still only one type of the virus circulating .


— University of Glasgow (@UofGlasgow) May 6, 2020

The centre’s CoV-GLUE resource tracks SARS-CoV-2’s amino acid replacements, insertions and deletions, which have been observed in samples from the pandemic.

To date, the database has catalogued 7,237 mutations in the pandemic.

Scientists said that while this may sound like a lot of change, it is a relatively low rate of evolution for a virus that has ribonucleic acid (RNA) as its genetic material.

They expect more mutations will continue to accumulate as the pandemic continues.

Most observed mutations would be expected to have no, or minimal, consequence to the virus’s biology, however tracking these changes can help scientists better understand the pandemic and how COVID-19 is spreading in the community.

The study is published in Virus Evolution and the work was funded by the Medical Research Council.

Reader Q&A: Why don’t viruses like the flu die off when no one is ill?

Asked by: Andrew Cirel, via email

Strictly speaking, viruses can’t ‘die off’ as they’re just inanimate strips of genetic material plus other molecules. But the reason that they keep coming back is because they’re always infecting someone somewhere it’s just that at certain times of the year, they’re less able to infect enough people to trigger a full-blown epidemic.

Many viruses flare up during the winter because people spend more time indoors in poorly-ventilated spaces, breathing in virus-laden air and touching contaminated surfaces. The shorter days also lead to lower levels of vitamin D, and this weakens our disease-fighting immune system. Experiments also suggest that the flu virus in particular remains infectious for longer in low temperatures.

But even when conditions aren’t ideal, viruses will find enough people to infect to ensure their survival, until they can come roaring back in an epidemic.

B.1.1.7 lineage (20I/501Y.V1)

The B.1.1.7 variant carries a mutation in the S protein (N501Y) that affects the conformation of receptor-binding domain. This variant has 13 other B.1.1.7 lineage-defining mutations ( Table), several of which are in the S protein, including a deletion at positions 69 and 70 (del69&ndash70) that evolved spontaneously in other SARS-CoV-2 variants and is hypothesized to increase transmissibility (2,7). The deletion at positions 69 and 70 causes S-gene target failure (SGTF) in at least one RT-PCR&ndashbased diagnostic assay (i.e., with the ThermoFisher TaqPath COVID-19 assay, the B.1.1.7 variant and other variants with the del69&ndash70 produce a negative result for S-gene target and a positive result for the other two targets) SGTF has served as a proxy in the United Kingdom for identifying B.1.1.7 cases (1).

Multiple lines of evidence indicate that B.1.1.7 is more efficiently transmitted compared with other SARS-CoV-2 variants circulating in the United Kingdom. U.K. regions with a higher proportion of B.1.1.7 sequences had faster epidemic growth than did other areas, diagnoses with SGTF increased faster than did non-SGTF diagnoses in the same areas, and a higher proportion of contacts were infected by index patients with B.1.1.7 infections than by index patients infected with other variants (1,3).

Variant B.1.1.7 has the potential to increase the U.S. pandemic trajectory in the coming months. To illustrate this effect, a simple, two-variant compartmental model was developed. The current U.S. prevalence of B.1.1.7 among all circulating viruses is unknown but is thought to be <0.5% based on the limited number of cases detected and SGTF data (8). For the model, initial assumptions included a B.1.1.7 prevalence of 0.5% among all infections, SARS-CoV-2 immunity from previous infection of 10%&ndash30%, a time-varying reproductive number (Rt) of 1.1 (mitigated but increasing transmission) or 0.9 (decreasing transmission) for current variants, and a reported incidence of 60 cases per 100,000 persons per day on January 1, 2021. These assumptions do not precisely represent any single U.S. location, but rather, indicate a generalization of conditions common across the country. The change in Rt over time resulting from acquired immunity and increasing prevalence of B.1.1.7, was modeled, with the B.1.1.7 Rt assumed to be a constant 1.5 times the Rt of current variants, based on initial estimates from the United Kingdom (1,3).

Next, the potential impact of vaccination was modeled assuming that 1 million vaccine doses were administered per day beginning January 1, 2021, and that 95% immunity was achieved 14 days after receipt of 2 doses. Specifically, immunity against infection with either current variants or the B.1.1.7 variant was assumed, although the effectiveness and duration of protection against infection remains uncertain, because these were not the primary endpoint of clinical trials for initial vaccines.

In this model, B.1.1.7 prevalence is initially low, yet because it is more transmissible than are current variants, it exhibits rapid growth in early 2021, becoming the predominant variant in March ( Figure 1). Whether transmission of current variants is increasing (initial Rt = 1.1) or slowly decreasing (initial Rt = 0.9) in January, B.1.1.7 drives a substantial change in the transmission trajectory and a new phase of exponential growth. With vaccination that protects against infection, the early epidemic trajectories do not change and B.1.1.7 spread still occurs ( Figure 2). However, after B.1.1.7 becomes the dominant variant, its transmission was substantially reduced. The effect of vaccination on reducing transmission in the near term was greatest in the scenario in which transmission was already decreasing (initial Rt = 0.9) (Figure 2). Early efforts that can limit the spread of the B.1.1.7 variant, such as universal and increased compliance with public health mitigation strategies, will allow more time for ongoing vaccination to achieve higher population-level immunity.

Low genetic diversity may be an Achilles heel of SARS-CoV-2

Scientists worldwide are racing to develop effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic. An important and perhaps underappreciated aspect of this endeavor is ensuring that the vaccines being developed confer immunity to all viral lineages in the global population. Toward this end, a seminal study published in PNAS (1) analyzes 27,977 SARS-CoV-2 sequences from 84 countries obtained throughout the course of the pandemic to track and characterize the evolution of the novel coronavirus since its origination. The principle conclusion reached by the authors of this work is that SARS-CoV-2 genetic diversity is remarkably low, almost entirely the product of genetic drift, and should not be expected to impede development of a broadly protective vaccine.

Although errors introduced during genome replication are a major source of genetic variation in all virus populations, limiting the fitness costs of accumulated errors is especially critical for coronaviruses, the RNA genomes of which are the largest known. For this reason, coronaviruses evolved nonstructural protein 14 (nsp14), which accompanies viral replicases during RNA synthesis and excises misincorporated ribonucleotides from nascent strands before they can be extended, thus preventing errors from becoming permanent. This error-correcting capacity was unknown among RNA viruses prior to its discovery in SARS-CoV-1 (2, 3), and it contributes to a replication error rate more than 10-fold lower than that of other RNA viruses (4, 5). This activity also likely contributes to the low genetic diversity of SARS-CoV-2, although to our knowledge nsp14 function in the novel coronavirus has yet to be investigated.

For many viruses, surface glycoproteins contain not only elements required for specific binding of cellular receptors, membrane fusion, and virus entry into the host cell but also epitopes recognized by neutralizing antibodies produced as part of an effective adaptive immune response. Hence, tracking genetic variation in the SARS-CoV-2 surface glycoprotein is of paramount importance for determining the likelihood of vaccine effectiveness or immune escape. To put this variation in perspective, Fig. 1 shows a graphical illustration of comparative genetic diversity among surface glycoproteins of select human pathogenic viruses, including SARS-CoV-2, correlated with the availability and effectiveness of respective preventive vaccines.

Comparative genetic diversity among coronaviruses and select viral pathogens. As indicated by the scale bar, sphere radius reflects average pairwise distances (APD) of viral surface glycoprotein gene sequences among different viruses. Diversities among coronaviruses (for which no vaccines have been developed to date) are indicated in red, and those of other viruses for which effective vaccines are available or unavailable are shown in blue and green, respectively. Since 2005, the average effectiveness of combination influenza seasonal vaccines (influenza A: H1N1, H2N3, influenza B) has been 40%. Accordingly, genetic diversity of influenza A is depicted by blue-green shading to reflect an intermediate level of vaccine effectiveness. Sequences were obtained from public databases and identical sequences were included only once. MEGA7 software was used to calculate APD among gene segments encoding proteins involved in attachment/entry: Spike or Spike-like human coronaviruses (SARS-CoV-2, 229E, NL63, OC43, and HKU1), spike glycoprotein (Ebola), HN (mumps), S (HBV), H (measles), Env (HIV-1), HA (influenza A), and E1 (HCV). More specifically, HIV-1 Group M subtypes A–D, F–H, J–K, CRF01_AE, and CRF02_AG HBV serotypes A–H HCV genotypes 1a–c, 2a–b, 4a, 5a, 6a, 6k, and 6m and influenza A H1N1 pdm09, seasonal H1N1, H3N2, and H5N1 were included. Majority-rule consensus of unique sequences for HIV-1 (Group M, N, O, and P), HBV, HCV, and influenza A was performed in Seaview v4.7. Total numbers of sequences analyzed: SARS-CoV-2 (21,554), 229E (25), NL63 (52), OC43 (79), HKU1 (38), Ebola (578), mumps (341), HBV (10,271), measles (38), HIV-1 (5,603), influenza A (133), and HCV (439).

Although genetic diversity is only one of many determinants of vaccine efficacy, there is a clear inverse correlation between these two metrics among viral pathogens examined in our analysis. Presumably due to its relatively recent origins, genetic diversity in the SARS-CoV-2 surface glycoprotein, spike, encoded by the S gene, is exceedingly low, even in comparison to other human coronaviruses. Toward the opposite extreme, diversity among influenza A surface glycoproteins is 437-fold greater than that measured in SARS-CoV-2. The relative age of influenza A (dating at least back to the 16th century) is certainly a major factor in this disparity, as is reassortment of genome segments encoding influenza A surface antigens hemagglutinin (HA) and neuraminidase (NA) (6). Indeed, sudden emergence of influenza A virus variants containing HA–NA combinations not previously encountered by contemporaneous human populations caused the pandemics of 1918 (H1N1), 1957 (H2N2), 1968 (H3N2), and 2009 (H1N1pdm09). Although coronavirus genomes are not segmented like those of influenza viruses, they are nevertheless capable of high rates of recombination. Hence, future emergence of new virulent derivatives of SARS-CoV-2 paralleling those observed with influenza A is a possibility that will require global monitoring of both animal and human reservoirs.

As differences in biology and epidemiology among these human viral pathogens are considerable, so is the extent of sequence divergence in genes encoding their respective envelope glycoproteins. HIV-1, for example, has fueled the AIDS pandemic for more than 40 y, during which time genetic diversity was acquired through both recombination and propagation of replication errors (7). Similarly, widespread sustained prevalence contributed to genetic diversity in hepatitis B virus (HBV) (8) and hepatitis C virus (HCV) (9), both causative agents of ongoing chronic hepatitis pandemics. Since these viruses cause chronic infections, their evolution is also shaped by immune pressure to a degree not possible with SARS-CoV-2, given the typical short course of COVID-19. However, with respect to our analysis, it is perhaps most important to recognize that the genetic diversities of human coronaviruses (i.e., 229E, NL63, OC43, HKU1, and now SARS-CoV-2), some of which may have been circulating in the population for centuries, are less than or comparable to those measured for mumps, measles, hepatitis B, and Ebola viruses, against which vaccines have been developed that are at least 88% effective (

The measured and well-supported conclusions of Dearlove et al. (1) markedly contrast with an early study of SARS-CoV-2 evolution that raised alarm at the emergence and spread of a “strain” more “aggressive” than the original (10). It was argued that the novel coronavirus population was divided into S and L “strains” distinguishable by two mutations at genome positions 8,782 (ORF1ab) and 28,144 (ORF8). In an addendum, the authors acknowledged that they provided no evidence supporting any epidemiological conclusion regarding the virulence or pathogenicity of SARS-CoV-2, and that their description of the “L type” as being more “aggressive” was inappropriate. That word was omitted from the subsequent print version of the article, each instance being replaced by a variation of “more frequently observed.” Unfortunately, online reports derived from this article were not as self-correcting or restrained, using phrases or titles such as “At least eight strains of the coronavirus are making their way around the globe, creating a trail of death and disease that scientists are tracking by their genetic footprints” (11), “the coronavirus is continuously mutating to overcome the immune system resistance of different populations” (12), and “Coronavirus: Are there two strains and is one more deadly?” (13) to describe and interpret the scientific findings presented in the aforementioned paper. It is hard to argue that these reports accurately portrayed the means, degree, and consequences of low-level accumulation of genetic diversity in SARS-CoV-2 to the public, and we hope such information is relayed more carefully and conscientiously in the future.

Despite the remarkable wealth of data currently available, careful temporally and geographically resolved analyses of genetic diversity in large SARS-CoV-2 datasets do not always produce consensus. One recent concern has been the basis for emergence of a mutation encoding a D614G amino acid substitution in the SARS-CoV-2 spike protein. First observed in Germany in late January 2020, this variant is now the dominant form among SARS-CoV-2 viruses worldwide. Korber et al. recently concluded that the ascendency of 614G was not a consequence of genetic drift but instead occurred because the mutation renders the virus more infectious (14). This conclusion was initially based on their observation that the proportion of sequences carrying the D614G mutation progressively increased in every region in Asia, Europe, Oceania, and North America that was well-sampled in the GISAID database ( Moreover, subsequent analyses showed that pseudotyped virus containing the 614G mutation spread more rapidly in cell culture, probably due to a structural alteration that reduced shedding of the S1 spike protein subunit (14 ⇓ –16).

Dearlove et al. (1) acknowledge that emergence of the 614G mutation may constitute an exception to their overarching conclusion that SARS-CoV-2 genetic variation is overwhelmingly due to genetic drift. However, as a caveat to accepting this determination prematurely, they cite a parallel finding that A82V and other mutations in the ebolavirus surface glycoprotein were associated with increased infectivity. In this case, subsequent analysis in cell culture showed that the degree of increased infectivity varied with cell type (17) and no phenotypic differences were observed when mutant viruses were evaluated in animal models (18). Moreover, the authors argue that because the 614G variant has relatively rarely been sampled in China, and there is no evidence for convergent evolution independently producing the same or a similar mutation, the hypothesis that 614G emerged as a consequence of a genetic bottleneck during spread of the virus from Asia to Europe remains viable.

It is perhaps even more important to note that the question of whether the 614G mutation increases infectivity has no bearing on the expected efficacy of vaccines currently under development. Indeed, amino acid position 614 is not located within the receptor binding domain, the motif expected to house epitopes most frequently recognized by neutralizing antibodies, and cell culture studies confirm that viruses pseudotyped with 614D or 614G spike variants are neutralized with equal effectiveness (19, 20). Taken together, these results are consistent with the central conclusion of Dearlove et al. (1) that the current state of SARS-CoV-2 genetic diversity should not be expected to impede development of a broadly protective vaccine.

It could be argued that maintaining the ∼30-kb RNA genome of SARS-CoV-2 reduces its tolerance for genetic diversity, rendering the novel coronavirus perhaps more susceptible to control by widespread immunization than might be expected for other RNA viruses. However, it is equally valid to suggest that because SARS-CoV-2 has infected and spread within an immunologically naïve population it has yet to experience the sort of immune pressure that helped shape the evolution of the endemic viruses shown in Fig. 1, and its own capacity to evolve remains unknown. Accordingly, we must continue to be diligent in tracking genetic changes in the novel coronavirus, both to follow their spread and quickly identify antigenic shifts should they occur. Yet, it is equally important to recognize that what we have observed to this point is slow genetic drift characteristic of a virus with a highly stable genome and to keep these and future observations on SARS-CoV-2 genetic diversity in the appropriate perspective, especially when communicating them to the general public.

Worrying evidence

There's some good news in all of this: rumors about this being an escaped weapons experiment make little sense in terms of what the genome sequences tell us about biology. Less reassuring, however, is what the sequences tell us about the giant natural experiment that may be going on around us. And that tells us there appears to be a large number of coronaviruses that are regularly exchanging genetic information. And, while exchanges are more common among viruses that infect the same species, it's entirely possible that contributions can come from much more distantly related ones.

The authors find evidence that the viruses from different species may experience distinct selective pressure, which isn't really surprising. But that also can produce difficult-to-predict results when those viruses hop to a new species—and the difficulty will rise if they then exchange information with other viruses native to that species.

Summing this up, there seem to be myriad coronaviruses out there (including plenty we don't know about), and some species are serving as labs in which new genetic combinations are created. And, right now, we only have a very partial window into the sort of potential out there in species that have frequent contacts with humans. And some research cited by the authors suggests that humans have been exposed to at least some of these viruses (based on antibodies to them)—fortunately without a major outbreak occurring.

All of which suggests that additional pandemics are a question of when, rather than if. But, of course, that had already been suggested in the aftermath of MERS and the original SARS, and the world as a whole did remarkably little to study the risk, work toward treatments, or plan for the pandemic's arrival. We can only hope that the more obvious example of COVID-19 will change that.