新冠病毒突变/变异意味着什么Genetic Variants of SARS-CoV-2
Genetic Variants of SARS-CoV-2—What Do They Mean? 新冠病毒变异意味着什么？Adam S. Lauring, MD, PhD1; Emma B. Hodcroft, PhD2
JAMA. Published online January 6, 2021. doi:10.1001/jama.2020.27124
Over the course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the clinical, scientific, and public health communities have had to respond to new viral genetic variants. Each one has triggered a flurry of media attention, a range of reactions from the scientific community, and calls from governments to either “stay calm” or pursue immediate countermeasures. While many scientists were initially skeptical about the significance of the D614G alteration, the emergence of the new “UK variant”—lineage B.1.1.7—has raised widespread concern. Understanding which variants are concerning, and why, requires an appreciation of virus evolution and the genomic epidemiology of SARS-CoV-2.
详见： https://jamanetwork.com/journals/jama/article-abstract/2775006
新型冠状病毒刺突蛋白Spike突变对中和抗体敏感性的影响：免疫逃逸？
New SARS-CoV-2 variants resistant to convalescent sera and and monoclonal antibodies
https://www.news-medical.net/news/20210125/New-SARS-CoV-2-variants-resistant-to-convalescent-sera-and-and-monoclonal-antibodies.aspx
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma
https://www.biorxiv.org/content/10.1101/2021.01.18.427166v1.abstract
Emerging SARS-CoV-2 variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies
https://www.nature.com/articles/s41423-021-00648-1
一项最新研究表明，首先在南非发现的B.1.351新冠变异毒株可能会使美国辉瑞（Pfizer）公司和德国BioNTech公司联合研发的新冠疫苗的抗体保护作用降低三分之二。
据美国有线电视新闻网（CNN）17日报道，辉瑞和美国得克萨斯大学医学部（UTMB）的研究人员通过基因工程改造新冠病毒，使其携带变异毒株B.1.351中发现的部分突变。研究者从15名接种了两剂辉瑞-BioNTech疫苗的接种者身上提取了血清样本，进行体外试验。
该研究显示，与较原始的新冠病毒毒株相比，辉瑞-BioNTech疫苗针对人工改造的毒株的抗体保护作用降低了三分之二。研究的初步结果2月17日发表在医学期刊《新英格兰医学杂志》上。
针对研究结果，得克萨斯大学医学部的一位研究者在接受采访时表示，尽管变异病毒可能降低辉瑞-BioNTech疫苗的效力，但该疫苗针对新冠病毒仍具有保护作用。而辉瑞公司和BioNTech也表示，疫苗仍对新冠病毒有中和效果，目前尚未有人体实验表明此种变异病毒将降低疫苗效果。
在此前英国、南非等国相继发现变异病毒后，多个国家报告境内出现变异病毒感染病例，如何应对变异病毒可能造成的危机已是各国政府及疫苗研究人员关注的重点之一，多家疫苗研发公司已就新冠变异对疫苗保护力的威胁进行研究。
英国牛津大学和阿斯利康（AstraZeneca）公司于本月初公布的两项研究结果表示，其联合开发的新冠疫苗对英国发现的变异病毒的有效率为75%，但对南非发现的变异病毒引起的轻度疾病的疗效有限。目前，南非政府已暂缓接种阿斯利康疫苗。
美国莫德纳（Moderna）公司的研究人员此前称该公司研发的疫苗对在英国和南非发现的变异毒株具保护作用，但该疫苗接种者对南非发现的变异毒株产生的免疫反应较弱。
美国生物技术公司诺瓦瓦克斯（Novavax）则于上月表示，研究显示该公司生产的疫苗对在英国发现的变异病毒的有效率为85.6%，但对南非发现的变异病毒有效率较低。
目前多个制药商已表示将对疫苗进行调整，希望增加对变异病毒的效力。阿斯利康此前曾表示将争取在秋季前研制出针对南非发现的变异病毒的改良疫苗，而辉瑞则在近日称将与监管机构讨论是否需要开发“加强版”疫苗或是增加注射剂量。
Multiple SARS-CoV-2 variants are circulating globally. Several new variants emerged in the fall of 2020, most notably:
In the United Kingdom (UK), a new variant of SARS-CoV-2 (known as 20I/501Y.V1, VOC 202012/01, or B.1.1.7) emerged with an unusually large number of mutations. This variant has since been detected in numerous countries around the world, including the United States (US) and Canada.
In South Africa, another variant of SARS-CoV-2 (known as 20H/501Y.V2 or B.1.351) emerged independently of B.1.1.7. This variant shares some mutations with B.1.1.7. Cases attributed to this variant have been detected outside of South Africa.
In Brazil, a variant of SARS-CoV-2 (known as P.1) emerged and was identified in four travelers from Brazil, who were tested during routine screening at Haneda airport outside Tokyo, Japan. This variant has 17 unique mutations, including three in the receptor binding domain of the spike protein.
Scientists are working to learn more about these variants to better understand how easily they might be transmitted and the effectiveness of currently authorized vaccines against them. At this time, there is no evidence that these variants cause more severe illness or increased risk of death. New information about the virologic, epidemiologic, and clinical characteristics of these variants is rapidly emerging.
CDC, in collaboration with other public health agencies, is monitoring the situation closely. CDC is working to detect and characterize emerging viral variants. Furthermore, CDC has staff available to provide on-the-ground technical support to investigate the epidemiologic and clinical characteristics of SARS-CoV-2 variant infections. CDC will communicate new information as it becomes available.
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Emerging Variants
B.1.1.7 lineage (a.k.a. 20I/501Y.V1 Variant of Concern (VOC) 202012/01)
This variant has a mutation in the receptor binding domain (RBD) of the spike protein at position 501, where amino acid asparagine (N) has been replaced with tyrosine (Y). The shorthand for this mutation is N501Y. This variant also has several other mutations, including:
69/70 deletion: occurred spontaneously many times and likely leads to a conformational change in the spike protein
P681H: near the S1/S2 furin cleavage site, a site with high variability in coronaviruses. This mutation has also emerged spontaneously multiple times.
ORF8 stop codon (Q27stop): mutation in ORF8, the function of which is unknown.
This variant is estimated to have first emerged in the UK during September 2020.
Since December 20, 2020, several countries have reported cases of the B.1.1.7 lineage, including the United States and Canada.
This variant is associated with increased transmissibility (i.e., more efficient and rapid transmission).
Currently there is no evidence to suggest that the variant has any impact on the severity of disease or vaccine efficacy.
B.1.351 lineage (a.k.a. 20H/501Y.V2)
This variant has multiple mutations in the spike protein, including K417T, E484K, N501Y. Unlike the B.1.1.7 lineage detected in the UK this variant does not contain the deletion at 69/70.
This variant was first identified in Nelson Mandela Bay, South Africa, in samples dating back to the beginning of October 2020, and cases have since been detected outside of South Africa.
The variant also was identified in Zambia in late December 2020, at which time it appeared to be the predominant variant in the country.
Currently there is no evidence to suggest that this variant has any impact on disease severity.
There is some evidence to indicate that one of the spike protein mutations, E484K, may affect neutralization by some polyclonal and monoclonal antibodies.1,2
P.1 lineage (a.k.a. 20J/501Y.V3)
The P.1 variant is a branch off the B.1.1.28 lineage that was first reported by the National Institute of Infectious Diseases (NIID) in Japan in four travelers from Brazil, sampled during routine screening at Haneda airport outside Tokyo.
The P.1 lineage contains 17 unique amino acid changes and 3 deletions.
This variant contains three mutations in the spike protein receptor binding domain: K417T, E484K, and N501Y.
There is evidence to suggest that some of the mutations in the P.1 variant may affect its transmissibility and antigenic profile, which may affect the ability of antibodies generated through a previous natural infection or through vaccination to recognize and neutralize the virus.
A recent study reported on a cluster of cases in Manaus, the largest city in the Amazon region, in which the P.1 variant was identified in 42% of the specimens sequenced from late December.3 In this region, it is estimated that approximately 75% of the population had been infected with SARS-CoV2 as of October 2020. However, since mid-December the region has observed a surge in cases. The emergence of this variant raises concerns of a potential increase in transmissibility or propensity for SARS-CoV-2 re-infection of individuals.
This variant has not yet been identified in the United States.
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Why Strain Surveillance is Important for Public Health
CDC has been conducting SARS-CoV-2 Strain Surveillance to build a collection of SARS-CoV-2 specimens and sequences to support public health response. Routine analysis of the available genetic sequence data will enable CDC and its public health partners to identify variant viruses for further characterization.
Viruses generally acquire mutations over time, giving rise to new variants. For instance, another strain recently emerged in Nigeria. CDC also is monitoring this strain but, at this time, it has shown no characteristics of greater concern to public health experts.
Some of the potential consequences of emerging variants are the following:
Ability to spread more quickly in people. There is already evidence that one mutation, D614G, confers increased ability to spread more quickly than the wild-type SARS-CoV-2. In the lab, 614G variants propagate more quickly in human respiratory epithelial cells, outcompeting 614D viruses. There also is epidemiologic evidence that the 614G variant spreads more quickly than viruses without the mutation.
Ability to cause either milder or more severe disease in people. There is no evidence that these recently identified SARS-CoV-2 variants cause more severe disease than earlier ones.
Ability to evade detection by specific diagnostic tests. Most commercial polymerase chain reaction (PCR) tests have multiple targets to detect the virus, such that even if a mutation impacts one of the targets, the other PCR targets will still work.
Decreased susceptibility to therapeutic agents such as monoclonal antibodies.
Ability to evade natural or vaccine-induced immunity. Both vaccination against and natural infection with SARS-CoV-2 produce a “polyclonal” response that targets several parts of the spike protein. The virus would likely need to accumulate multiple mutations in the spike protein to evade immunity induced by vaccines or by natural infection.
Among these possibilities, the last—the ability to evade vaccine-induced immunity—would likely be the most concerning because once a large proportion of the population is vaccinated, there will be immune pressure that could favor and accelerate emergence of such variants by selecting for “escape mutants.” There is no evidence that this is occurring, and most experts believe escape mutants are unlikely to emerge because of the nature of the virus.
Analysis of sequences from the African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Nigeria, identified two SARS-CoV-2 sequences belonging to the B.1.1.207 lineage. These sequences share one non-synonymous mutation in the spike protein (P681H) in common with the B.1.1.7 lineage but does not share any of the other 22 unique mutations of B.1.1.7 lineage. The P681H residue is near the S1/S2 furin cleavage site, a site with high variability in coronaviruses. At this time, it is unknown when this variant may have first emerged. Currently there is no evidence to indicate this variant has any impact on disease severity or is contributing to increased transmission of SARS-CoV-2 in Nigeria.
“Wild-type” refers to the strain of virus – or background strain – that contains no major mutations.
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Strain Surveillance in the US
In the United States, sequence-based strain surveillance has been ramping up with the following components:
National SARS-CoV-2 Strain Surveillance (“NS3”): Since November 2020, state health departments and other public health agencies have been regularly sending CDC SARS-CoV-2 samples for sequencing and further characterization. This system is now being scaled to process 750 samples nationally per week. One strength of this system is that it allows for characterization of viruses beyond what sequencing alone can provide.
Surveillance in partnership with national reference laboratories: CDC is contracting with large national reference labs to provide sequence data from across the United States. As of December 29, CDC has commitments from these laboratories to sequence 1,750 samples per week and anticipates being able to increase this number.
Contracts with universities: CDC has contracts with seven universities to conduct genomic surveillance in collaboration with public health agencies.
Sequencing within state and local health departments: Since 2014, CDC’s Advanced Molecular Detection Program has been integrating next-generation sequencing and bioinformatics into the U.S. public health system. Several state and local health departments have been applying these resources as part of their response to COVID-19. To further support these efforts, CDC released $15 million in funding, with COVID supplemental funds, through the Epidemiology and Laboratory Capacity Program on December 18, 2020.
The SPHERES consortium: Since early in the pandemic, CDC has led a national consortium of laboratories sequencing SARS-CoV-2 (SPHERES) to coordinate U.S sequencing efforts outside of CDC. The SPHERES consortium consists of more than 160 institutions, including academic centers, industry, non-governmental organizations, and public health agencies.
Through these efforts, anonymous genomic data are made available through public databases for use by public health professionals, researchers, and industry. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants
https://www.biorxiv.org/content/10.1101/2021.01.25.427948v1 Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization
http://biorxiv.org/cgi/content/short/2021.01.25.428137 The E484K mutation in the SARS-CoV-2 spike protein reduces but does not abolish neutralizing activity of human convalescent and post-vaccination sera.
Sonia Jangra, Chengjin Ye, Raveen Rathnasinghe, Daniel Stadlbauer, Personalized Virology Initiative (PVI) Study Group, Florian Krammer, Viviana Simon, Luis Martinez-Sobrido, Adolfo Garcia-Sastre, Michael Schotsaert
doi: https://doi.org/10.1101/2021.01.26.21250543
Abstract
One year in the coronavirus disease 2019 (COVID-19) pandemic, the first vaccines are being rolled out under emergency use authorizations. It is of great concern that newly emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can escape antibody-mediated protection induced by previous infection or vaccination through mutations in the spike protein. The glutamate (E) to Lysine (K) substitution at position 484 (E484K) in the receptor binding domain (RBD) of the spike protein is present in the rapidly spreading variants of concern belonging to the B.1.351 and P.1 lineages. We performed in vitro microneutralization assays with both the USA-WA1/2020 virus and a recombinant (r)SARS-CoV-2 virus that is identical to USA-WA1/2020 except for the E484K mutation introduced in the spike RBD. We selected 34 sera from study participants based on their SARS-CoV-2 spike ELISA antibody titer (negative versus weak , moderate or strong positive ). In addition, we included sera from five individuals who received two doses of the Pfizer SARS-CoV-2 vaccine BNT162b2. Serum neutralization efficiency was lower against the E484K rSARS-CoV-2 (vaccination samples: 3.4 fold; convalescent low IgG: 2.4 fold, moderate IgG: 4.2 fold and high IgG: 2.6 fold) compared to USA-WA1/2020. For some of the convalescent donor sera with low or moderate IgG against the SARS-CoV-2 spike, the drop in neutralization efficiency resulted in neutralization ID50 values similar to negative control samples, with low or even absence of neutralization of the E484K rSARS-CoV-2. However, human sera with high neutralization titers against the USA-WA1/2020 strain were still able to neutralize the E484K rSARS-CoV-2. Therefore, it is important to aim for the highest titers possible induced by vaccination to enhance protection against newly emerging SARS-CoV-2 variants. Two vaccine doses may be needed for induction of high antibody titers against SARS-CoV-2. Postponing the second vaccination is suggested by some public health authorities in order to provide more individuals with a primer vaccination. Our data suggests that this may leave vaccinees less protected against newly emerging variants.
https://www.medrxiv.org/content/10.1101/2021.01.26.21250543v1 Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity
https://www.cell.com/cell/fulltext/S0092-8674(21)00080-5
Highlights
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The receptor-binding motif (RBM) is a highly variable region of SARS-CoV-2 spike
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RBM mutation N439K has emerged independently in multiple lineages
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N439K increases spike affinity for hACE2; viral fitness and disease are unchanged
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N439K confers resistance to several mAbs and escapes some polyclonal responses
Summary
SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild-type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the FDA, and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization
https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00044-5
Highlight
Generation of SARS-CoV-2 spike mutants that escape antibody neutralization.
Mutant S477N is resistant to neutralization by multiple monoclonal antibodies.
Mutant E484K is less sensitive to neutralization by convalescent human sera.
Sequential selection identifies mutants that escape neutralization by antibody cocktails.
Abstract
Neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics. However, viral escape mutants could compromise efficacy. To define immune-selected mutations in the S protein, we exposed a VSV-eGFP-SARS-CoV-2-S chimeric virus, in which the VSV glycoprotein is replaced with the S protein, to 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) and generated 50 different escape mutants. Each mAb had a unique resistance profile, although many shared residues within an epitope of the RBD. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera. Additionally, sequential selection identified mutants that escape neutralization by antibody cocktails. Comparing these antibody-mediated mutations with sequence variation in circulating SARS-CoV-2 revealed substitutions that may attenuate neutralizing immune responses in some humans and thus warrant further investigation. SARS-CoV-2 Vaccines and the Growing Threat of Viral Variants
https://jamanetwork.com/journals/jama/fullarticle/2776039
John P. Moore, PhD1; Paul A. Offit, MD2
In November 2019, a bat coronavirus made its debut in the human population. Since that time, the virus has continued to adapt, resulting in a series of viral variants. The question that the world faces in early 2021 is whether these new variants will escape recognition by vaccine-induced immunity.
Protection against coronavirus disease 2019 (COVID-19) is mediated in large part by an immune response directed against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-protein. The S-protein is responsible for virus-cell binding and is the target for virus-neutralizing antibodies (NAbs). Although this is not strictly proven, most vaccine researchers believe that NAbs induced by vaccination are protective against COVID-19. NAbs bind to the S-protein at a few sites, usually in or near the receptor-binding domain (RBD); in doing so, NAbs prevent the virus from attaching to the ACE2 receptor on human cells.
Variants in the S-protein that increase the amount of virus shed from an infected person or that increase its affinity for the ACE2 receptor are likely to increase virus transmission, an important problem in the context of a pandemic. Furthermore, the same or similar alterations can change the shape of the S-protein and impair or even destroy NAb binding sites. Hence, by extrapolation, vaccine efficacy might be compromised. These “escape mutations” typically arise when the virus is put under selective pressure by antibodies that limit but do not eliminate viral replication. Under these conditions, the virus might then find a way to escape this pressure and restore its ability to reproduce more efficiently. The scenario of virus evolution in the face of suboptimal immunity is one reason extending the interval between the first and second dose of a SARS-CoV-2 vaccine might be problematic.
Evolutionary biology is now occurring across the globe. The first major shift in the properties of SARS-CoV-2 took place early in the pandemic—around March and April 2020—when the original strain was replaced worldwide by a new variant called D614G.1 The relevant mutation in this variant, which is located in the S-protein, has been shown to increase the replication efficiency and transmissibility of the virus.2 Although this variant did not escape recognition by NAbs, it was a warning of what could happen.
In August 2020 another variant started to spread in the UK (where surveillance for such events is particularly thorough), and its contribution to the pandemic in that country increased rapidly from November 2020 through January 2021. Often called the “UK strain,” but more formally known as B.1.1.7, this variant has now been detected in many countries, including the US. The key sequence change in the S-protein is called N501Y, which again appears to increase the transmissibility of SARS-CoV-2, although in a manner subtly different from D614G. Regarding protection by vaccination, however, again fortunately, the location of the N501Y change makes it unlikely to affect most of the NAb binding sites on the RBD.3 For example, recently released data show that serum samples from the recipients of the Pfizer-BioNTech and Moderna mRNA vaccines are equally effective at neutralizing viruses that contain or lack the N501Y change.4,5
A more transmissible variant now circulating in southern California, CAL.20C, has an RBD sequence change called L452Y that is thought to act similarly to N501Y.6 Its sensitivity to vaccine sera remains to be determined.
There is now, however, a more troubling new variant identified in South Africa, the N501Y.V2 variant (or B.1.351). A close relative to N501Y.V2 with similar properties has now also been identified in Brazil (P.1), but much less is known about this variant. The N501Y.V2 strain has many more sequence changes than both the D614G and B.1.1.7 variants, and those sequence changes are more worrisome because they are located in or close to the RBD; these sequence changes also affect another NAb target, the N-terminal domain.
The number and positioning of these mutations immediately raised concerns among vaccine researchers. New data show that those concerns were not misplaced. Rockefeller University researchers have shown that the relevant N501Y.V2 sequence changes within the RBD modestly reduce the efficiency with which mRNA vaccine-induced antibodies neutralize test viruses in the laboratory.7 In addition, a National Institutes of Health study now shows that NAbs induced by the Moderna mRNA vaccine are about 6-fold less active against the N501Y.V2 (B1.351) strain.5
It remains unclear whether the reduction in the neutralization sensitivity of the N501Y.V2 strain to vaccine-induced antibodies is enough to seriously reduce vaccine efficacy. First, mRNA vaccines also induce virus-specific helper T cells and cytotoxic T cells, both of which might be involved in protection against challenge. Also, the mRNA vaccines, in particular, induce such a strong NAb response that there could be enough “spare capacity” to deal with reductions in the sensitivity of the variant to NAbs. In other words, N501Y.V2 (and the related virus from Brazil) may be less sensitive to NAbs, but not to an extent that will cause widespread vaccine failure. However, vaccines that appear to induce lower levels of NAbs, such as the inactivated vaccines developed in China and India, may be less effective. It is too early to know how the replication-defective simian or human adenovirus vector-vaccines (Johnson & Johnson/Janssen’s, AstraZeneca’s, and the Russian “Sputnik V”) or the adjuvanted purified protein vaccines (Novavax and Sanofi/GSK) might be affected. Much work is now being performed worldwide to better understand how these different vaccines are affected by the N501Y.V2 and related variants. An important clue should emerge when several phase 3 vaccine efficacy trials now ongoing in South Africa are completed. Will the increasing dominance of N501Y.V2 in that country affect how well these vaccines protect the trial participants? Time will tell.
In addition to avoiding recognition by vaccine-induced immunity, variants have also become less susceptible to neutralizing monoclonal antibodies (nMAbs). The N501Y change in the B.1.1.7 variant, for example, is sufficient to almost ablate the activity of several nMAbs, and the South African team’s study shows that almost all of the nMAbs tested against N501Y.V2 were now ineffective.8 The nMAbs that are approved by the Food and Drug Administration to treat SARS-CoV-2 infection need to be carefully assessed against all these new variants.
Given the rise of these viral variants, several steps should be taken.
First, SARS-CoV-2 viruses must be immediately isolated and characterized from individuals who have been fully vaccinated but are nonetheless admitted to the hospital with COVID-19. This would likely be the first sign that variant viruses are becoming resistant to vaccine-induced immunity.
Second, the US should create and maintain an active sequencing and surveillance system to identify these variants quickly once they arise. While the UK has been excellent in this regard, the US and much of the rest of the world has not. International cooperation is essential to do this properly.
Third, it would be of value to create a central repository of serum samples from people in the US who have been immunized with SARS-CoV-2 vaccines. This resource would enable researchers to test their neutralizing capacities against any new variants as soon as they are identified. In this way, it will not be necessary to depend on pharmaceutical companies, who have limited quantities of serum samples generated from phase 3 trials, to do these studies. A central repository should include samples representing all the approved vaccines, as well as those still in phase 3 trials, to enable gauging both the depth and breadth of neutralization resistance.
Fourth, it is essential to reduce the global spread of new variants, particularly N501Y.V2 and its related Brazilian variant. While it is likely that these viruses are already present in the US, the more often they are reintroduced, the more likely they will make it into a superspreader event, with very serious consequences for wider spread.9
Fifth, the designs of the mRNA and replication-defective adenovirus vaccines can be adjusted to accommodate the key sequence changes present in the new variants. The initial stages of this process are fairly straightforward and can be accomplished rapidly.
Sixth, like those that have circulated throughout 2020, the new variants are not spread by aerosolization in a manner similar to measles virus nor do they travel long distances. Wearing masks, physical distancing, and applying common sense can prevent their spread. Covid-19: What new variants are emerging and how are they being investigated?
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n158 (Published 18 January 2021)
The new, more transmissible variant of SARS-CoV-2 found in England is just one of many variations of the virus being detected around the world. Elisabeth Mahase looks at what we know so far
What do we know about the new variant emerging from Brazil?
This variant, known as P.1 or VOC202101/02 in the UK, was first detected in travellers from Brazil who arrived in Japan in January 2021. It involves 17 unique amino acid changes, three deletions, four synonymous mutations, and one 4nt insertion. It has several mutations that are known to be biologically important, including E484K and N501Y.
The N501Y mutation, which is also a feature of the English variant,1 has been linked to increased infectivity and virulence in mouse models.2 Meanwhile, the E484K mutation is thought to be associated with escape from the neutralising antibodies produced by the body against SARS-CoV-2.3 This mutation is present in the South African variant as well.
P.1 has not yet been detected in the UK, and travel bans have been put in place to try to prevent it reaching the country. There is, however, another variant from Brazil (known as VUI202101/01 in the UK) which contains a small number of mutations that has been found in the UK. As of 14 January 2021, eight cases of this variant—which appears to be of less concern—have been confirmed. Public Health England (PHE) said the “spread and significance of this variant remains under investigation.”
Susan Hopkins, PHE covid strategic response director, said, “For now, our advice following detection of a Brazilian variant in the UK remains the same, even though this is not the variant detected in Manaus with more mutations: the best way to stop the spread of the virus is to wash your hands, wear a face covering, and keep your distance from others. While in lockdown, it’s important that we stay at home unless it’s absolutely essential to go out.”
What do we know about the South African variant?
The South African variant emerged around the same time as the English one, and has since been detected in at least 20 countries. Genomic data from South Africa suggested that the variant, known as 501Y.V2, quickly displaced other circulating lineages in the country as it appears to have a higher viral load and is therefore more transmissible.4 This variant shares similarities with the English and Brazilian variants in that it contains both the N501Y and E484K spike protein mutations.
Do the current vaccines work against the Brazilian, English, and South African variants?
The three main vaccines—Pfizer BioNTech, Moderna, and Oxford AstraZeneca—all target the spike protein of the virus, where these variants have mutations. Researchers are still fairly confident, however, that the vaccines will work against them—although they are not sure whether protection could be reduced—because the spike protein is so large that many mutations would be needed to completely escape. Studies are now underway to test whether the vaccines are effective against these new variants.
Could the virus still mutate to escape the vaccines?
In an interview with The BMJ,5 Andrew Pollard, who leads the Oxford vaccine clinical trials, said the crucial period will be when lots of people are vaccinated, as this will put the virus under a lot of pressure. “When that happens some viruses just can’t compete against that immunity. Will it mutate instead? With this coronavirus we don’t know the answer to that question yet, and that’s why surveillance is going to be critical in the year ahead to make sure that we’re not in a position where, at the point of population immunity, the virus escapes. And if it does, we need to know that, so that we can redesign the vaccines,” Pollard said. He added that the Pfizer, Moderna, and Oxford vaccines are “relatively straightforward to redesign for a new variant.”
Is there any link between the Oxford vaccine trials—carried out in Brazil and South Africa—and the new variants?
Pollard doesn’t think so. He told The BMJ, “The number of people in the vaccine trials is so small that it’s unlikely that our efforts would put any pressure on the virus to drive it to select new variants. Most trials only have a few hundred people vaccinated in cities of hundreds of thousands or millions of people. I don’t think vaccination has anything to do with new variants today.”
He explained, however, that the variants may be arising in Brazil and South Africa because of high transmission (as many as 40-50% of people being infected) in populations living in crowded conditions. Pollard said, “In those settings, variants of the virus that emerge that are able to spread despite existing post-infection immunity will be selected. If that’s the case, it doesn’t necessarily mean that we’re going to find ourselves in a position where vaccines don’t work against hospitalisation or severe disease, but it may be more difficult to prevent milder disease and transmission. We need to monitor the situation carefully and work out the process that would be needed to make an adjusted vaccine, should the need arise.”
How is the UK monitoring and studying new variants?
The Covid-19 Genomics UK (COG-UK) consortium is carrying out large scale and rapid whole genome sequencing of virus samples, which enables it to identify new variants. It currently provides 48% of the genomic data supplied to GISAID, a global initiative which carries out real time surveillance of the pandemic.
The G2P-UK National Virology Consortium has been launched to work with COG-UK to study how mutations may affect key outcomes, the transmissibility of variants, the severity of illness they cause, and their response to vaccines and treatments.
The group is headed up by Wendy Barclay, head of infectious disease and chair in influenza virology at Imperial College London. She told a Science Media Centre briefing that there were two variants in Brazil being watched—one that was picked up in some travellers into Japan, and the other which is more prevalent in Brazil at the moment. She added, “The sequences that are in the spike protein there, are in the spike protein receptor domain. Studies from other groups and our own are suggesting that they might impact the way that some people’s antibodies can see the virus. It’s important that we carry out this work now and carry it out carefully and in several different laboratories to really firm up those results, because they have big implications.”
How will the new variants be investigated?
G2P-UK co-lead Michael Malim from King’s College London said, “Once a sequence of interest is identified we’ll be able to synthesise that spike gene and make virus particles in the laboratory. Then we’ll test the sensitivity of that virus to inhibition of infection in laboratory models to a range of sera from vaccines and natural infection, and work out if there is a change. It would take about two to three weeks from knowing which sequence to focus on to having those results. So, pretty quickly, we would know where the variant, for example, could potentially break through vaccination.”
Are countries collaborating as variants arise?
A global surveillance system is something that the World Health Organization is working on, according to Barclay. She said, “A group like ours could play a role. Surveillance and update systems will require the basic biology. They need underpinning biology that will come from the studies that we, and other groups around the world, do. That will feed into the WHO draft plan for how we deal with this virus, which is going to be with us for the foreseeable future.” SARS-CoV-2 Worldwide Replication Drives Rapid Rise and Selection of Mutations across the Viral Genome: A Time-Course StudyPotential Challenge for Vaccines and Therapies
https://www.medrxiv.org/content/10.1101/2021.02.04.21251111v1
501Y.V2 and 501Y.V3 variants of SARS-CoV-2 lose binding to Bamlanivimab in vitro
Haolin Liu, Pengcheng Wei, Qianqian Zhang, Zhongzhou Chen, Katja Aviszus, Walter Downing, Shelley Peterson, Lyndon Reynoso, Gregory Downey, Stephen Frankel, John Kappler, Philippa Marrack, Gongyi Zhang
Abstract
We generated several versions of the receptor binding domain (RBD) of the Spike protein with mutations existing within newly emerging variants from South Africa and Brazil. We found that the mutant RBD with K417N, E484K, and N501Y exchanges has higher binding affinity to the human receptor compared to the wildtype RBD. This mutated version of RBD also completely abolishes the binding to a therapeutic antibody, Bamlanivimab, in vitro.
https://www.biorxiv.org/content/10.1101/2021.02.16.431305v1
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Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies
View ORCID ProfileDelphine Planas,View ORCID ProfileTimothée Bruel,View ORCID ProfileLudivine Grzelak, Florence Guivel-Benhassine, Isabelle Staropoli, Françoise Porrot,View ORCID ProfileCyril Planchais,View ORCID ProfileJulian Buchrieser,View ORCID ProfileMaaran Michael Rajah, Elodie Bishop, Mélanie Albert, Flora Donati,View ORCID ProfileSylvie Behillil,View ORCID ProfileVincent Enouf, Marianne Maquart, Maria Gonzalez, Jérôme De Sèze, Hélène Péré,View ORCID ProfileDavid Veyer, Aymeric Sève,View ORCID ProfileEtienne Simon-Lorière,View ORCID ProfileSamira Fafi-Kremer,View ORCID ProfileKarl Stefic,View ORCID ProfileHugo Mouquet,View ORCID ProfileLaurent Hocqueloux, Sylvie van der Werf,View ORCID ProfileThierry Prazuck,View ORCID ProfileOlivier Schwartz
doi: https://doi.org/10.1101/2021.02.12.430472
Abstract
SARS-CoV-2 B.1.1.7 and B.1.351 variants emerged respectively in United Kingdom and South Africa and spread in many countries. Here, we isolated infectious B.1.1.7 and B.1.351 strains and examined their sensitivity to anti-SARS-CoV-2 antibodies present in sera and nasal swabs, in comparison with a D614G reference virus. We established a novel rapid neutralization assay, based on reporter cells that become GFP+ after overnight infection. B.1.1.7 was neutralized by 79/83 sera from convalescent patients collected up to 9 months post symptoms, almost similar to D614G. There was a mean 6-fold reduction in titers and even loss of activity against B.1.351 in 40% of convalescent sera after 9 months. Early sera from 19 vaccinated individuals were almost as potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Nasal swabs from vaccine recipients were not neutralizing, except in individuals who were diagnosed COVID-19+ before vaccination. Thus, faster-spreading variants acquired a partial resistance to humoral immunity generated by natural infection or vaccination, mostly visible in individuals with low antibody levels. Binding Profile Assessment of N501Y: a More Infectious Mutation on the Receptor Binding Domain of SARS-CoV-2 Spike Protein
https://europepmc.org/article/ppr/ppr279619
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 and has accumulated nearly a hundred million reported infections thereafter. This highly transmissible and pathogenic coronavirus has caused a pandemic of acute respiratory disease, coronavirus disease 2019 (COVID-19), which has caught extensive attention and greatly changed people’s lifestyles all over the world. As an RNA virus, SARS-CoV-2 mutates rapidly as the virus replicates. The world health organization is now closely monitoring the emergence of a new variant, N501Y, on the spike protein. This N501Y variant is found to have higher transmission ability and infectivity, and is believed to be related to the rapid increase of COVID-19 cases in December 2020 in the UK. It was recently reported that the N501Y variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies. The Tyr mutation at 501 is located at the receptor binding domain (RBD) of the spike protein, the area that directly contacts human ACE2 (hACE2). It’s urgent to figure out the driving force of the new mutant’s enhanced infectivity. Thus, a computational aided binding profile prediction is made to investigate the binding affinity alteration and potential structural change of the N501Y mutant. The resulting structures of N501Y mutant from MD simulations could be used to develop drug inhibitors against hACE2/RBD binding. 2021年2月23日，中国食品药品检定研究院王佑春，黄维金，中国疾病预防控制中心许文波，南华大学瞿小旺共同通讯在Cell 在线发表题为“No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants”的研究论文，该研究用18种假型病毒进行的实验表明，除了鼠ACE2过表达的细胞外，501Y.V2变体在多种细胞类型中均未赋予增加的感染力，在小鼠中，ACE2过表达的细胞被观察到感染力大大增加。值得注意的是，501Y.V2变体对17种中和单克隆抗体中的12种的敏感性大大降低，并且恢复期患者和免疫小鼠血清对这些变体的中和能力也降低了。中和抗性主要是由刺突蛋白受体结合域中的E484K和N501Y突变引起的。此外，该研究检测到的501Y.V2变体的抗中和性表明潜在的单克隆抗体和疫苗功效受损的可能性。 牛津大学Zhou DaMing等人在Cell 在线发表题为“Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera”的研究论文，该研究描述了使用大量恢复期和被疫苗血清样品的B.1.351结构功能分析。受体结合结构域突变提供了更紧密的ACE2结合，并从很大程度上由E484K驱动的单克隆抗体中和中逃逸，尽管K417N和N501Y共同作用于一些重要的抗体类型。在许多情况下，恢复期和某些疫苗血清似乎无法针对这种变异提供有限的保护。 Increased transmission of SARS-CoV-2 lineage B.1.1.7 (VOC 2020212/01) is not accounted for by a replicative advantage in primary airway cells or antibody escape
https://doi.org/10.1101/2021.02.24.432576
Abstract
Lineage B.1.1.7 (Variant of Concern 202012/01) is a new SARS-CoV-2 variant which was first sequenced in the UK in September 2020 before becoming the majority strain in the UK and spreading worldwide. The rapid spread of the B.1.1.7 variant results from increased transmissibility but the virological characteristics which underpin this advantage over other circulating strains remain unknown. Here, we demonstrate that there is no difference in viral replication between B.1.1.7 and other contemporaneous SARS-CoV-2 strains in primary human airway epithelial (HAE) cells. However, B.1.1.7 replication is disadvantaged in Vero cells potentially due to increased furin-mediated cleavage of its spike protein as a result of a P681H mutation directly adjacent to the S1/S2 cleavage site. In addition, we show that B.1.1.7 does not escape neutralisation by convalescent or post-vaccination sera. Thus, increased transmission of B.1.1.7 is not caused by increased replication, as measured on HAE cells, or escape from serological immunity.
https://www.biorxiv.org/content/10.1101/2021.02.24.432576v1 Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies
https://www.nature.com/articles/s41591-021-01294-w
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.
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