SARS-CoV-2 spike protein mutations: Difference between revisions

In [[#Update History|December, 2020]], scientists in the '''United Kingdom''' discovered that among thousands of  mutations in SARS-CoV-2 detected in the UK and elsewhere, coronavirus with a particular set of mutations appeared to be rapidly becoming the predominant ''lineage''<ref name="lineage">PMID: 32669681</ref><ref name="a." /> for new infections in parts of England<ref name="rambaut" /><ref name="coguk1" /><ref name="phe1" />.

is termed '''B.1.1.7''' or '''VOC 202012/01'''<ref name="nervtag1" /><ref name="phe1">[https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/948152/Technical_Briefing_VOC202012-2_Briefing_2_FINAL.pdf Investigation of novel SARS-CoV-2 variant. Variant of Concern 202012/01. Technical briefing 2.] published December 28, 2020 by [http://www.gov.uk/phe Public Health England].</ref>. Among more than 700 defined lineages<ref name="a.">[https://cov-lineages.org/lineages/lineage_A.html PANGO Lineages], a list of more than 700 defined lineages with references where available.</ref><ref name="pango">[https://virological.org/t/tracking-the-international-spread-of-sars-cov-2-lineages-b-1-1-7-and-b-1-351-501y-v2/592 Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2], Áine O'Toole ''et al.'', posted January 13, 2021.</ref> it is the first globally distributed, well characterized mutant lineage recognized late in the pandemic (see [[#Notes|Note 1]]).

In late December, 2020, there was news from '''South Africa''' of another lineage becoming prevalent there, termed '''501Y.V2'''<ref name="gisaid1">[https://www.gisaid.org/references/gisaid-in-the-news/novel-mutation-combination-in-spike-receptor-binding-site/ Novel variant 501.V2 with triple spike receptor binding site substit[utions] posted December 21, 2020 by the GSAID Influenza and Coronavirus sequences Initiative.</ref>, 501.V2, or '''B.1.351'''<ref name="cdc1">[https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html Emerging SARS-CoV-2 Variants], CDC report, update of January 3, 2021.</ref>.

In December, 2020, many scientists believed that B.1.1.7 is more contagious<ref name="nervtag1">[https://app.box.com/s/3lkcbxepqixkg4mv640dpvvg978ixjtf/file/756964987830 NERVTAG/SPI-M Extraordinary meetingon SARS-CoV-2 variant of concern 202012/01 (variant B.1.1.7)], December 21, 2020, from the UK Government [https://www.gov.uk/government/groups/new-and-emerging-respiratory-virus-threats-advisory-group New and Emerging Respiratory Virus Threats Advisory Group].</ref>, but there remained some uncertainty, since the increase in B.1.1.7 could also be related to founder effects or variations in human behaviors in regions of England<ref name="racaniello1">[https://www.virology.ws/2020/12/24/sars-cov-2-uk-variant-does-it-matter/ SARS-CoV-2 UK variant: Does it matter?], a 25 min video explanation recorded December 21, 2020, by Vincent Racaniello, Professor of virology at Columbia University, New York City.</ref>. However, by early January, 2021, it appeared very likely that B.1.1.7 and 501Y.V2 are more contagious<ref name="leonhardt1">[https://nyti.ms/2X7JT7z A simple chart shows why the new coronavirus variants are so worrisome], David Leonhardt, New York Times, January 4, 2021. A chart of new daily coronavirus cases shows Britain and South Africa surging, far exceeding rates in neighboring countries.</ref>.

In January, 2021, lineage '''B.1.429'''<ref name="a." /> with mutation '''L452R''' was reported to be expanding rapidly in Northern California, USA<ref name="santaclara">[https://www.sccgov.org/sites/covid19/Pages/press-release-01-17-2021-COVID-19-variant-more-frequent-in-CA.aspx COVID-19 Variant First Found in Other Countries and States Now Seen More Frequently in California], January 17, 2021, Santa Clara County Public Health, California, USA.</ref>. From late 2020 into early 2021, this lineage expanded from 4% of samples to 25%<ref name="deadline">[https://deadline.com/2021/01/another-new-covid-19-variant-in-l-a-vaccine-resistant-denmark-1234675834/ Another New Covid-19 Variant Discovered In L.A. Might Be Vaccine Resistant, Researcher Says; Strain First Identified In Denmark] by Tom Tapp in ''Deadline'', January 18, 2021.</ref>.

Also in January, 2021, the lineage '''P.1''' was found to have increased rapidly in Manaus, Brazil<ref name="P1.1">[https://www.the-scientist.com/news-opinion/a-guide-to-emerging-sars-cov-2-variants-68387 A Guide to Emerging SARS-CoV-2 Variants] by Katarina Zimmer, ''The Scientist'', January 26, 2021.</ref><ref name="manaus1" />. P.1 has 10 mutations in the spike protein, including 3 in common with the South African lineage 501Y.V2 (N501Y, K417N, and E484K)<ref name="manaus1">[https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings], Nuno R. Faria ''et al.'' on behalf of the CADDE Genomic Networ,, January 12, 2021.</ref>. P.1 was found in the USA in January, 2021<ref name="P1.1" />.

 

 

'''B.1.617''' was first detected in October, 2020<ref name="617who">[https://www.who.int/docs/default-source/coronaviruse/situation-reports/20210427_weekly_epi_update_37.pdf COVID-19 Weekly Epidemiological Update for April 25, 2021] from the World Health Organization.</ref>. By the end of April, 2021, B.1.617 was predominant in India, where a devastating surge of COVID-19 was overwhelming hospitals<ref name="617who" /><ref name="617scientist">[https://www.the-scientist.com/news-opinion/what-scientists-know-about-the-b-1-617-coronavirus-variant-68733 What Scientists Know About the B.1.617 Coronavirus Variant] in ''The Scientist'', by Shauna Williams, May 3, 2021.</ref><ref name="617nature">[https://www.nature.com/articles/d41586-021-01059-y India’s massive COVID surge puzzles scientists], ''Nature'', by Smriti Mallapaty, April 21, 2021.</ref>. In addition to India, B.1.617 was identified in the USA, UK, and Singapore<ref name="617who" />.

====B.1.351====

The B.1.351 lineage (also called '''501Y.V2''' or 501.V2) accounted for more than half of new cases in South Africa in late December, 2020<ref name="gisaid1" />. This lineage is also suspected to have a higher rate of transmission. Its mutations of greatest concern include one in common with B.1.1.7 (N501Y) plus two different mutations that are, like N501Y, in the receptor binding domain of the spike protein:

These mutations also increase binding affinity for ACE2<ref name="zahradnik" />. Unlike B.1.1.7, 501Y.V2 retains His 69 and Val 70 (not deleted)<ref name="cdc1" />.

 

 

Sequence position 677 is close to the [[SARS-CoV-2 spike protein priming by furin|furin cleavage site]] at <span class="text-red">'''PRRAR'''</span> (681-684). The consequences of these mutations are under investigation.

====B.1.617====

The defining mutations in B.1.617 include L452R, P681R, and E484Q. '''L452R''' is present in B.1.429 the US "California" lineage, and confers resistance to convalescent serum antibodies<ref name="convalescent" />. '''P681R''' occurs in B.1.1.7, is in the [[SARS-CoV-2 spike protein priming by furin|furin cleavage site]] and is suspected of increasing contagiousness<ref name="617who" />. '''E484Q''' is similar to E484K, present in the "South African" lineage B.1.351 / 501Y.V2, and is thought to contribute to evasion of immunity<ref name="617who" /><ref name="greaney">PMID: 33592168</ref>.

While the mutations in B.1.1.7 seem unlikely to make current anti-COVID-19 vaccines less effective, there is more concern regarding the additional mutations in 501Y.V2<ref name="smc1">[https://www.sciencemediacentre.org/expert-reaction-to-the-south-african-variant/ Expert reaction to the South African variant], Science Media Centre of the UK, January 4, 2021.</ref>. Unfortunately, poor management of COVID-19 and inconsistent therapy maneuvers have favored development of mutations that may evade the initial wave of vaccines<ref name="bieniasz">[https://www.virology.ws/2021/01/05/musings-of-an-anonymous-pissed-off-virologist/ Musings of an anonymous, pissed off virologist] by Paul Bieniasz, Professor at Rockefeller University, January 5, 2021.</ref>. Antibodies in the blood of half of people who have recovered from COVID-19 are unable to neutralize 501Y.V2<ref name="wibmer">[https://www.biorxiv.org/content/10.1101/2021.01.18.427166v1 SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma], preprint posted January 19, 2021.</ref>, but other forms of immunity, such as T-cells, may still be protective. On January 28, 2021, Novavax reported that its vaccine, which was 90% effective in the UK, was '''only 50% effective in South Africa''', where ~90% of cases were 501Y.V2<ref name="novavax1">[https://ir.novavax.com/node/15506/pdf Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial], posted January 28, 2021 by Novavax.</ref>. The next day, Johnson and Johnson announced similar results<ref name="jnj1">[https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial#_ftn1 Johnson & Johnson Announces Single-Shot Janssen COVID-19 Vaccine Candidate Met Primary Endpoints in Interim Analysis of its Phase 3 ENSEMBLE Trial], January 29, 2021.</ref>. Experts believe that present vaccines could be modified for greater effectiveness against these mutants, if necessary, withinin a few months<ref name="smc1" />. Moderna began development of a vaccine modified to combat 501Y.V2 in January, 2021<ref name="moderna-501.v2">[https://www.businessinsider.com/moderna-to-test-coronavirus-vaccine-to-fight-south-africa-variant-2021-1 Moderna is designing a new version of its COVID-19 shot to fight the variant first found in South Africa] by Andrew Dunn and Allison DeAngelis, ''Business Insider'', January 25, 2021.</ref>. On March 26, 2021, public health officials in the UK announced a plan to begin booster vaccinations in September with variant-adapted vaccines<ref name="ukboosters">[https://www.yahoo.com/news/exclusive-over-70s-booster-covid-205453613.html Exclusive: Over-70s to get booster Covid vaccines from September] by Ben Riley-Smith in ''The Telegraph'', March 26, 2021, quoting vaccines minister Nadhim Zahawi.</ref>.

 

South Africa announced stopping the use of its supply of Astra-Zenica vaccine February 7, 2021<ref name="haltsa">[https://www.bbc.com/news/world-africa-55975052 Covid: South Africa halts AstraZeneca vaccine rollout over new variant], BBC News, February 8, 2021.</ref>. This was based on a small trial limited to young participants showing only about 20% effectiveness at preventing mild disease from 501Y.V2. Whether this vaccine prevents severe disease from 501Y.V2 in older people remained unclear<ref name="haltsa" />.

An early report found that B.1.1.7 does not increase hospitalization or death compared to the wild type SARS-CoV-2<ref name="phe1" />. Later evidence raised a "realistic possibility" of increased mortality<ref name="hornby1">[https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/955239/NERVTAG_paper_on_variant_of_concern__VOC__B.1.1.7.pdf NERVTAG note on B.1.1.7 severity], Peter Horby ''et al.'', January 18, 2021.</ref><ref name="reutersUKdeath">[https://www.businessinsider.com/why-uk-coronavirus-variant-may-be-deadlier-2021-1 UK officials say people who get the contagious coronavirus variant may have a higher risk of death.] Aylin Woodward for Reuters, January 25, 2021.</ref>. An analysis of statistics in February, 2021, by the UK Government ''New and Emerging Respiratory Virus Threats Advisory Group'' (NERVTAG) concluded that "it is likely that infection with VOC B.1.1.7 is

Morbidity and mortality for the other variant lineages remains under investigation.

He refers to the UK's COVID-19 Genomics Consortium (COG-UK)<ref name="cog1">[https://www.sanger.ac.uk/collaboration/covid-19-genomics-uk-cog-uk-consortium/ COVID-19 Genomics UK (COG-UK) Consortium], Wellcome Sanger Institute, UK.</ref><ref name="coguk">[https://www.cogconsortium.uk/ COVID-19 Genomics Consortium UK (CoG-UK)].</ref>. In contrast to the UK, the USA has done far less SARS-CoV-2 genome sequencing, leaving the spread of variants in the USA largely unknown<ref name="zimmer1">[https://www.nytimes.com/2021/01/06/health/coronavirus-variant-tracking.html U.S. Is Blind to Contagious New Virus Variant, Scientists Warn] by Carl Zimmer, New York Times, January 6, 2021.</ref>.

 

By the end of December, 2020, B.1.1.7 had been detected in at least 18 countries<ref name="18countries">[https://www.businessinsider.com/new-coronavirus-variant-all-the-countries-where-its-been-identified-2020-12 These are all countries that have already reported cases of the new, possibly more infectious coronavirus variant from the UK], Business Insider, December 29, 2020.</ref>, plus the United States<ref name="usa1">[https://www.huffpost.com/entry/new-covid-uk-confirmed-us-colorado_n_5feba1fdc5b66809cb34f0f9 New COVID-19 Variant From U.K. Confirmed In U.S. For First Time], Huffington Post, December 29, 2020.</ref>. By January 18, 2021, B.1.1.7 infections were detected in 20 states of the United States<ref name="20states">[https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html US COVID-19 Cases Caused by Variants], update of January 18, 2021. Centers for Disease Control and Prevention, USA.</ref>. By mid-February, 2021, B.1.1.7 was detected in 83 countries<ref name="b.1.1.7">[https://cov-lineages.org/global_report_B.1.1.7.html B.1.1.7 Report], PANGO Lineages, February 17, 2021.</ref>.

Children, not yet vaccinated, are a dangerous reservoir of variants, according to evidence presented in May, 2021<ref name="children">[https://www.medrxiv.org/content/10.1101/2021.05.22.21257660v1 Emergence of SARS-CoV-2 variants of concern in the pediatric population of the United States], a preprint posted May 24, 2021.</ref>.

*December 27, 2020: Added this section ''Update History''. Named and visualized the specific mutations of concern in the [[#501.V2|South African lineage 501Y.V2]], with a new citation<ref name="gisaid1" />.

*January 7, 2021: Added a preprint showing that some of the mutations in B.1.1.7 and 501Y.V2 increase binding affinity between the spike protein and its receptor ACE2<ref name="zahradnik" />.

*January 9, 2021: Added alternate name B.1.351 for 501Y.V2<ref name="cdc1" />.

*January 25, 2021: Convalescent plasma often ineffective against 501Y.V2<ref name="wibmer" /> and Moderna developing variant vaccine<ref name="moderna-501.v2" />.

*January 29, 2021: Cited a report by Novavax of lower vaccine effectiveness in South Africa<ref name="novavax1" />, and evidence that the USA is doing far too little virus genome sequencing<ref name="zimmer1" />.

*May 24, 2021: Added evidence that unvaccinated children are a reservoir of variants<ref name="children" />.