Variants! The Shape-Shifting Challenge of COVID-19

William A. Haseltine

• Publisher: ACCESS Health International
• Year: 2021
• Edition: 1
• eBook ISBN:
  9780578854243
• Topic: Medicine
• Subtopic: Infectious Diseases

The Variants are Here

The UK variant (B.1.1.7)

The first reports that a new variant, more dangerous than D614G might exist, came from news reports from the United Kingdom. Despite lockdowns, new infections were rising rapidly in Southern England during the fall of 2020. Then came the dramatic announcement from the Prime Minister's office. A unique and potentially dangerous variant was preferentially spreading in those areas experiencing a dramatic uptick in infection (Figure 18, 19, 20). In record time, a preprint was available detailing changes in the viral genome. Fast forward to February 2021: the variant has been detected in more than 50 countries, has jumped from 3.3% to 14% of cases in France in less than a month, and is projected by experts to become dominant in US hotspots in a matter of weeks. A preprint published February 3 also verified that more people are dying of this variant than ones prior-- increasing the chances of death for those infected by about 35 percent. Whether it is more lethal than the last dominant strain or simply reaching a greater proportion of vulnerable populations remains to be seen.

The genome sequence of the new variant revealed not one but 23 changes as compared to early strains, 20 of which alter protein structures in addition to D614G.

The collective shock of that paper, felt by government leaders, public health officials, and scientists alike, is still with us.

Figure 18. Estimate of true positive rates for classification of B.1.1.7 infection. The color gradient shows the probability of sampling a B.1.1.7 sequence conditional on sampling any sequence with 69-70del.

Source: Volz et al., 2021

Figure 19. List of countries that have reported B.1.1.7 detection, October vs December 2020.

Source: GISAID

Figure 20. Map of states where local transmission of B.1.1.7 has been detected as of January 18, 2021.

Source: Corum & Zimmer, 2021

Why shock? The genome sequence of the new variant revealed not one but 21 changes as compared to early strains, 18 of which alter protein structures in addition to D614G. The new variant is now designated B.1.1.7 (aka the UK variant). Most of the 18 differences result in a change of one amino acid for another. Two are small deletions of one and two amino acids. Several changes in the nucleotide sequence of the virus do not result in any amino acid change. Eight of the changes are in the spike protein. Others are scattered about the genome, potentially altering the function of the replicative enzyme complex (orf1ab), the M protein (a virus particle surface protein), one in orf3b and several in orf8. Almost all work to date has focused on the S protein as this is the preferred vaccine target. Variants such as B.1.1.7 are known to be more contagious but have shown us they can change still further. The B.1.1.7 variant, for example, recently acquired the immune-evasive E484K mutation.

Figure 21. A linear overview of the B.1.1.7 (UK) genome.

Figure 22. Mutations in the viral spike identified in B.1.1.7 (UK) in addition to D614G.

Source: Wang et al., preprint

I will describe each change as it is relevant to understanding the UK variant. As it happens, other variants now popping up around the world contain some amino acid changes identical to the UK variant as well as changes unique onto themselves.

Figure 21 is a linear display of the B.1.1.7 genome, while Figure 22 zooms in on the S protein. The functional regions of the protein in Figure 22 are highlighted in different colors, which I refer to in the following sections.

The signal peptide sequence

The initial amino acids 1-12(3) are called the signal peptide sequence. This short region directs the S protein to exit the cell membrane. The virus buds through the cell membrane, surrounding the core of the virus with a membrane decorated with the spike protein. The signal peptide is often cleaved from the mature protein as it exits the cell.

The N-terminal domain

The next region (blue) is the N-terminal domain. In the mature spike, this region folds up into a structure near the top of the spike aside the receptor-binding domain. The function of the N-terminal domain is unknown.

The receptor-binding domain

The receptor-binding domain, amino acids 331-528 (purple) folds up into a compact structure that sits atop the spike. When open, it presents a flat surface that binds tightly to the ACE2 receptor. The precise fit at the atomic level between the surface receptor-binding domain of the ACE2 protein and electrostatic attraction between oppositely charged amino acids on two surfaces determines how tightly the two proteins stick to one another (Figures 23, 24, 25). This region is the primary target of protective antibodies that block the virus's ability to bind the receptor. No receptor binding, no infection.

Think of pieces of a puzzle, each of which carries a magnetic charge. Not only must there be an exact match in the shape to the two opposing pieces, but the magnetic poles must also be complementary, positives opposite negatives (Figure 26). The puzzle pieces may fit loosely or tightly depending on the precise details of the shape. Even if the pieces fit, the magnetic poles must also match, otherwise even pieces with an exact match would repel one another. This is a very good analogy for the necessity of complementary shapes and charges that determine how well the receptor binding domain binds to the ACE2 receptor. Each amino acid has its own shape and charge characteristics. Any change in the shape or charge of the amino acid substitution will affect binding (Figures 27, 28).

Figure 23. Left panel, top view of SARS-COV-2 spike with one RBD in the “up” conformation (pdb: 6zgg). RBD and NTD are colored green and peach, respectively. The positions of ‘inner’ and ‘outer’ sides are indicated on the “up” RBD with the ACE2-binding site colored yellow. The three panels to the right show the antibody footprints on RBD.

Source: Wang et al., preprint

Figure 24. Global comparison between RBD-WT and RBD-62 shows overall similarity. Please note that the orientation of the receptor-binding domain is reversed compared to other figures below, with the ACE2 receptor on top.

Source: Zahradnik et al., preprint

Figure 25. Cartoon representation of the Cryo-EM structure of ACE2 (cyan) in complex with RBD-62 RBM (magenta) with the RBD-62 mutations resolved in the density (orange spheres).

Source: Zahradnik et al., preprint

These bits of the virus are like puzzle pieces made of individual atoms. One atom out of place will decrease how well the pieces fit together.

Figure 26. These bits of the virus are like puzzle pieces made of individual atoms. One atom out of place will decrease how well the pieces fit together. The blue repr...

Table of contents

• Preface
• Introduction
• Coronaviruses
• The Code Crackers
• What code did the original SARS-CoV-2 Wuhan strain crack?
• Seasonal Population Immunity
• Will population immunity to SARS-CoV-2 be permanent or seasonal?
• The Variants are Coming: D614G
• The Variants are Here
• The UK variant (B.1.1.7)
• The South African Variant (B.1.351 or 501.V2)
• How do variants arise?
• Witnessing the birth of variants in real-time
• Gazing into the Crystal Ball
• Covid-19 Control in the Variant Era
• August 2021 Update
• March and April 2021 Update
• February 2021 Update
• Frequently Asked Questions
• Chapter 1: Viruses as Code Crackers
• Why COVID? Nature’s Code Cracking Machine Intelligence
• Want to Prevent Another Coronavirus Epidemic?
• What AIDS Taught Us About Our Coronavirus Response
• Lessons From AIDS For The COVID-19 Pandemic: We Can Learn From Parallels Between The Coronavirus And HIV Crises
• Chapter 2: What Are Variants and Where Do They Come From?
• One Step Closer To Understanding The Origin Of SARS-CoV-2
• The Way That COVID-19 Tricks The Immune System Could Result In More Severe Illness
• A Mutation Shows Why the Coronavirus Is Such A Formidable Foe
• A Tale Of Four Cities: Wuhan, Seattle, New York, Chicago
• How The Covid-19 Virus Changes
• Are We Creating Immune Resistant Variants Of SARS-CoV-2?
• New Covid-19 Variants Reshape Our Understanding Of Reinfection
• Researchers Identify New Covid-19 Variant In Ohio
• Chapter 3: How Bad Can It Get?
• Here's what's worrying about the coronavirus variant
• New Covid-19 Variants In One Country Pose A Threat To All Countries
• Can SARS-CoV-2 Become Even More Troublesome Than The U.K. And South African Variants?
• For Insight On New Covid-19 Variants, Look To Natural History Of Coronaviruses
• This Devastating Covid-19 Outbreak In Brazil Is A Warning To The Rest Of The World
• A Tale Of Two Viruses
• SARS-CoV-2 Immunity: A Moving Target
• Chapter 4: Population Immunity Is A Myth
• COVID Immunity: How Protected Are You?
• Can America Handle A Second Wave?
• Immunity To COVID-19 Infection May Fade Quickly
• We're Wasting Time Talking About Herd Immunity
• What Does Disappearing Immunity To COVID-19 Mean For A Vaccine?
• Herd Immunity: A Reckless And Ineffective Strategy
• Why We Can’t Rely On Natural Immunity To Protect Us From Covid-19
• Why We Can’t Rely On Natural Immunity To Protect Us From COVID-19
• Herd Immunity Is A Fantasy
• Herd Immunity Will Not Defeat COVID-19
• Herd Immunity Is A Double Tragedy In The Making
• New Study Offers More Evidence That Immunity To Covid-19 Fades Quickly
• New Research On Flu Vaccines Sheds Light On Covid-19 Vaccines
• What Are Autoantibodies? The Latest Risk Factor For Severe Covid-19
• Covid-19 Reinfection Is Possible And Should Inform Pandemic Priorities Moving Forward
• The Trouble With Herd Immunity And Covid-19 Vaccines
• Chapter 5: How Do Variants Affect Treatments?
• Monoclonal Antibodies Could Help Fight Against Coronavirus
• Progress In Monoclonal Antibodies For The Treatment And Prevent-Of-COVID-19
• This Nasal Spray Could Be The Breakthrough We Need To End Covid-19
• Chapter 6: How Do Variants Affect Vaccines?
• Lessons For COVID-19 From The Early Days Of AIDS
• What If There’s No COVID Vaccine?
• What COVID-19 Reinfection Means For Vaccines
• Vaccines Need To Be Cheap And Accessible Worldwide
• How To Decipher The New Pfizer Study On Vaccines And Variants
• Who Are The Vaccinated That Still Become Infected?
• How New Covid-19 Variants Might Impact Vaccines
• Chapter 7: What Is To Be Done?
• It’s Time To Recalibrate: New Covid-19 Strains Will Only Make The Pandemic Worse
• Why The U.S. Needs To Step Up Covid-19 Genome Sequencing
• Why Patterns In Covid-19 Variation Might Resemble Seasonal Flu
• Chapter 8: Multiple New Variants Emerge
• Covid-19 Could End Up Like The Flu—Or Worse
• Weighing Biden's First Executive Orders to Address COVID-19
• Persistently Infected Covid-19 Patients: A Potential Source For New Variants
• Rapid Spread Of Variants Across Europe Is A Dire Warning For The U.S.
• This Region Of The Covid-19 Virus Is One We Can’t Ignore
• How One Covid-19 Patient’s Infection Foreshadowed The Rise Of New Variants
• What Are The 677 Mutations? New Covid-19 Variants Found In The US
• UK Approves Human Challenge Trials For Covid-19, But At What Cost?
• NBA Study Reveals The UK Variant May Last Longer In Human Hosts
• Variants Could Cause A Rapid Rise In Covid-19 Cases In The U.S. Unless We Implement These Public Health Measures
• Pfizer/BioNtech And Moderna MRNA Covid-19 Vaccines Closely Mimic The Immune Response Of Natural SARS-CoV-2 Infections
• A New Covid-19 Variant From Nigeria Raises Increased Concerns For Containment And Vaccination
• If I Had Covid-19, Should I Still Get Vaccinated? Absolutely
• Identification of a Novel Covid-19 Variant Cluster Isolated from a Sick Newborn in US Capital
• New York Finds Its Own Covid Variants. The News Is Not Good
• Covid-19 Cases Are Rising Again Globally
• Should Anticoagulants Be Used Early Or Late In Patients Hospitalized With Covid-19: Two Conflicting Answers
• Self-Testing: A Route To School Re-Opening – The Austrian Example
• The California Variant Is More Transmissible, Evokes Worse Symptoms, And May Resist Vaccines
• Schools Must Reconsider Accelerating Plans To Reopen In Light Of Dangerous New Covid-19 Variants
• Chapter 9: More Variants, More Consequences
• Italian Scientists Create Live SARS-CoV-2 Neutralization Escape Variant
• New York Covid-19 Variants Are Causing Concern
• Variants: Forewarned Is Forearmed— For Those Who Listen
• More Cause For Concern Around Covid-19 And Schools
• T-Cell Responses Hold Up Against SARS-CoV-2 Variants, Study Finds
• Covid-19 Reinfections Are Real And Serious—All The More Reason To Be Vaccinated
• New Study Using Live Virus Explores Whether Pfizer-BioNTech Vaccine Protects Against Variants
• New Hope For A Covid-19 Vaccine That Protects Against All Variants
• Novavax Covid-19 Vaccine Performs Well In Clinical Trials, But Variants Remain A Threat
• AstraZeneca Vaccine Fails To Protect Against The South African Variant, Says Study
• A New Variant In The Philippines
• Science will save us in our battle against COVID-19
• Spring Break Could Trigger A National Surge In Cases Fueled By Variants
• From Cats And Dogs To Minks And Mice, Covid-19 Variants Are Infecting The Ecosystem
• Persistence Of Covid-19 Antibodies Varies Widely From Person To Person
• New Belgian Variant Illustrates The Versatility Of SARS-CoV-2 In Escaping Immune Suppression
• Despite Progress, Protecting The Population Against Covid-19 Variants Remains Complex
• The Pfizer/BioNTech Covid-19 Vaccine Is Less Effective Against The South African And UK Variants Than Against The Original Virus, According To A New “Real-World” Study From Israel
• An Indian SARS-CoV-2 Variant Lands In California. More Danger Ahead?
• A Dangerous New Covid-19 Variant Detected In Oregon
• New Tanzanian Variant Detected In Angola From An Entirely New Branch Of SARS-CoV-2
• Chapter 10: Emergence of the Delta Variant
• The Recent Rise of Indian Covid-19 Cases Display The Dangers Of SARS-CoV-2 Variants
• New Antiviral Drug Cocktail Could Help India Control Brutal Covid-19 Surge
• Vaccines Vs Variants: Three Studies Provide New Insight
• Booster Shots For mRNA Vaccines Likely Required Within Six Months To Protect Against Covid-19 Variants
• Newly Discovered Antibody Neutralizes Covid Variants By Locking Receptor-Binding Domain In A Closed Position
• A Third SARS-CoV-2 Variant Of Interest (Potentially Concern) Emerges From Sub-Saharan Africa
• Singapore’s Outbreak Highlights A Challenging Road Ahead For Covid-19 Containment
• Infection Through “Fleeting Contact” With The Delta Variant Leads To Lockdowns Across Australia
• The Delta Dilemma: Loosening Covid-19 Controls At A Time Of Increased Danger
• An Argument For Covid-19 Booster Shots To Protect The Vulnerable
• Λ!!: A New Threat On The Rise In South America
• New Studies Highlight Promising Candidates For Second-Generation Covid-19 Vaccines
• The UK's Dangerous And Deadly Gamble
• A Situation Update On Covid-19 Variants And Vaccines
• What We Need To Know About The Future Of Covid Variants
• A Warning About The Future Of Covid-19 From The Scientific Advisory Group For Emergencies Of The United Kingdom
• Chapter 11: Other Resources
• 501Y.V1 Variant B.1.1.7 Lineage (UK Variant)
• Appendix
• Acknowledgements
• References