Is Sars-CoV-2 already targeting the vaccinated?

Will future variants of Sars-Cov-2 tailor themselves to target the vaccinated?  Given that up to 90% of the population of some countries are now fully vaccinated, the question should perhaps be: Why would Sars-CoV-2 NOT target the vaccinated? 

Selective pressure on the virus may mean an increasing drift towards variants that can overcome vaccines, as we are already seeing with Omicron.

There is some evidence in the scientific literature that the global vaccination campaign may have, through selective pressure, encouraged the virus to target the vaccinated.

  • In this Medrxiv preprint, “COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance”, the authors state that “This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2.”
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  • In this PLOS paper, the authors assert that there is a “risk of rapid evolutionary escape from biomedical interventions targeting evolution”, and “predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population.”
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  • In this Frontiersin.org paper, “Implication of SARS-CoV-2 Immune Escape Spike Variants on Secondary and Vaccine Breakthrough Infections”, the authors state: “The increasing degree of immunity in the human population is inevitably conferring a great deal of selective pressure on the virus that promotes the rise of antibody escape mutants. The emergence of immune escape mutants is perhaps most apparent in chronic COVID-19 patients as documented in multiple reports.”
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  • This UK government paper suggested ways in which Sars-CoV-2 may evolve in future: “Antigenic ‘shift’: Natural recombination events that insert a different spike gene sequence (or partial sequence) from human CoVs MERS-CoV… This would recombine into the ‘body’ of SARS-CoV-2 that is capable of high replication in human cells. The consequence could be a virus that causes disease at a level similar to COVID-19 when it first emerged but against which our current battery of spike glycoprotein-based vaccines would not work.
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  • In this Virolyvj paper, the authors say “we speculate that with continued circulation, vaccination and convalescent sera therapy, further positively selected for mutations in the NTD are likely to occur.”

 

Shown below, there certainly seems to be a bias towards infecting the vaccinated in the daily case figures from Denmark’s SSI. Double and triple vaccinated individuals were making up ~90% of all new daily cases recently.

Shown above, from the latest Danish report for vaccine breakthrough infections, it is clear that the vaccinated make up far more of new Covid cases than the unvaccinated.

Shown below, nearly 300,000 cases of Covid are vaccine breakthroughs for those with two doses, and nearly 35,000 cases are breakthrough cases for those with three doses.

 

Clearly, Sars-CoV-2 will become under ever greater selective pressure to infect the vaccinated as the pool of unvaccinated people decreases.  Deliberately targeting the vaccinated cohort may be the only possible way for the virus to survive in future.

Addendum:
You may not feel comfortable with the issues this post deals with, but if you haven’t considered the key question in this post – Could Sars-CoV-2 start targeting the vaccinated? –  then you simply haven’t been paying attention for the last two years.

Selective pressure forcing Sars-CoV-2 to target the vaccinated is not only a possibility, with the Omicron variant, it may have already started.

 

Denmark: ~90% of Omicron cases are double or triple vaccinated *17 UPDATES*

Preprint: Omicron is the product of extensive evolution that has left no obvious traces of intermediate forms

The Omicron variant identified in Southern Africa in late November 2021 is the product of extensive evolution within an infection context that has so far left no obvious traces of intermediate forms since it diverged from the B.1.1 lineage (presumably at some time in mid to late 2020).

“Our analysis identifies three clustered sets of mutations in the Spike protein, involving 13 amino acids that have previously been highly conserved across SARS-CoV-2 and other Sarbecoviruses. This dramatic about-face in evolutionary dynamics at these 13 sites suggests that Omicron’s Spike protein structure has accommodated significant sequence change, likely in response to selective pressures favoring increased transmission,immune evasion, or viral replication—either at the population level or in a single or group of chronically infected individuals—and has potentially acquired new functionality.”

Preprint: Selection analysis identifies significant mutational changes in Omicron that are likely to influence both antibody neutralization and Spike function

 

 

Photo by CDC on Unsplash

CDC: Addition of SARS-CoV and SARS-CoV-2 chimeric viruses to select agents and toxins list

Today, the Centers for Disease Control and Prevention (CDC)’s Division of Select Agents and Toxins published an Interim Final Rule adding SARS-CoV/SARS-CoV-2 chimeric viruses resulting from any deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors to the list of HHS select agents and toxins. In addition, the work to create this chimeric virus is a ‘restricted experiment’ and requires prior approval from CDC before performing the experiment.

HHS/CDC believes that immediate regulatory oversight of these experiments and the resulting chimeric viruses is essential to protect the public from the potential consequences of a release of these viruses.

CDC, 17th November 2021

 

H/T, the extraordinary Alina Chan:

 

 

 

25th February 2020: “We have contained this. I won’t say [it’s] airtight, but it’s pretty close to airtight,”

 

 

B.1.1.529 Omicron: Sars-Cov-2 variant with extremely high number of Spike mutations

“Currently only 4 sequences so would recommend monitoring for now. Export to Asia implies this might be more widespread than sequences alone would imply. Also the extremely long branch length and incredibly high amount of spike mutations suggest this could be of real concern (predicted escape from most known monoclonal antibodies)”

Conserved Spike mutations – A67V, Δ69-70, T95I, G142D/Δ143-145, Δ211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F

Conserved non-Spike mutations – NSP3 – K38R, V1069I, Δ1265/L1266I, A1892T; NSP4 – T492I; NSP5 – P132H; NSP6 – Δ105-107, A189V; NSP12 – P323L; NSP14 – I42V; E – T9I; M – D3G, Q19E, A63T; N – P13L, Δ31-33, R203K, G204R

Github entry

 

 

 

** NOW would be a really good time to prevent B.1.1.529 from entering the UK by instituting proper border controls. We don’t have to resign ourselves to endless infections and death by new variants **

 

 

South Africa: new variant B.1.1.529 has outcompeted Delta in just two weeks

 

Image by Gerd Altmann from Pixabay

Preprint: Emergence and widespread circulation of a recombinant SARS-CoV-2 lineage in North America

We present a detailed phylogenetic analysis of four SARS-CoV-2 lineages (B.1.627, B.1.628, B.1.631 and B.1.634) in order to investigate the possibility of virus recombination among them.

Prompted by reports of unusual genetic similarities among several Pango lineages detected mainly in North and Central America, we present a detailed phylogenetic analysis of four SARS-CoV-2 lineages (B.1.627, B.1.628, B.1.631 and B.1.634) in order to investigate the possibility of virus recombination among them. Two of these lineages, B.1.628 and B.1.631, are split into two distinct clusters (here named major and minor).

We conclude that the B.1.628 major cluster originated from a recombination event between a B.1.631 major virus and a lineage B.1.634 virus. This scenario inferred from genetic data is supported by the spatial and temporal distribution of the three lineages, which all co-circulated in the USA and Mexico during 2021, suggesting this region is where the recombination event took place. We therefore support the designation of the B.1.628 major cluster as recombinant lineage XB in the Pango nomenclature. The widespread circulation of lineage XB across multiple countries over a longer timespan than the previously designated recombinant XA lineage raises important questions regarding the role and potential effects of recombination on the evolution of SARS-CoV-2 during the ongoing COVID-19 pandemic.

 

Preprint: Emergence and widespread circulation of a recombinant SARS-CoV-2 lineage in North America

 

Preprint: Genome recombination between Delta and Alpha variants of SARS-CoV-2

 

 

Image by PIRO4D from Pixabay

France: new coronavirus variant B.1.640 detected in Finistère, Brittany

A new coronavirus variant has been identified in a school in Finistère in October 2021, and named B.1.640.  Twenty-four people, 18 children and six adults in contact with them, have been affected by this new mutation that is unlike any other. A variant so far removed from those in circulation that it took time to identify it.

On October 15, a Covid-19 cluster was identified at Mona Ozouf public elementary school in Bannalec, Finistère. Eighteen students tested positive. As a precaution, two classes are closed out of the twelve in the school. Then two more. And three more. To prevent the spread of the virus during school holidays, the municipality is asking associations to suspend activities.

Further research, by sequencing at Rennes University Hospital, revealed to scientists an “abnormal strain” and “very particular”.  The specimen presents, in fact, multiple unprecedented mutations. Particularly on its Spike protein, the strategic key that allows the virus to enter human cells. A small part of this protein has, in particular, disappeared compared to the forms of the Spike proteins of other variants of the coronavirus.

Le Telegramme report (in French)

 

B.1.640 has already made it onto the ECDC list of variants being monitored, and is listed as originally being sequenced in the Republic of Congo:

 

B.1.640 is also listed in the UK list of variants being monitored:

 

More from France:

 

France: B.1.640 declared a VOI after more than 500 cases found

 

France: new Sars-CoV-2 variant B.1.640.2 with N501Y and E484K detected

 

 

Image by Christel SAGNIEZ from Pixabay

Evidence of two global Covid waves in 2020, and estimating the pandemic start date

Global Covid waves have been easy to spot in 2021 with their distinctive sine wave pattern, but what about 2020, when testing was largely limited to those with symptoms until late into that year?

There seems to be evidence of two previous global waves of Sars-Cov-2 in 2020, and it may be possible to estimate a start date for the pandemic by simply rolling the 120 day global cases wave rate back to 2019.

Firstly, let’s take another look at the evidence of a regular global Covid wave rate in 2021. It’s about 120 days between the trough of each wave:

 

In our updated global cases wave chart below, you can see faint signs that the global wave pattern for Covid cases extended right through 2020, and possibly as far back as the start of the pandemic in 2019. There are now five waves showing, and a sixth global wave has just started.

 

The global deaths chart below shows clearer evidence of 5 global waves so far, with the sixth wave starting in October 2021. Note that the timing of the wave *peaks* for deaths or cases is far less important than the timing of the global *troughs* for confirmed cases.

If the wave timings are correct, it means that the very first Wuhan *peak* in Covid cases would have occurred between Christmas 2019 and New Year 2020, with the trough coming on the 29th of February 2020.

By rolling the global cases wave rate back even further though, we can estimate the start of the pandemic:

We estimate that the start of the pandemic was on or around the 1st November 2019, a date calculated by deducting 120 days from the 29th February 2020.

That would be just after the 2019 Military World Games ended in Wuhan

That is, of course, unless there were prior, unrecorded cases….

 

Update 6th November 2021:

This article in Science Magazine seems to agree with our estimation

“Consequently, the index case in Hubei likely contracted SARS-CoV-2 on or around 4 November 2019 (95% upper HPD: 15 October; 99% upper HPD: 7 October)”

Science Magazine: Timing the SARS-CoV-2 index case in Hubei province

 

More in our Decoding Sars-Cov-2 series:

 

 

 

Preprint: Molecular evidence for SARS-CoV-2 in samples collected since late summer 2019 in Lombardy

 

UK: The Alpha variant rears its ugly head again

A big surprise in the latest UK sequencing figures show that the Alpha variant has made something of a comeback this week. Even though the percentage of Alpha cases is still tiny compared to that of Delta, the figure of more than 400 Alpha cases is the highest since mid-June 2021.

It’s unclear whether this is a localised outbreak (it may be part of the unfolding superspreader event of the Boardmasters festival in Cornwall for example), or whether these are cases scattered across the UK, but to see such a resurgence after so many weeks of Delta dominance is something of a shock as the Alpha variant was far less effective at breaking through vaccine protection than the Delta variant is.

After weeks of just a handful of Alpha cases in the UK, there is suddenly a spike of over 400 new cases:

 

Confirmation that the Delta variant has dipped recently:

Charts and data courtesy of CovSpectrum.org

 

 

 

Image by Josch13 from Pixabay

New C.1.2 variant mutating 41 times a year, twice as fast other known Sars-CoV-2 variants

Scientists first detected C.1.2 in May 2021, finding that it was descended from C.1, which scientists found surprising as C.1 had last been detected in January. The new variant has “mutated substantially” compared to C.1 and is more mutations away from the original virus detected in Wuhan than any other Variant of Concern or Variant of Interest detected so far worldwide.

The study also found that the C.1.2 lineage has a mutation rate of about 41.8 mutations per year, which is nearly twice as fast as the current global mutation rate of the other variants. The scientists stated that this short period of increased evolution was also seen with the Alpha, Beta and Gamma variants, suggesting that a single event, followed by a spike in cases, drove faster mutation rates.

Jerusalem Post report

Medrxiv preprint: The continuous evolution of SARS-CoV-2 in South Africa: a new lineage with rapid accumulation of mutations of concern and global detection

 

Delta attempting to brute-force its way past the human immune system

 

 

 

Photo by Abby Savage on Unsplash

The future of Sars-CoV-2: Multiple vaccine breakthrough infections in one patient

The patient had three RT-PCR confirmed SARS-CoV-2 infections. Two breakthrough infections occurred in quick succession with the first over 3 weeks after complete vaccination with COVISHIELD and despite post-vaccination seroconversion. The first breakthrough infection was due to the Alpha variant and the second due to the Delta variant. The Delta variant infection resulted in hypoxia, hospitalization, and illness lasting seven weeks. Serial serology, acute phase reactants, and chest imaging supported WGS in establishing distinct episodes of infection. WGS established a fully vaccinated family member as the index case.

Research article: Severe SARS-CoV-2 Breakthrough Reinfection With Delta Variant After Recovery From Breakthrough Infection by Alpha Variant in a Fully Vaccinated Health Worker

 

Preprint: Just three mutations for SARS-CoV-2 to escape from highly neutralizing convalescent plasma

Preprint: Just three mutations for SARS-CoV-2 to escape from highly neutralizing convalescent plasma

“Only three mutations were sufficient to generate this escape variant.”  This work shows that, under strong immune pressure, SARS-CoV-2 can use mutations in both the N-terminal domain and the receptor-binding domain to escape potent polyclonal neutralizing responses. Indeed, after a long period under immune selective pressure, SARS-CoV-2 evolved to evade the immunity of a potent polyclonal serum from a COVID-19 convalescent donor. Only three mutations were sufficient to generate this escape variant. The new virus was resistant to 70% of the neutralizing antibodies tested and had a decreased susceptibility to all convalescent sera.

Preprint: SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma

 

Delta attempting to brute-force its way past the human immune system

USA: Republican Mike McCaul’s final report into the origins of the Sars-CoV-2 pandemic

Mike McCaul’s final report on the origins of the pandemic can be downloaded here.

A House Republican lawmaker’s investigation into the origins of COVID-19 is raising concerns that the pandemic outbreak stemmed from a genetically modified virus which leaked from the Wuhan Institute of Virology, the Chinese city where the disease was first detected in December 2019.

The Hill article

Github: AY.3.1 – a new sub-lineage of AY.3 concentrated in Mississippi, USA

AY.3 is the main variant being sequenced weekly in Mississippi (>70% of all recent sequences), most falling within this sub-lineage of AY.3 that is distinguished by the mutations described below (>60% of all recent sequences). For example, of 91 Pangolin-typeable sequences generated on 13 July 2021 by Dr. Robinson’s team, from broad sampling across Mississippi, 68 are AY.3 and 13 are unclassified B.1.617.2. Of those 81 Delta sequences, 60 are this new sub-lineage (those sequences are not yet in GISAID and are thus not included in the counts above for the USA or MS). Thus, there is clear epidemiological relevance of this sub-lineage in a region of the USA.

Github: A new sub-lineage of AY.3 concentrated in Mississippi, US

 

USA: AY.3 genomes increasing faster than Delta B.1.617.2

 

Image by Mark Dawdy from Pixabay

UK SAGE Bombshell Report: The Long Term Evolution of Sars-CoV-2

Scenario One: A variant that causes severe disease in a greater proportion of the population than has occurred to date.  Scenario Two: A variant that evades current vaccines.  Scenario Three: Emergence of a drug resistant variant after anti-viral strategies.  Scenario Four: SARS-CoV-2 follows an evolutionary trajectory with decreased virulence.

 

Scenario One: A variant that causes severe disease in a greater proportion of the population than has occurred to date. For example, with similar morbidity/mortality to other zoonotic coronaviruses such as SARS-CoV (~10% case fatality) or MERS-CoV (~35% case fatality).

Likelihood of increased severity phenotype: Realistic possibility.

 

Scenario Two: A variant that evades current vaccines. This could be caused by: Antigenic ‘shift’: Natural recombination events that insert a different spike gene sequence (or partial sequence) from human CoVs MERS-CoV (highly unlikely due to the low frequency of MERS-CoV infections), or from currently circulating endemic human CoVs (more likely due to the prevalence of these viruses). This would recombine into the ‘body’ of SARS-CoV-2 that is capable of high replication in human cells. The consequence could be a virus that causes disease at a level similar to COVID-19 when it first emerged but against which our current battery of spike glycoprotein-based vaccines would not work. 

Likelihood: Realistic possibility.

 

Scenario Three: Emergence of a drug resistant variant after anti-viral strategies. This could be caused by: Emergence of new variants following the administration of directly acting antiviral therapies. As we begin to use directly acting antiviral drugs it is highly likely a variant will be selected that had resistance to individual agents. For example, drugs that target the viral 3C protease, drugs that target the polymerase, monoclonal antibodies that target the spike glycoprotein. If the drugs are used as a mono therapy, then resistant variants have a high probability of emerging. This may render all drugs in that category unusable.

Likelihood: Likely – unless the drugs are used correctly.

 

Scenario Four: SARS-CoV-2 follows an evolutionary trajectory with decreased virulence. This could be caused by: Variants arising with increased transmissibility but decreased pathogenesis/virulence as the virus becomes fully adapted to the human host becoming an endemic infection. Coupled with the likelihood of eventual high populations immunity the infection produces less disease. In other words, this virus will become like other human CoV that causes common colds, but with much less severe disease predominantly in the old or clinically vulnerable. 

Likelihood: Unlikely in the short term, realistic possibility in the long term.

 

Download the entire report here

GOV.UK SAGE Website Link

 

So what is Plan B if the vaccines fail with a new #coronavirus super-variant?