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Research and analysis
Long term evolution of SARS-CoV-2, 26 July 2021
Paper prepared by academics on the viral evolution of COVID-19.
From:
Scientific Advisory Group for Emergencies
Published
30 July 2021
Can we predict the limits of SARS-CoV-2 variants and their phenotypic consequences?
As eradication of SARS-CoV-2 will be unlikely, we have high confidence in stating that there
will always be variants. The number of variants will depend on control measures.
We describe hypothetical scenarios by which SARS-CoV-2 could further evolve and acquire,
through mutation, phenotypes of concern, which we assess according to possibility. For this
purpose, we consider mutations in the ‘body’ of the virus (the viral genes that are expressed
in infected cells and control replication and cell response), that might affect virus fitness and
disease severity, separately from mutations in the spike glycoprotein that might affect virus
transmission and antibody escape.
We assess which scenarios are the most likely and what impact they might have and consider
how these scenarios might be mitigated. We provide supporting information based on the
evolution of SARS-CoV-2, human and animal coronaviruses as well as drawing parallels with
other viruses.
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). This could be caused by:
1. Point mutations or recombination with other host or viral genes. This might occur through
a change in SARS-CoV-2 internal genes such as the polymerase proteins or accessory
proteins. These genes determine the outcome of infection by affecting the way the virus is
sensed by the cell, the speed at which the virus replicates and the anti-viral response of
the cell to infection. There is precedent for Coronaviruses (CoVs) to acquire additional
genes or sequences from the host, from themselves or from other viruses.
2. By recombination between two VOC or VUIs. One with high drift (change in the spike
glycoprotein) from the current spike glycoprotein gene used in the vaccine and the other
with a more efficient replication and transmission determined by internal genes, for
example, a recombination between beta and alpha or delta variants respectively.
Alternatively, recombination may occur between two different variants with two different
strategies for overcoming innate immunity, combining to give an additive or synergistic
change of phenotype resulting in higher replication of the virus – and potentially increased
morbidity and mortality.
Likelihood of genotypic change in internal genes: Likely whilst the circulation of SARSCoV-2 is high.
Likelihood of increased severity phenotype: Realistic possibility.
Impact: High. Unless there is significant drift in the spike glycoprotein gene sequence,
then the current spike glycoprotein-based vaccines are highly likely to continue to
provide protection against serious disease. However, an increase in morbidity and
mortality would be expected even in the face of vaccination since vaccines do not
provide absolute sterilising immunity i.e. they do not fully prevent infection in most
individuals.
...
Scenario Two: A variant that evades current vaccines. This could be caused by:
3. 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.
Impact: High for a completely new spike, medium/low if a spike from a seasonal CoV is
introduced since we expect a proportion of the population to have antibodies to these
endemic viruses.
4. A longer-term version of shift whereby SARS-CoV-2 undergoes a reverse zoonotic event
into an animal reservoir(s). This virus is then on a separate evolutionary trajectory
because the virus animals is subject to different selection processes than in humans.
The SARS-CoV-2 decedents then re-emerge into humans at a later time when vaccines
that have been updated to keep pace with drift in humans sufficiently mismatched so as
not able to provide immunologic cross protection.
Likelihood: Realistic possibility. Impact: Medium.
...
Scenario Three: Emergence of a drug resistant variant after anti-viral strategies. This
could be caused by:
6. 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. Impact: medium unless a scenario
arises where drugs are needed more widely.
...
Scenario Four: SARS-CoV-2 follows an evolutionary trajectory with decreased
virulence. This could be caused by:
7. 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.
...
https://assets.publishing.service.go...SARS-CoV-2.pdf
Long term evolution of SARS-CoV-2, 26 July 2021
Paper prepared by academics on the viral evolution of COVID-19.
From:
Scientific Advisory Group for Emergencies
Published
30 July 2021
Can we predict the limits of SARS-CoV-2 variants and their phenotypic consequences?
As eradication of SARS-CoV-2 will be unlikely, we have high confidence in stating that there
will always be variants. The number of variants will depend on control measures.
We describe hypothetical scenarios by which SARS-CoV-2 could further evolve and acquire,
through mutation, phenotypes of concern, which we assess according to possibility. For this
purpose, we consider mutations in the ‘body’ of the virus (the viral genes that are expressed
in infected cells and control replication and cell response), that might affect virus fitness and
disease severity, separately from mutations in the spike glycoprotein that might affect virus
transmission and antibody escape.
We assess which scenarios are the most likely and what impact they might have and consider
how these scenarios might be mitigated. We provide supporting information based on the
evolution of SARS-CoV-2, human and animal coronaviruses as well as drawing parallels with
other viruses.
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). This could be caused by:
1. Point mutations or recombination with other host or viral genes. This might occur through
a change in SARS-CoV-2 internal genes such as the polymerase proteins or accessory
proteins. These genes determine the outcome of infection by affecting the way the virus is
sensed by the cell, the speed at which the virus replicates and the anti-viral response of
the cell to infection. There is precedent for Coronaviruses (CoVs) to acquire additional
genes or sequences from the host, from themselves or from other viruses.
2. By recombination between two VOC or VUIs. One with high drift (change in the spike
glycoprotein) from the current spike glycoprotein gene used in the vaccine and the other
with a more efficient replication and transmission determined by internal genes, for
example, a recombination between beta and alpha or delta variants respectively.
Alternatively, recombination may occur between two different variants with two different
strategies for overcoming innate immunity, combining to give an additive or synergistic
change of phenotype resulting in higher replication of the virus – and potentially increased
morbidity and mortality.
Likelihood of genotypic change in internal genes: Likely whilst the circulation of SARSCoV-2 is high.
Likelihood of increased severity phenotype: Realistic possibility.
Impact: High. Unless there is significant drift in the spike glycoprotein gene sequence,
then the current spike glycoprotein-based vaccines are highly likely to continue to
provide protection against serious disease. However, an increase in morbidity and
mortality would be expected even in the face of vaccination since vaccines do not
provide absolute sterilising immunity i.e. they do not fully prevent infection in most
individuals.
...
Scenario Two: A variant that evades current vaccines. This could be caused by:
3. 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.
Impact: High for a completely new spike, medium/low if a spike from a seasonal CoV is
introduced since we expect a proportion of the population to have antibodies to these
endemic viruses.
4. A longer-term version of shift whereby SARS-CoV-2 undergoes a reverse zoonotic event
into an animal reservoir(s). This virus is then on a separate evolutionary trajectory
because the virus animals is subject to different selection processes than in humans.
The SARS-CoV-2 decedents then re-emerge into humans at a later time when vaccines
that have been updated to keep pace with drift in humans sufficiently mismatched so as
not able to provide immunologic cross protection.
Likelihood: Realistic possibility. Impact: Medium.
...
Scenario Three: Emergence of a drug resistant variant after anti-viral strategies. This
could be caused by:
6. 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. Impact: medium unless a scenario
arises where drugs are needed more widely.
...
Scenario Four: SARS-CoV-2 follows an evolutionary trajectory with decreased
virulence. This could be caused by:
7. 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.
...
https://assets.publishing.service.go...SARS-CoV-2.pdf
