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Worrisome coronavirus mutation seen in
U.K. variant and in some U.S. samples
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https://www.washingtonpost.com/health/new-covid-mutation-uk-variant/2021/02/02/a164f17a-6577-11eb-886d-5264d4ceb46d_story.html
Feb. 2, 2021
As far back as last June, researchers at Regeneron, the maker of monoclonal antibodies, a treatment for coronavirus, reported in the journal Science that they had identified the E484K mutation as a roadblock for their product. The company formulated an antibody cocktail to overcome the resistance produced by the mutation.
A coronavirus mutation that appears to limit the protection of vaccines against infection has appeared in the United Kingdom, which is already struggling with a highly transmissible and apparently more lethal virus variant.
The worrisome mutation, at a site on the virus RNA called E484K, has drawn close scrutiny from infectious-disease experts, who have given it the nickname "Eeek."
In addition to its appearance in the U.K. variant, it has been seen in variants that spread rapidly in South Africa and Brazil. It has also been identified in recent days in a handful of cases in the United States. Two new cases of the South Africa variant were confirmed Tuesday just outside the nation's capital, in Montgomery County.
The mutation alters the structure of the virus's spike protein - the target for vaccines and many naturally produced antibodies. The mutation may help the virus to elude detection and make neutralization by the human immune system less efficient. In effect, it makes the virus stealthier, a great concern to vaccine developers, who seek to train antibodies to zero in on recognizable invaders and destroy them.
The appearance of the E484K mutation in some infections caused by the U.K. variant is "a worrying development, though not entirely unexpected," said Julian Tang, a clinical virologist at University of Leicester.
"We have to come down hard on this variant," said British Health Secretary Matt Hancock. "Our mission must be to stop its spread all together."
All viruses mutate, and SARS-CoV-2 is evolving as it circulates in tens of millions of people globally, a recipe for further mutation as the virus adapts itself to the human species.
The "Eeek" mutation is not actually new: It has reared up in genomic sequences many times since the start of the pandemic, and virologists have long understood that it was potentially problematic. But it appears to do little in isolation, and gained widespread attention only recently, after it began appearing in tandem with other mutations in the rapidly spreading variants in South Africa and Brazil, said Greg Armstrong, director of the advanced molecular detection program at the Centers for Disease Control and Prevention.
A public database analyzed by The Washington Post showed 213 genomic sequences containing the mutation in the United States, dating to an initial case in Utah last March 15.
"It's popped up several times in several lineages," Armstrong said. "By itself, it seems to come and go."
To date, there are no homegrown "variants of concern," he said. The CDC is closely monitoring one variant in California that is responsible for many cases there - and which does not contain the "Eeek" mutation - but Armstrong said there is no consensus it is truly more transmissible.
The CDC is still ramping up its genomic surveillance efforts, however, and the United States does not yet have complete awareness of the many lineages of the coronavirus in circulation. A CDC forecast last month suggested that, based on United Kingdom data, the variant circulating there could become dominant in the United States by some point in March as it outcompeted other variants.
Whether that would drive yet another surge depends on vaccination rates. The CDC model showed overall case numbers could still decline - though only gradually - if the country vaccinated a million people a day while the variant spread.
Scientists point out that there is much that they do not know or understand about these virus strains or why SARS-C0V-2, after a protracted period of relative stability, has shape-shifted in the past few months.
"We honestly don't have a good answer for why this is happening all of a sudden," Armstrong said.
Clinical trial data announced last week have indicated that vaccines were less effective in preventing infections with variants in South Africa featuring the mutation - but dramatically lowered the chance of severe illness or death.
One study also found preliminary evidence that patients in South Africa who had survived an earlier bout with the more common coronavirus were becoming infected a second time - though not severely ill - after exposure to the variant with the E484K mutation. Another alarming data point has come from Brazil, where researchers fear the variant there has reinfected people who had recovered from an earlier bout with the virus.
Armstrong and other scientists said the spread of coronavirus variants has not changed our understanding of how the virus is transmitted, nor negated the desirability of getting vaccinated. The vaccines still offer protection and are crucial to crushing the pandemic, disease experts emphasized.
"The really important thing is, if you look at who went to the hospital and who died, the vaccines are really effective," said Jeremy Luban, a virologist at the University of Massachusetts Medical School.
As far back as last June, researchers at Regeneron, the maker of monoclonal antibodies, a treatment for coronavirus, reported in the journal Science that they had identified the E484K mutation as a roadblock for their product. The company formulated an antibody cocktail to overcome the resistance produced by the mutation.
The E484K mutation has appeared multiple times in coronavirus lineages across the planet, but that does not always translate into a functionally different version of the virus - something that would merit the term "variant" or "strain."
"The thing about the variants is that they are characterized by multiple mutations. We don't actually know what part is played by most of those mutations," said William Hanage, an epidemiologist at the Harvard T.H. Chan School of Public Health.
He pointed out that mutations that hamper immunity do not obliterate it.
"It's not that immunity falls off a cliff," he said. "Some people will still be somewhat protected."
"Eeek" has been the focus of attention in recent weeks because it is present in B.1.351 and P.1, the variants first identified in South Africa and Brazil, respectively. The United Kingdom strain, B.1.1.7, has spread more widely than the other two, but was considered less problematic until now because it did not contain the E484K mutation.
As of Monday, the U.K. variant had been detected in 467 infections in the United States, according to Washington Post data. The CDC's Armstrong said Tuesday that the E484K mutation is not present in any of those cases. It is still very rare in the United Kingdom, turning up in 11 infections there, according to a report published by Public Health England.
The report also offered preliminary evidence that the variant could be 65 percent more lethal.
Jennifer Nuzzo, an epidemiologist at the Johns Hopkins Center for Health Security, said in an email that the appearance of coronavirus variants in the United States means that the country needs to "increase the urgency" of disease prevention efforts: "Vaccines, social distancing, masks, testing, contact tracing, isolation and quarantine are more essential than ever for reducing the spread of the virus."
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UK finds more coronavirus cases with 'concerning' mutations
By Michelle Roberts
Health editor, BBC News online
https://www.bbc.com/news/health-55900625
Public Health England is investigating cases of coronavirus with 'worrying' new genetic changes that have been found in some regions of the UK.
Tests show they have a mutation, called E484K, that is already seen in the South Africa variant.
Although this change may reduce vaccine effectiveness, the current ones in use should still work, say experts.
There have been 11 cases in Bristol and a cluster of 32 cases in Liverpool.
Urgent testing for the South Africa variant is already starting in parts of England and could be rolled out to other areas seeing different variants with the same E484K mutation.
Scientists working with Public Health England found a small number of cases of the UK 'Kent' variant with the E484K mutation - it was seen in 11 out of 214,159 samples that they tested, and predominantly from the South West of England.
It is likely there may be more cases that haven't yet been found. The Liverpool area has seen 32 cases of original coronavirus that have the E484K mutation too.
• How worrying are the new variants?
• Which areas will have mass testing for Covid variant?
It's not unexpected that variants are appearing or that they will continue to change - all viruses mutate as they make new copies of themselves to spread and thrive.
Dr Julian Tang, a virus expert at the University of Leicester, described the finding as "a worrying development, though not entirely unexpected".
He said it was important people follow the lockdown rules and get cases of coronavirus down to prevent opportunities for the virus to mutate further.
"Otherwise not only can the virus continue to spread, it can also evolve."
He said that allowing spread could allow a "melting pot" for different emerging variants.
Scientists have already been checking what these new mutations might mean for existing coronavirus vaccines that were designed around earlier versions of the virus that started the pandemic.
Some research appears to show E484K may help the virus evade parts of the immune system called antibodies.
But early results from Moderna suggest its vaccine is still effective against variants with this mutation - although the body's immune response may not be as strong or prolonged.
Two new coronavirus vaccines that could be approved soon - one from Novavax and another from Janssen - also appear to offer good cover against variants, protecting against serious illness.
Even in the worst case scenario, vaccines can be redesigned and tweaked to be a better match in a matter or weeks or months, if necessary, say experts.
A silver lining may be that the variants are mutating in a similar way rather than diverging from each other.
Prof Ravi Gupta from the University of Cambridge said: "This gives us a sign that it has certain favoured routes - and we can work to block those off with a vaccine."
Former UK health secretary Jeremy Hunt said the race was on to vaccinate as many people as quickly as possible in order to keep a step ahead of the virus.
Measures such as washing your hands, keeping your distance from other people and wearing a face covering will still help prevent infections.
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Coronavirus strain in UK picks up mutation that could impact vaccines, experts say
By Michael Nedelman, CNN
https://www.cnn.com/2021/02/02/health/variant-mutation-e484k/index.html
Paul Bieniasz, a virologist at the Rockefeller University, noted that the E484K mutation has "appeared sporadically" in multiple samples for months, but until recently it didn't appear to offer the virus an advantage in populations with no preexisting immunity.
But it's a different story in places like South Africa, where many people had been previously infected. On Monday, Dr. Anthony Fauci noted "a very high rate of reinfection to the point where previous infection does not seem to protect you," citing the work of colleagues in South Africa.
Updated 11:01 PM ET, Tue February 2, 2021
(CNN)A mutation that could allow Covid-19 to escape antibody protection has now been found in samples of a rapidly spreading strain in the UK, according to a report Monday by Public Health England.
The mutation, called E484K, was already part of the genetic signature of variants linked to South Africa and Brazil.
According to the PHE report, the mutation has been newly detected in at least 11 samples of the UK's B.1.1.7 strain. It also appears some of these samples may have acquired this mutation independently, instead of spreading from a single case.
This could mean a variant already known to be more transmissible also risks becoming somewhat resistant to the immune protection offered by vaccines, or more likely to cause reinfection among people who were previously infected, experts say.
"This doesn't appear to be great news for vaccine efficacy," said Joseph Fauver, associate research scientist in epidemiology at the Yale School of Public Health.
He added the new finding is also something to keep monitoring in the US, where efforts to look for variants through genetic sequencing have lagged behind the UK. The fact that we've only seen this in the UK "may be a result of their robust genomic surveillance program," Fauver said.
Evidence of immune escape
Experts say it's too early to predict whether this development will greatly impact the trajectory of Covid-19 in the UK and around the world.
However, there is some research suggesting that E484K may be a key culprit behind why certain vaccines appear less effective in South Africa.
Novavax recently announced its vaccine was 89% effective in its Phase 3 UK trial, but only appeared 60% effective in a separate Phase 2b study conducted in South Africa. Similarly, in Johnson & Johnson's Phase 3 trial, efficacy differed by country: 72% in the US versus 57% in South Africa. In both trials, 90 to 95% of cases in South Africa were linked to the B.1.351 variant, which contains the E484K mutation.
But much of the early evidence on this so-called "escape mutant" comes from research in the lab, showing that antibodies appear less able to bind spike proteins arising from the mutation.
The latest example comes from a new study finding that antibodies from vaccinated people were less effective at neutralizing a synthetic virus resembling those in the PHE report -- meaning, they contained pivotal mutations from B.1.1.7, plus E484K.
Adding the E484K mutation appeared to raise the bar for the level of antibodies needed to prevent the lab-made virus from infecting cells, when compared to B.1.1.7 mutations on their own.
The study sampled blood from 23 people who had received a single dose of the Pfizer/BioNTech vaccine three weeks prior, with a median age of 82. The study was not able to demonstrate how this impacted people's actual likelihood of becoming infected with virus variants.
Citing the genomics database GISAID, the study also tallied a slightly higher total of cases than the PHE report: two unrelated cases in Wales and a cluster of more than a dozen in England, appearing as early as the first half of December 2020.
Vaccines more important than ever
Paul Bieniasz, a virologist at the Rockefeller University, noted that the E484K mutation has "appeared sporadically" in multiple samples for months, but until recently it didn't appear to offer the virus an advantage in populations with no preexisting immunity.
But it's a different story in places like South Africa, where many people had been previously infected. On Monday, Dr. Anthony Fauci noted "a very high rate of reinfection to the point where previous infection does not seem to protect you," citing the work of colleagues in South Africa.
The B.1.1.7 strain first spotted in the UK has now been found in at least 70 countries worldwide, including about 470 known cases in the US, according to the US Centers for Disease Control and Prevention.
Experts say that aggressive testing, adhering to Covid-19 guidelines and rapidly rolling out vaccines are more important than ever in light of these spreading variants.
"We need to get as many people vaccinated as quickly as we possibly can," Fauci previously said. "Even though there is a diminished protection against the variants, there's enough protection to prevent you from getting serious disease, including hospitalization and deaths."
SARS-CoV-2 B.1.1.7 escape from mRNA vaccine-elicited neutralizing antibodies
The phase I/II studies of the Pfizer-BioNTech BNT162b2 vaccine determinedthe immunogenicity of different dosing regimens. In this study,we assess antibody responsesinduced three weeks after vaccination with the firstdoseof BNT162b2 following the rollout in the UK. In addition, by using a panel of human neutralizing monoclonal antibodies (mAbs)we show that the B.1.1.7 variant can escape neutralization mediated by most NTD-specific antibodies tested and by a fraction of RBM-specific antibodies. We also show that the recent appearance of the E484K mutation in B.1.1.7 isolates from the UK, similarly to the B.1.351 and P1 isolates, results in incremental loss of neutralization by BNT162b2 mRNA-elicited antibodies.
https://www.citiid.cam.ac.uk/wp-content/uploads/2021/02/POST-SUBMISSION_vaccine-DCv2-2.pdf
This study reports on the neutralisation escape from sera collected after one dose of the BNT162b2 vaccine. The participants of this study had a median age of over 80,in line with the targeting of this age group in the initial rollout of the vaccination campaign in the UK. Participants showed similar neutralising activity against wild type pseudovirus as in the phase I/II study, with geometric mean titres of 24 and 29,respectively12. The three mutations in S(N501Y, A570D, ΔH69/V70) did not appear to impact neutralisationin a pseudovirus assay. However,we demonstrated that a pseudovirus bearing Sprotein with the full set of mutations presentin the B.1.1.7 variant (i.e., ΔH69/V70, Δ144, N501Y, A570D, P681H, T716I, S982A, D1118H) did result in reduced neutralisation by sera from vaccinees. A reduction in neutralization titres from mRNA-elicited antibodies in volunteers who received two doses(using both mRNA-1273 and BNT162b2vaccines) was also observed by Wang et al.33using pseudoviruses carrying the N501Y mutation. Another study reported on a modest and not significant (average 1.2 fold)reduction ofneutralization against the B.1.1.7 variant in sera from individuals vaccinated with two doses of mRNA-127334. The level of neutralizing antibodies observed in both of these studies wasapproximately one log higher than the one observed in the cohort of vaccinees described in this study. This may be relatedto the older age of the individuals from this study as well as to the fact that these were exposed to only one dose of the BNT162b2 vaccine. In general, it is expected that the effect of mutations on the neutralization by polyclonal serum antibodies might be more prominent on low-titre in contrast to high-titre sera. It is important to study virus neutralisation at lower serum neutralisation titres because decline in neutralisation titres over time is expected to occur following vaccination.
E484K has been shown to impact neutralisation by monoclonal antibodies or convalescent sera, especially in combination with N501Y and K417N16,37-39. Worryingly,we have shown that there are multiple B.1.1.7 sequences in the UK bearing E484K with early evidence of transmission as well as independent aquisitions.We measuredfurther reduction neutralisationtitersby vaccine sera when E484K was present alongside the B.1.1.7 Smutations. Consistent with our findings, Wu and co-authors34have shown that variants carrying the E484K.
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