Covid-19 new variants—known unknowns

On 25 March 2021, The BMJ hosted a webinar on new variants. An expert panel discussed what these are, where they come from, and what they might do, as well as what we know about how particular variants influence transmission, severity, and immunity, and what this means for the future of the pandemic. Nikki Nabavi and Juliet Dobson report

The webinar was inspired by an editorial published in The BMJ entitled “Covid-19’s known unknowns.” The key message: “The more certain someone is about covid-19, the less you should trust them.” Register for future events here

New variants: what are they, where do they come from, and what might they do? 

Aine O’ Toole, University of Edinburgh, provided a snapshot of where we are: “For SARS-CoV-2 we see on average one new mutation transmitted every couple of weeks . . . variants aren’t a new thing. There are new variants. But scientists have been tracking variants of SARS-CoV-2 for over a year now,” she said. 

“So we know that the virus will continue to mutate and evolve and spread and generate new variants. But we don’t know necessarily what those variants will be, nor do we know where they’ll occur or when they’ll occur. We need to sequence to detect these variants and places. What little genomic surveillance may have SARS-CoV-2 diversity that’s largely unaccounted for? We know that there are biases in the data set, but we don’t know the extent of these biases or how much we can infer from the bias samplings of populations. We also know that people are the means by which the virus spreads, so we can try to account for some of these viruses”

Ravindra Gupta, University of Cambridge, discussed what we know about why new variants have emerged and some of the factors that may be responsible, although he added the caveat that, of course, as with all covid unknowns, we don’t know for sure.

“Soon after the pandemic was declared, it was recognised that some people were shedding virus for a considerable number of days and weeks . . . increasingly it was realised that shedding was enriched in individuals who had suboptimal immunity.”

Gupta described the case of two immunocompromised patients and used them to illustrate how the virus is mutating. “We think that new variants are emerging within a host, learning to adapt the immune system to acquire multiple mutations. Some are designed to escape. Some are designed to restore infectivity,” she concluded.  

Wendy Barclay, Imperial College London, spoke about why some variants are more transmissible and what we can learn from lab experiments.

What we’re interested in doing is understanding the genetic features of that virus (B.1.1.7) that enable it to transmit so well, she said. 

“It could be, for example, that a variant allows increased shedding owing to higher replication. And if someone is infected or shedding is prolonged, there’s more chance of this person meeting susceptible individuals. It could be that the virus causes different kinds of disease, spreads to different parts of the body, making emissions more likely. Such emitted viruses might survive better in the environment, or it could be at the other end, in the recipient, that a lower dose of virus is required to initiate productive infection. 

“And that could be for many reasons. Maybe the virus, for example, is good at evading the innate immune response. Or it got to an increased number of susceptible individuals, perhaps because it’s now capable of evading acquired immunity. 

“The known unknowns here is that we know there are variants. We know they have genetic differences. But what do those genetic differences mean in terms of our ability to control the virus in future?”

What do we know about how particular variants influence transmission, severity, and immunity? 

Muge Cevik, University of St Andrews, B.1.1.7 variant

Muge Cevik, University of St Andrews discussed the B.1.1.7 variant, how we detected B.1.1.7 in the UK, and what we know about the severity and mortality associated with this variant.

“One of the most consistently debated subjects is whether this variant is particularly more infectious in younger people, children, and younger adults. Data from November to December 2020 showed that the ratio age share of the variant was higher in 10-19 year olds. England was in lockdown with the rest, but the schools were back to full time teaching at the time. And when we include the rest of the data from December to January, then basically the difference has disappeared. So we concluded that there was no evidence to suggest that the variant favours certain age groups more than others. 

And towards the end of November, you can see that children, basically secondary school children, had the highest prevalence in all age groups. This could be related to  in-school transmission around the time when B.1.1.7. was circulating. But this was also around the time when a national lockdown was in place. So adults were connecting with each other much less. So in a way, children had the most mobility data at the time. 

“We’ve come to the conclusion that B.1.1.7 is about 1.5 times more transmissible across all age groups [than other variants], but no more in children than in adults. And fitness advantage has been observed in different countries. There’s evidence to suggest increased mortality, hospitalisation. But this is mainly seen over the age of 65, [in people] with comorbidities. We need to make sure that this amplification of transmission and severity will happen where the burden and gaps in our mitigation measures already existin nursing homes, prisons, shelters, and workplaces. And we still need more data to understand the biological mechanisms for transmission advantage.” 

Richard Lessells, University of KwaZulu-Natal, South Africa, B.1.351

Richard Lessells, University of KwaZulu-Natal, South Africa, started his discussion on the B.1.351 variant by sharing some South African SARS-CoV-2 statistics, as he acknowledged some false reports of Africa being “spared” of the epidemic. “Unfortunately that couldn’t be further from the truth.” Lessells explained that South Africa had experienced two waves—the first in June-August 2020 and the second in December 2020- January 2021. “We became aware of this variant around November, around the same time as B.1.1.7,”  but it was sampled in October and the  analysis showed that it probably emerged even earlier than that, perhaps as South Africa was coming out of its first wave. “What we know,” said Lessells, “is that it emerged from a part of the country that was particularly affected by the first wave, and had a substantial proportion of the population infected.” 

When considering the distribution of SARS-CoV-2 lineages over time, Lessells showed that multiple different lineages were circulating in South Africa during the first wave, but that once the B.1.351 (501Y.V2) variant emerges, it very rapidly became the predominant lineage picked up in genomic surveillance. “It displaces the other lineages. Within a few weeks it accounts for 80-90%, and is now very close to 100% of the genomes we are sampling in South Africa.”.

It was clear that the variant had some sort of evolutionary advantage—and through mathematical modelling, early estimates showed that B.1.351 was 50% more transmissible than previously circulating lineages. “This made sense to us as it was consistent with some of the initial estimates around B.1.1.7, and these two variants have this shared mutation; the N501Y,” suggesting that this was the reason for the high transmissibility that both these variants share. However, Lessells stressed that it could also be explained by 501Y.V2 evading 21% of previously acquired immunity, without any increased transmissibility. This means  it could be able to reinfect previously infected individuals, who had acquired “immunity.”

Lessells concluded that genomic data strongly imply that 501Y.V2 spreads more efficiently throughout the population, which may relate to transmissibility or immune evasion, or both. Evidence around immune evasion and risk of reinfection remains unclear, and whether 501Y.V2 is associated with increased disease severity and death remains unknown.

Esther Sabino, University of Sao Paolo, P1

Esther Sabino, University of Sao Paolo, explained howthe epidemic in Brazil started in late February 2020. While  there are still many unknowns about the P1 variant, the key mutations involved are K417T, E484K, and N501Y. The transmissibility with the P1 variant is increased, allowing it to spread more efficiently throughout the population. 

Sabino cited a mathematical model used to investigate the P1 variant, according to which P1 was 10-80% more likely to result in death. No clarity exists, however, about other factors that may have driven up death rates, and so the lethality of the P1 variant still needs to be confirmed. Immune evasion from previous infection seems likely, as several cases of reinfection have been reported.

Future of the pandemicsequencing 

Jeff Barrett, Wellcome Sanger, discussed sequencing genomes to detect the new variants. He shared images of the large scale fridges, where remains of completed PCR tests are sent to be used as virus samples and are sequenced. “We are now sequencing between 10-20,000 virus samples every week and rapidly putting those data into the hands of academics and public health agencies in the UK.” 

He shared that his team focus mainly on “reducing the time between when the swab is up someone’s nose and when the sequence is in the hands of public health agencies,” which  at the start was about two weeks, whereas now it is just under 1 week. Barrett pointed out the difficulties faced along the way with  supply chains, as a result of Brexit and the pandemic.

“What we hope is that other countries can learn from the fact that we discover these things going forward”, added Barrett, who cited Denmark as an example, where scientists have also sequenced a huge fraction of positive tests, which informed the country’s tighter restrictions.

“If B.1.1.7 hasn’t swept your country yet, act fast!” concluded Barrett, “If it has, vaccinate fast and watch out for variants that may be well less neutralised by vaccines (for example,B.1.351). And either way—sequence as many cases as possible in 2021 and beyond. We need to know what is happening so that when we get ahead of the virus, we can stay ahead of it  by adjusting vaccines or changing lockdown measures.”

Implications for international law and travel 

Alexandra L Phelan, Georgetown University, Washington, DC, USA,  explained that the law governing international spread of disease initially  developed during the Industrial Revolution, when sudden movement took place through steamships and steam trains crossing borders. This happened alongside the very beginnings of germ theory and  a lack of understanding about what control measures would be legitimate. “As a result, serious human rights violations followed.”

“Much of our current international law, despite being adopted post-SARS in 2002-03, is really built on these sort of historical norms,” Phelan added.

The laws aim to prevent, protect against, control, and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, but also avoid unnecessary interference with international traffic and trade., “this unnecessary interference has become a touch point during the pandemic because it doesn’t necessarily mean no interference with international traffic and trade. We haven’t had sufficient guidance on this, partly because of a lack of historical evidence to really work out how we should introduce nuance into the ‘idea of ‘necessary’ in light of covid-19 and the emergence of new variants.” 

Phelan discussed vaccine passports. “We’ve seen businesses and countries and regional blocs seeking to adopt their own vaccination passports, but the reality is, this is governed by international law. There are two ways in which you could have a vaccine passport recommended, and one would be through the fact that we are in a public health emergency of international concern, which gives the World Health Organization jurisdiction to make the recommendation. At this stage, WHO has not recommended the use of vaccination passports, and that’s because it’s quite complex. That’s why we have only one disease with that level of detail – yellow fever, which draws on an international certificate of vaccination.”

 “There is scope for countries to achieve consensus on this. If we have this fragmented approach where businesses, airlines, or governments are implementing their own vaccine passport scheme, we start to really run into issues with inequitable global vaccine distribution, which means some parts of the world will be able to travel and others will not.”

Phelan concluded that “our existing international law is insufficient, and variants exacerbate this issue.” 

How variants affect vaccine efficacy and implications for policy

Akiko Iwasaki from Yale University in the US, discussed vaccine efficacy for variants of concern. She shared unknowns such as the fact that some variants can cause reinfection, but we do not have  enough data to confirm the extent of this. Some variants (E484K, L452R) seem to reduce vaccine efficacy and pre-existing natural immunity, so we do not know whether T-cell responses are sufficient to protect against the variants of concern. Variants of concern may also increase host range and resistance from interferon.

Iwasaki suggested that what we can do to prevent the spread of variants of concern includes vaccinating as soon as possible with the existing vaccines, as those tested so far prevent severe and lethal covid caused by the variants of concern. She also highlighted the importance of increasing viral genome surveillance and subsequently adapting the vaccines to match the variants of concern in the target regions. Such adjusted vaccines can be given as boosters or as a first shot. Iwasaki added that we should aggressively treat immunocompromised patients with mAb cocktails to eliminate development of new variants, as well as developing transmission blocking vaccines.

This webinar was part of The BMJ‘s series of covid-19 known, unknowns webinars. Find out more and register for future events here

Nikki Nabavi, editorial scholar, The BMJ

Juliet Dobson, editor, The BMJ

Competing interests: none declared.


Panel and agenda

New variants: what are they, where do they come from, and what might they do? 

Chair: George Davey Smith, University of Bristol (UK)

– Aine O’ Toole (Edinburgh University, UK )—Summary of the current variants and their mutation rates and biases in interpretation

– Ravindra Gupta, (Cambridge University, UK)—How variants emerge/ selection pressure

– Wendy Barclay (Imperial College London, UK)—Why some variants are more transmissible: lab experiments

What do we know about how particular variants influence transmission, severity and immunity? 

Chair: Kamran Abbasi, The BMJ

– Muge Cevik (University of St Andrews, UK) on B.1.1.7 variant

– Richard Lessells (University of KwaZulu-Natal, S Africa) on B.1.351

– Esther Sabino (University of Sao Paolo, Brazil) on P1

Future of the pandemic

Chair: Allyson Pollock, Newcastle University (UK)

– Jeff Barrett (Wellcome Sanger, UK ) on Surveillance/genomics

– Alexandra L Phelan (Georgetown University, Washington, DC, USA) on what variants mean for border closures

– Akiko Iwasaki (Yale University, New Haven, CT, USA) on how variants affect vaccine efficacy and implications for policy