Can new variants of COVID harm vaccines? Laboratories struggle to discover

As concerns over the rapidly spreading coronavirus variants grow, laboratories around the world are rushing to discover the biology of these viruses. Scientists want to understand why the SARS-CoV-2 variants identified in the United Kingdom and South Africa appear to be spreading so quickly and whether they can decrease vaccine potency or overcome natural immunity and lead to a wave of reinfections.

“Many of us are struggling to understand the new variants, and the million dollar question is what will this mean for the effectiveness of the vaccines that are currently being administered,” said Jeremy Luban, virologist at the University of Massachusetts Medical School in Worcester .

The first laboratory results are emerging and many more are expected in the coming days, as researchers rush to probe the viral variants and their constituent mutations in cell and animal models of SARS-CoV-2, and test them against antibodies produced by vaccines and natural infections. “Next week, we’ll have a lot more information,” said Vineet Menachery, a virologist at the University of Texas Medical Branch in Galveston, whose team is preparing to study the variants.

Underlying biology

The researchers identified both variants of the coronavirus in late November and early December 2020 through genome sequencing. A genomic effort by COVID-19 across the UK determined that a variant of the virus now known as B.1.1.7 was behind the increase in the number of cases in southeastern England and London; the variant has now spread to the rest of the UK and has been detected in dozens of countries around the world (see ‘Viral sequences’).

And a team led by bioinformatics Tulio de Oliveira from the University of KwaZulu-Natal in Durban, South Africa, connected¹ a rapidly growing epidemic in the country’s Eastern Cape Province for a variant of the coronavirus they call 501Y.V2. The UK and South Africa variants emerged independently, but both carry a bevy of mutations – some of them similar – in the coronavirus spike protein, whereby the virus identifies and infects host cells and serves as the primary target of our immune response.

Epidemiologists studying the growth of variant B.1.1.7 in the United Kingdom estimate it to be about 50% more transmissible than existing viruses in circulation.^two – a vision that contributed to the UK government’s decision to enter a third national blockade on 5 January. “Epidemiology has really shown us the way here,” says Wendy Barclay, a virologist at Imperial College London and a member of a group that advises the UK government in its response to B.1.1.7.

But it is important, adds Barclay, that scientists determine the underlying biology. “Understanding what properties of the virus make it more transmissible allows us to be more informed about political decisions.”

One challenge is to unravel the effects of the mutations that distinguish strains in the UK and South Africa from their close relatives. Variant B.1.1.7 carries 8 changes that affect the spike protein and several others in other genes; South African 501Y.V2 samples carry up to 9 changes in the peak protein. Determining who is responsible for the rapid spread of variants and other properties is a “huge challenge,” says Luban. “I don’t think there is a single mutation responsible for all of this.”

Much of the focus is centered on a change in the spike protein that is shared by both strains, called N501Y. This mutation alters a part of the peak, called the receptor-binding domain, which attaches to a human protein to allow infection. A hypothesis suggested in previous studies is that the N501Y change allows the virus to attach itself to cells more strongly, making infection easier, says Barclay.

The N501Y mutation is one of several that Menachery’s team is preparing to test in hamsters, a model for transmitting SARS-CoV-2. He was part of a team that reported³ last year that a different mutation in the spike protein allowed viruses to grow at higher levels in the upper respiratory tract of hamsters, compared to viruses without change. “This is what I hope for with these mutations,” he says. “If that’s the case, it will boost your transferability.” A report published in late December supports this hypothesis: he found more SARS-CoV-2 genetic material in smears from people infected with variant B.1.1.7, compared to those infected with viruses without the N501Y change.

Antibody tests

The rapid spread of variants has sparked efforts to contain their spread, through blockages, border restrictions and intensified surveillance. Adding to the sense of urgency is the concern that the variants may weaken the immune responses triggered by previous vaccines and infections. Both variants harbor mutations in regions of the spike protein that are recognized by potent “neutralizing” virus-blocking antibodies: the receptor-binding domain and a portion called the N-terminal domain, says Jason McLellan, a structural biologist at the University of Texas. Austin, who studies peak coronavirus proteins. This raises the possibility that antibodies to these regions could be affected by the mutations.

As a result, academic and government researchers and vaccine developers are now working around the clock to resolve the issue. “This is crazy speed,” says Pei-Yong Shi, a UTMB virologist who is collaborating with Pfizer to analyze the blood of participants in his successful vaccine test. In a related experiment, a team led by colleague Menachery found that the 501Y mutation at least did not drastically affect the activity of neutralizing antibodies in the convalescent serum – the portion of blood containing antibodies taken from people who recovered from the COVID infection. . This suggests that the 501Y mutation is unlikely to alter immunity, adds Menachery, who posted the data on Twitter on December 22nd.

But other mutations can. The main one is another mutation of the receptor-binding domain that Oliveira’s team identified in the 501Y.V2 variant, called E484K. His team is working with virologist Alex Sigal at the Africa Health Research Institute in Durban to test the variant against convalescent serum and serum from people who have been vaccinated in trials. The first results of these studies should be public in a few days, says Oliveira.

Immune escape

There is emerging evidence that the E484K mutation may allow the virus to escape some people’s immune responses. In a December 28 prepress⁴, a team led by immunologist Rino Rappuoli, of the Fondazione Toscana Life Sciences in Siena, Italy, cultivated SARS-CoV-2 in the presence of low levels of a person’s convalescent serum. The goal was to select viral mutations that would escape the diverse repertoire of antibodies generated in response to infection. “The experiment shouldn’t necessarily work,” says McLellan, a co-author. But within 90 days, the virus caught three mutations that made it impervious to the person’s serum – including the E484K mutation in the South African variant and the N-terminal domain changes found in it and in the UK variant. “That was surprising,” says McLellan, because it suggested that the individual’s entire antibody response against SARS-CoV-2 was directed against a small portion of the peak protein.

The strain developed in the laboratory proved to be less resistant to convalescent sera from other people. But the experiment suggests that mutations like E484K and changes in the N-terminal domain carried by both variants it can affect how antibodies generated by previous vaccines and infections recognize them, says McLellan.

Both Moderna and BioNtech, which co-developed an RNA vaccine with drug giant Pfizer, said they expect their jabs to work against the UK variant and that testing is underway. These studies involve measuring the activity of neutralizing antibodies in the blood of people who received the vaccine.

An urgent question is whether these changes will alter the effectiveness of vaccines in the real world, says Jesse Bloom, a viral evolutionary biologist at Fred Hutchinson Cancer Research Center in Seattle, Washington. In a January 4 preprint⁵, his team also reported that E484K and several other mutations can escape recognition by antibodies in convalescent sera from people to varying degrees.

But Bloom and other scientists are hopeful that mutations in the variants will not substantially weaken vaccine performance. Injections tend to cause colossal levels of neutralizing antibodies, so a small drop in potency against variants may not matter. Other arms of the immune response triggered by vaccines, such as T cells, may not be affected. “If I had to bet now, I would say that vaccines will remain effective for the things that really count – preventing people from getting sick mortally,” says Luban.