Could the new COVID variants harm vaccines? Laboratories are scrambling to find out

As concern grows about faster-spreading variants of the coronavirus, labs around the world are rushing to detect the biology of these viruses. Scientists want to understand why the SARS-CoV-2 variants identified in the UK and South Africa seem to be spreading so quickly, and whether they could decrease the potency of vaccines or overcome natural immunity and lead to a wave of re-infections .

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

The first lab results are coming and many more are expected in the coming days, as researchers rush to probe viral variants and their constitutive mutations in cell and animal models of SARS-CoV-2, and test them against the antibodies caused by vaccines and infections. “By next week we’ll have a lot more information,” says Vineet Menachery, a virologist in the medical branch of the University of Texas at Galveston, whose team is preparing to study the variants.

Underlying biology

The researchers spotted the two variants of the coronavirus in late November and early December 2020 through genome sequencing. A UK-wide COVID-19 genomics effort determined that a variant of the virus now known as B.1.1.7 was behind the surge in the number of cases in the south -est of 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 bioinformaticist Tulio de Oliveira from the University of KwaZulu-Natal in Durban, South Africa, has connected.¹ a rapidly growing epidemic in the country’s Eastern Cape province to a variant of the coronavirus they call 501Y.V2. The British and South African variants emerged independently, but both carry a multitude of mutations – some similar – in the coronavirus spike protein, through which the virus identifies and infects host cells and which serves as a primary target for our immune response.

Epidemiologists studying the growth of the B.1.1.7 variant in the UK have estimated that it is around 50% more transmissible than existing viruses in circulation² – an insight that contributed to the UK government’s decision to initiate a third nationwide lockdown on January 5. “Epidemiology has really shown us the way here,” says Wendy Barclay, a virologist at Imperial College London and a member of a group advising the UK government on its response to B.1.1.7.

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

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

Much of the attention is focused on a change in the spike protein that is shared by the two lines, called N501Y. This mutation changes part of the tip, called the receptor binding domain, which locks onto a human protein to allow infection. One hypothesis raised in previous studies is that changing N501Y allows the virus to attach more strongly to cells, which facilitates infection, says Barclay.

The N501Y mutation is one of many mutations that Menachery’s team is about to test in hamsters, a model of transmission of SARS-CoV-2. He was part of a team that reported³ last year, a different mutation in the spike protein allowed viruses to grow to higher levels in the upper respiratory tract of hamsters, compared to viruses without change. “That’s what I expect with these transfers,” he says. “If so, it will drive their transmissibility.” A report published at the end of December confirms this hypothesis: it found more genetic material of SARS-CoV-2 in the swabs of people infected with the B.1.1.7 variant, compared to those infected with viruses lacking the N501Y change.

Antibody tests

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

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

But other mutations could. Chief among these is another receptor binding domain mutation that de Oliveira’s team identified in the 501Y.V2 variant, called E484K. His team is working with virologist Alex Sigal of the African Institute for Health Research 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 made public in a few days, says de Oliveira.

Immune breakout

There is new evidence that the E484K mutation can allow the virus to evade immune responses in some people. In a December 28 preprint⁴, a team led by immunologist Rino Rappuoli, at Fondazione Toscana Life Sciences in Siena, Italy, cultured SARS-CoV-2 in the presence of low levels of a person’s convalescent serum. The aim was to select for viral mutations that escape the diverse repertoire of antibodies generated in response to infection. “The experiment wasn’t necessarily supposed to work,” says McLellan, co-author. But within 90 days, the virus had detected 3 mutations that made it impermeable to the person’s serum – including the E484K mutation in the South African variant and the N-terminal domain changes found in this and in the variant. British. “It 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 spike protein.

The strain developed in the laboratory was found to be less resistant to the recovery sera of other people. But experience suggests that mutations such as E484K and N-terminal domain changes carried by both variants could affect how antibodies generated by vaccines and past infections recognize them, McLellan says.

Moderna and BioNtech, which co-developed an RNA vaccine with pharmaceutical giant Pfizer, said they expected their injections to work against the UK variant and that testing was underway. These studies consist of measuring the activity of neutralizing antibodies in the blood of people who have received the vaccine.

An urgent question is whether such changes will alter the actual effectiveness of vaccines, says Jesse Bloom, viral evolutionary biologist at the 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 recovering sera from people to varying degrees.

But Bloom and other scientists are hoping that mutations in the variants won’t significantly weaken vaccine performance. The injections tend to cause huge levels of neutralizing antibodies, so a small drop in their potency against the variants may not matter. Other arms of the immune response triggered by vaccines, such as T cells, may not be affected. “If I were to bet now, I would say vaccines will remain effective for the things that really matter – keeping people from getting seriously ill,” Luban says.