LONDON – There is “a realistic possibility” that infection with the B 1.1.7 variant of SARS-CoV-2 is associated with a 30% to 40% increased risk of death compared to earlier variants of the virus, according to scientists on the U.K. government’s New and Emerging Respiratory Virus Threats Advisory Group (Nervtag).

That conclusion is based on studies by three university groups, linking community PCR testing to mortality.

Previous research by Public Health England indicated that although more transmissible, B 1.1.7 was not more lethal. That assessment was changed on Jan. 22 when government chief scientist Patrick Vallance announced Nervtag’s findings. However, he was very cautious, saying, “I want to stress there’s a lot of uncertainty around these numbers. We need more work to get a precise handle on it, but it obviously is a concern that [the variant] has an increase in mortality as well as an increase in transmissibility.”

While preliminary, the data are statistically significant, covering 850,000 confirmed cases and 1,900 deaths, said John Edmunds, professor at the Center for the Mathematical Modeling of Infectious Diseases at the London School of Hygiene & Tropical Medicine, and a member of Nervtag.

“It’s quite a large sample size and the confidence intervals are significant,” Edmunds said. Since the three analyses considered by Nervtag were completed, other groups have applied different methods to analyze the same dataset. “They get the same results,” Edmunds said.

Public Health England based its initial conclusion that B 1.1.7 is not more lethal on a matched cohort study, which found no evidence of a significant difference in risk of hospitalization or death at 28 days follow-up.

However, a more recent analysis with longer follow-up time, and which also was weighed up by Nervetag in reaching its conclusion of greater lethality, identified an increased risk ratio for death.

While other groups have since confirmed the findings of the three initial studies, there remains uncertainty, said Peter Horby, professor of emerging infectious diseases at Oxford University, who is chair of Nervtag.

When community PCR tests are linked to mortality, the number of deaths is higher in people infected with B 1.1.7. However, since the time lag from infection to hospitalization is relatively long, it is not yet possible to detect that difference by analyzing hospital data on deaths.

“What we’ve not detected yet, is if once in hospital more people are dying [from B 1.1.7] than other variants,” Horby said. “Data will accrue in the coming weeks, at which time the analyses will become more definitive.”

Various factors make it hard to unpick whether B 1.1.7 is more lethal than earlier variants. More deaths are occurring because many more people are getting infected, and with more people being hospitalized there is severe pressure on hospitals, which could be undermining care. In addition, many people who die in the hospital have not been tested for SARS-CoV-2 in the community.

On the other hand, improved treatments mean that overall fatality rates are much lower than in the first wave of the pandemic in March – April 2020.

Since being detected in the U.K. last September, B 1.1.7 has been found in more than 60 countries. On Jan. 16 the U.S. CDC reported it has been picked up in 12 U.S. states. Modeling data indicate B 1.1.7 “has the potential to increase the U.S. pandemic trajectory in the coming months” and is likely to become the predominant variation by March this year, according to the CDC.

Moderna testing booster shot

It is not known what it is about B 1.1.7 that might make it more lethal. The finger of blame is pointed at the N501Y mutation in the receptor binding domain of the spike protein, which changes asparagine to tyrosine. It is thought that change means the virus binds more strongly to human cells, which would increase initial infections and enable it to replicate faster in host lung cells. “That’s the most plausible explanation for the increase in transmissibility and increased mortality,” Horby said.

The emergence of B 1.1.7 and variants in South Africa and Brazil also with mutations in the spike protein, has raised significant concerns that vaccines directed against the spike protein could lose their effect.

Pfizer Inc./Biontech SE have reported a couple of in vitro studies showing their vaccine, Comirnaty is not affected by B 1.1.7.

Of greater concern, the National Institute for Communicable Diseases in South Africa has shown the B 1.351 variant (also referred to as 501Y.V2) first detected there, is able to escape neutralization by monoclonal antibodies, including those being used to treat COVID-19 patients, and by convalescent plasma from previously infected individuals.

On Jan. 25, Moderna Inc. announced results from in vitro neutralization studies testing sera from individuals who received its COVID-19 vaccine against B 1.1.7 and B 1.351.

There was no significant impact on neutralizing titers against B 1.1.7 relative to prior variants.

There was a six-fold reduction in neutralizing titers relative to earlier variants in the case of B 1.351, but Moderna said neutralizing antibodies “remain above levels that are expected to be protective.”

Despite that, the Cambridge, Mass.-based company said it will test whether a adding a third dose of vaccine increases neutralizing antibodies against emerging variants. It also will start preclinical and phase I studies of a version of its vaccine specifically designed to be effective against B 1.351.

“Leveraging the flexibility of our mRNA platform, we are advancing an emerging variant booster candidate,” said Stéphane Bancel, CEO of Moderna. This is “out of an abundance of caution,” against the variant first identified in South Africa, to see if it will be more effective in boosting titers against B 1.351 and potentially future variants, he said.