LONDON – A new variant of SARS-CoV-2 with an unprecedented number of mutations in the Spike protein which is the target of most COVID-19 vaccines has been detected in South Africa, where it now appears to be driving a rapid increase in the number of infections.

Although diagnosed cases of COVID-19 in the country are low, a big increase was observed in the last seven days, according to the South African health minister Joe Phaahla. On Nov. 16 there were 273 cases. By Nov. 25 this had risen to more than 1,200 cases. “The indication from our scientific colleagues is that we are observing what looks like a new variant,” Phaahla said.

More than 80% of these cases were from a single province, Gauteng. Initially cases appeared to be clustered, but over time there has been more widespread dispersal of infections across the province.

Viral genome sequencing of positive samples from people who had positive PCR tests in Gauteng province led to the identification of the new variant, B.1.1.529.

Tulio de Oliveira, director of the Centre for Epidemic Response and Innovation in South Africa, said, “Unfortunately we have detected a new variant which is a reason for concern … We expect unfortunately to see a very big increase in infections.” He and colleagues have requested an urgent sitting of the World Health Organization’s working group on virus evolution and expect B.1.1.529 to be designated as a variant of concern and given a Greek letter name.

De Oliveira said some of the mutations are “well characterized with known phenotypic impact” but many others are rarely observed until now and not well characterized, so their possible impact is uncertain. Urgent work has started to understand the full significance of the mutations, he said.

B.1.1.259 has a very unusual constellation of mutations and a mutation profile that is different from known variants of concern, agreed Sharon Peacock, director of the U.K. COVID-19 genomics consortium and professor of public health and microbiology at Cambridge University.

“B.1.1.259 has around 50 mutations, but more than 30 of these are in the Spike protein, the region of the protein that interacts with human cells prior to cell entry. The receptor binding motif, the part that binds to [the human ACE2] cell receptor, has 10 mutations,” Peacock said.

This is a bigger number than previous variants of concern, causing worries that the effectiveness of vaccines will be undermined.

While several of the mutations in B.1.1.529 occur in other variants of concern, and/or have been associated with partial immune escape, some have rarely been observed together in the same variant before, according to Francois Balloux, professor of computational systems biology and director of the genetic institute at University College London.

“From the suite of mutations, we can expect that B.1.1.529 is less well recognized by neutralizing antibodies that bind to the spike protein, Balloux said. “As such, we anticipate B.1.1.529 is more likely to (re-)infect people who acquired immunization from vaccination and previous infection.” 

Based on the limited evidence available so far, B.1.1.529 probably qualifies as a variant of Concern. “It will likely be elevated to that status before the end of the week,” said Balloux.

Geographic spread

At present the R value, as a measure of the growth rate of COVID-19 for South Africa as a whole, is 1.47, but initial estimates for Gauteng province are that the R value is 1.93, indicating the growth rate is considerably higher than in the rest of the country. However, B.1.1.529 has a mutation that leads to Spike gene target failure, meaning parts of the gene targeted by PCR tests are false negative (though the test remains positive overall if a person is infected). In the last week there has been a very rapid rise in the number of positive PCR tests from around the country in which this proxy for B.1.1.529 was picked up.

B.1.1.529 also has been detected in Botswana and in Hong Kong (from a traveler from South Africa).

“Analysis of PCR tests in South Africa has shown a rapid increase in Spike gene target failure PCR tests in numerous provinces,” Peacock said. This needs to be confirmed by sequencing, but data presented by the South African Health Ministry in a briefing on Nov. 25 suggests that the variant is widely disseminated in the country.

Studies are now being conducted in South Africa to look at antibody neutralization and the way in which B.1.1.529 interacts with T cells.

These studies will confirm whether there is reduced immunity in standard lab assays, but will take several weeks to complete. “It will also be necessary to get real-world data on whether immunity is reduced to vaccines, and to past infection,” said Peacock.

There is no indication as yet on whether B.1.1.529 leads to a change in disease severity.

Looking at variants over time in South Africa, the Beta variant was associated with the second wave of infection, which was replaced by the Delta variant that drove the third wave. “Initial observations suggest that B.1.1.529 was able to become established in Gauteng province and outcompete Delta,” Peacock said.

There are several explanations for this. A large super-spreader event linked to B.1.1.529 would give the impression of outcompeting Delta, which is otherwise the fittest variant seen to date. “But the other explanation is that B.1.1.529 can actually outcompete Delta,” said Peacock. Further studies are required to confirm this.

While the full significance of the new variant is not known, aspects of the epidemiology in South Africa that justify the alert the county’s health ministry put out on Thursday are:

• the rapid increase in cases in Gauteng province with a raised R value, linked to the detection of B.1.1.529;
• the detection of cases across numerous provinces in South Africa based on a PCR test with Spike gene target failure;
• hints the new variant may be outcompeting the Delta variant;
• and the very large number of mutations present in the spike protein, some of which have been associated previously with increased transmission and immune evasion, and some of which have not been characterized.

“This situation is reminiscent of the epidemiology of Alpha in Kent [U.K.] around a year ago. There was a surge in cases, but it was not clear whether this was due to one or more super-spreader events or was associated with a more transmissible virus,” Peacock said. “Rapid spread in South Africa could be due to super-spreader events or other factors. But there are sufficient red flags to assume the worst rather than hope for the best and take a precautionary approach.”

Countries in Europe have suspended all flights from South Africa, and five other countries in the south of Africa - Namibia, Zimbabwe, Botswana, Lesotho and Eswatini. The EU is now proposing an “emergency brake” to stop all air travel from the region to Europe.

Peacock spearheaded the genomic surveillance of SARS-CoV-2 in the U.K. In South Africa De Oliveira and colleagues established a national genomics surveillance network in February 2020. The detection of B.1.1.529 highlights the continued importance and need for genomic surveillance of SARS-CoV-2 and access to relevant samples to do this, Peacock said.