It has been a year since Wuhan health authorities first issued a bulletin about a cluster of pneumonia cases of unknown cause, first bringing what would become the COVID-19 pandemic to the attention of the World Health Organization (WHO).
Now, a mutation that significantly increases SARS-CoV-2’s transmissibility has been detected in the U.S.
On Dec. 29, Colorado public health authorities reported the first known case of infection with the SARS-CoV-2 VUI 202012/01 (Variant Under Investigation, year 2020, month 12, variant 01), also called B.1.1.7, variant in the U.S. The patient in question, a male in his 20s, has not traveled internationally, indicating that the variant is already circulating more widely in the U.S.
B.1.1.7. was first reported on Dec. 14 by U.K. health authorities, prompting stricter lockdowns domestically and border shutdowns internationally.
Despite those efforts, the variant has since been reported in multiple countries – including, as of yesterday, the U.S.
Simultaneously, a similar new variant has been reported in South Africa.
Maria van Kerkhove, technical lead on COVID-19 for the WHO, told reporters at a press conference that the variants are “two separate virus variants that have emerged simultaneously.”
Both share a mutation (N501Y) in the spike protein in one of the amino acids that is key for SARS-CoV-2 to bind to its receptor, and increases viral binding to the ACE2 entry receptor in mice.
The South African variant, called (501Y.V2), also has seven other mutations in the spike protein, including two that are biologically important, researchers from the University of Kwa-Zulu Natal reported in a paper published on the preprint server Medrxiv in advance of peer review.
B.1.1.7 has a total of 17 mutations that lead to amino acids changes, and another six that don’t, researchers from the COVID-19 Genomics Consortium UK reported, also in advance of peer review.
In addition to N501Y, another amino acid mutation that appears to be key to B.1.1.7’s increased transmissibility is P681H. That amino acid is part of a cleavage site for the enzyme furin, and the mutation appears to make the virus more susceptible to cleavage, which increases its ability to enter epithelial cells.
B.1.1.7 also has a two amino-acid deletion (69-70del) that appears to help the virus evade the immune system. 69-70del has emerged before, including in mink in an outbreak that prompted Denmark to order the killing of 17 million farmed mink in November.
However, in mink, the mutation did not appear to increase transmissibility, at least not to the same extent. At the WHO press conference, Marion Koopmans, who is the head of the Erasmus Medical Center Department of Viroscience, said that mink also have “mutations of some concern… but not to the degree that we are currently discussing.”
As recently as November, an analysis of nearly 47,000 SARS-CoV-2 genomes from COVID-19 patients could not identify any recurrent mutations that were convincingly tied to increased transmissibility in humans, leading its authors to speculate that SARS-CoV-2 “may have already reached its fitness optimum in the human host by the time it was identified as a novel virus.”
Unfortunately, that speculation now appears to have been incorrect. A paper published to the preprint server Biorxiv by researchers from University College London concluded that in B.1.1.7, 69-70del “enhances viral infectivity, indicating its effect on virus fitness is independent to the N501Y RBM.”
Emergence of the new variant has coincided with high levels of travel and low levels of social distancing for the Christmas holiday, and the effects of both on increased transmission are still being teased out.
But so far, the best estimate is that mutations make the new variant from 40% to 70% more transmissible.
Severity unchanged, susceptibility unclear
For now, the increased transmissibility of the new variant does not appear to coincide with increased clinical severity. Van Kerkhove said that there were no significant differences in hospital admissions, case fatality and hospital readmission within 28 days between individuals infected with B.1.1.7 and other variants – one piece of good news, or at least the absence of additional bad news.
With health care systems operating at or above capacity in many countries, though, a higher death rate will result from higher infection rates if more severe cases need to be triaged.
Whether the mutations will reduce the effectiveness of vaccines, which work at least in part by raising an immune response to the spike protein, is not yet clear. The leading vaccines target more than one epitope, making it unlikely that one mutation in the spike protein will render them ineffective.
Lower effectiveness, though, is possible. And because the N501Y mutation enables stronger binding of the spike protein to the ACE2 receptor, it could enable the virus to tolerate more mutations in the spike protein – which could then reduce or further reduce the protective abilities of current vaccines.
The University College London group warned against this possibility in its Biorxiv preprint with respect to 69-70del as well. “Enhanced surveillance for the ΔH69/V70 deletion with and without [receptor binding domain] mutations should be considered as a priority,” they wrote. “Such “permissive” mutations have the potential to enhance the ability of SARS-CoV-2 to generate vaccine escape variants that would have otherwise significantly reduced viral fitness.”
At the WHO press conference, David Heymann, who is a professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine and head of the Centre on Global Health Security, stressed that even a fully effective vaccine is “not an excuse for people to let down their guard.”
Heymann’s prediction is that SARS-CoV-2 will ultimately become endemic, either in humans or in an animal reservoir, and that reducing its ability to mutate will remain an important public health goal.
“The more we allow it to spread, the more opportunity it has to change,” he warned.