Variants: Forewarned Is Forearmed— For Those Who Listen

(Posted on Wednesday, March 3, 2021)

We now know the adaptive power of SARS-CoV-2 variants. Newly described Covid-19 variants isolated in the United Kingdom, South African, Brazil, the United States, and Nigeria appear to be more transmissible, resist neutralization. and may be more virulent. Now turn back the wheels of time. Were we to know about this variant future, perhaps we could have been prepared. As it turns out, one scientist, Dr. Li Lanjuan, and her colleagues at Zhejiang University provided that early warning.

In a set of two papers released in March and April 2020, Dr. Lanjuan revealed what today is common knowledge. After deep sequencing patients from Hangzhou, Lanjuan identified a series of mutations in the genome and specifically in the spike protein. Her studies spelled out the potential dangers of rapidly mutating virus, one that not only could change,  but a change in critical regions that could affect how well the virus might be transmitted and its potential to cause severe disease.

Perhaps Li Lanjuan’s studies did not draw international attention as she speculated that as the virus adapted, it would like become less rather than more virulent. Nonetheless, the studies had an essential part of the story right. SARS-CoV-2 is a shape-shifting virus on par with influenza. Remarkably, the virus’s ability to change and to change rapidly was reported in mid-March and April 2020 at a time most dramatically underestimated the potential for change. So often wrong in science, conventional wisdom held that because coronaviruses change slowly because they have an error-correcting mechanism. At the time, no one could offer a convincing explanation of why cold-causing coronaviruses return year after year like influenza, often to infect the same person. We now know that cold-causing coronaviruses and SARS-CoV-2 change rapidly to avoid immunity. Will Rodgers is reported to have said, “It isn’t what we don’t know that is the problem. It’s that so much of what we know ain’t so!”

Li commented on the high volume emergence of one specific mutation to several European samples’ spike protein. This mutation conferred greater viral load to those that the virus-infected. The mutation is D614G. Over the next few months, D614G came to dominate every strain and infection of SARS-CoV-2 and is likely a driving force behind the spring and summer 2020 surges of Covid-19. Dr. Li was the first to identify the implications of the D614G variant. In the April 2020 paper, she wrote. “…specifically, we note the following A23403G (D614G in S) found a group 192 of 231 viral sequences, most of which were isolated in Europe.” The first notice of the potential importance of the D614G mutation outside of China was reported by Bette Korber in early May 2020, to widespread skepticism regarding its relevance. In the figure below, Li displays the widespread appearance of variants across continents, including D614G in Europe.

Among the other mutations in Dr. Li’s papers of note are several the S or spike protein. The spike protein mutation at position 215 ( D215H) is also present in the highly infectious and immune-resistant South African variant. The S protein mutation at position 682 (R682Q) escapes neutralization by a therapeutic monoclonal antibody. Another mutation at position 247 (S247R) in the N-terminal domain of the S protein, observed in these early isolates, falls with the N-terminal domain of the S protein.

Mutations external to the S protein are not without their effects on the virus. For instance, South Africa, Brazil, New York, and others, and this exact mutation in the Japanese variant. All of these mutations found in other variants are noted in the figure below along with unique mutations Li noted.

Another of Li Lanjuan’s prescient insights is the importance of mutants adjacent to the S protein’s two cleavage sites, the furin cleavage site between that S1 and S2 proteins, and the cleavage at the site proximal to the fusion peptide. Her speculation that these mutants confer increase infectivity by enhancing cleavage is recapitulated in the current literature regarding similar variants. The early studies note the “looped out structures” of the regions,  rendering them especially vulnerable to proteases.

Dr. Li’s research, coupled with her observation of the rapidly growing number of mutations in the GISAID database as early as one year ago, were red flags that went unremarked for too long. Had we heeded this warning, we would not now be playing a desperate game of catchup by ramping up genomic sequencing efforts in the US and worldwide. Forewarned is forearmed… if anyone is paying attention.

Read the full article on Forbes.

Originally published on March 3, 2021.