The rate at which new variants have appeared over the past few months is alarming. In the past few weeks alone, along with the insurgence of the United Kingdom (B.1.1.7) and South African (B.1.351) variants, more have been identified in Brazil, Ohio, and now California. The increased rates of infection and deaths in Manaus, Brazil, despite prior infections affecting 76% of the population, serves as a warning that a new variant may reinfect a population infected with an earlier strain. A similar situation may be occurring in Southern California. Here we examine their situation in more detail.
One of the few vigorous SARS-CoV-2 genome sequencing efforts in the US comes from Cedars Sinai Hospital in Los Angeles. Analyzing countless samples on the lookout for the dangerous emerging variants, researchers found a strain all its own as far back as July. Only a single sample at the time, not much was thought of it. Fast forward to January and the California variant (CAL.20C) accounts for half of the analyzed isolates.
CAL.20C has three unique amino acid substitutions in its spike protein. The spike protein is the part of the virus that interacts and locks into proteins from the human host cell, essentially the key to open the host to the virus. Among these are S13I and W152C in the N-terminal domain, and L452R in the receptor-binding domain.
It is possible that S13I increases the efficiency of cleavage on the 12 amino-peptide terminal, which may increase the volume of S-protein on the host cell. This would lead to a more infectious virus. Additionally, W152C may boost immune-resistance or N-terminal domain efficiency, or something else. We need more data on these two placements before we can draw definitive conclusions from these two substitutions.
The L452R substitution provides a bit clearer insight. The L452R substitutes one positively charged amino acid for another. The arginine (R) side chain is longer than that of lysine (L). The longer reach may improve the binding of the spike protein to the ACE2E receptor. To understand the relationship between the receptor-binding domain and the ACE2 receptor, think of magnetic puzzle pieces. Not only must the shape be an exact match for the two pieces to fit, but the magnetic poles must be aligned as well. Variation in shape or polarity may affect the fit of the pieces. L452R may improve the fit of the two pieces.
According to preliminary data from the Fred Hutchinson Cancer Research Center, which isolated mutation placements to test for immune escape, a mutation to the 452 placement escaped slightly more than a mutation to the 501 placement. N501Y is commonly attributed to the immune-resistance of B.1.1.7. If this preliminary data is any indicator, CAL.20C may be able to escape neutralizing antibodies about as well as B.1.1.7. Again, more data is needed to draw any conclusions about this emerging variant, but the sooner we know the better.
We now know what we’ve long speculated: homegrown SARS-CoV-2 variants are mutating right under our noses. This is a logical development, as the US has more infections than any other country in the world, by far. We now know the existence of this and the Ohio variants. The likelihood that more remain undetected is high. Labs around the country should follow the lead of Cedar Sinai and genome sequence as many samples as they can. Identifying emerging variants is the first step to understanding and controlling their spread.
Unfortunately, as more variants arise, the chances that the in-distribution vaccines cover every variant dwindles. Ample data is available to suggest that B.1.351 is up to ten-fold immune-resistant to several vaccines, and could likely reinfect those previously infected. As P.1 carries many of the same mutations, there is a strong chance it is as well.
In all likelihood, Covid-19 vaccines will need to be adapted annually, as we do with the flu. Manufacturers will need to guess, as they do for flu, which SARS-CoV-2 variants will arise in which region at which time. Most of all, we must reinforce and tighten infection control measures in the United States, despite the apparent waning in infection rates. If these variants grow out of control, we will face another large wave of infections, hospitalizations, and deaths. We are likely to be living with Covid-19 for a long time. The question is, can we figure out a way to manage Covid-19 spread without the significant loss of life we’ve all experienced this past year?