Finding the Next COVID-19 Variant

Brittany Niccum, PhD, is a commercial product manager at Beckman Coulter Life Sciences who started as an applications scientist. Prior to joining Beckman Coulter Life Sciences, as a postdoctoral fellow, she studied the evolution of bacteria at Tufts University using cheese as a model organism. She also studied microbial evolution at Indiana University for her PhD.

Since it first appeared in humans in late 2019, the SARS-CoV-2 virus has copied itself trillions of times in human cells. Each of these replications is a tiny evolutionary experiment of natural selection, where viruses with advantageous mutations survive long enough to be replicated themselves. With the emergence of four major families of new variants,  it’s clear the COVID-19 virus can readily adapt to vaccines, monoclonal antibodies, and antivirals, according to recent analyses by computational biologists¹ and virologists.²  

Biologists around the world have identified new variants like Delta and Omicron by sequencing the genetic material in samples from people infected with SARS-CoV-2. Their work has revealed how advantageous mutations in the spike protein (a surface protein that the virus uses to enter cells) can produce proteins capable of evading detection by the human immune system. From a diagnostic perspective, knowing exactly who is and isn’t infected is crucial. But to try and predict where the next variant will emerge, researchers need to start pooling their resources—and their samples. 

In the early days of the pandemic, when the world grappled with severe diagnostic test shortages, some labs began pooling samples from patients to make the best use of a scarce resource. Although surveillance testing is different from diagnostic testing (the former focuses on populations whereas the latter tests individuals), the idea of pooling samples to maximize throughput persisted.  

For surveillance, what matters is sequencing as many viral genomes as possible, not linking each sample to an individual—similar to looking for a needle in a haystack, where the next COVID-19 variant is the needle. Attempting to sequence individual samples would be equivalent to examining each piece of hay to find any needles. Pooling samples to quickly sort through the “hay” and identify needles allows researchers to spend more time examining the needles. Some surveillance strategies, such as sequencing SARS-CoV-2 virus found in wastewater, use naturally pooled samples.³ But scientists can also do this in the lab using automated liquid handlers to randomly mix samples. 

Imagine four different samples (A, B, C, and D) for sequencing. A lab can pool them as AB, BC, and CD, so that instead of sequencing four samples, they only need to sequence three. If a variant of interest turns up in both BC and CD, researchers can focus their time sequencing group C more deeply to identify the parts of the virus that are evolving. This strategic pooling lets scientists focus their attention on the small number of viral samples from which new variants may emerge, rather than sifting through the white noise that is the majority viral adaptations.⁴ 

By comparing large numbers of viral sequences, scientists can begin to narrow down the parts of SARS-CoV-2 that are most impacted by the process of natural selection. This, in turn, can provide valuable clues as to which aspects of the virus are most likely to change in the future—and just as importantly, which aren’t.⁵  

Viral antigens less prone to accumulate mutations could make good targets for antiviral and vaccine development. Those viral proteins that do tend to change rapidly, such as the spike protein and other areas of the virus recognized by the immune system, can be mapped to the SARS-CoV-2 genome to determine which potential variants should be flagged by surveillance systems. 

As COVID-19 lingers in the human population in the years to come, genomic surveillance and pooled samples will allow scientists to track more viral sequences with fewer resources, perhaps giving us a head start in responding to the next variant. 

Resources

1. Telenti A, Hodcroft EB, Robertson DL. The evolution and biology of SARS-CoV-2 variants. Cold Spring Harbor perspectives in medicine. 2022;12(5):a041390. doi: 10.1101/cshperspect.a041390 
2. DeGrace MM et al. Defining the risk of SARS-CoV-2 variants on immune protection. Nature. 2022;605(7911):640-52. doi: 10.1038/s41586-022-04690-5 
3. Larsen DA, Wigginton KR. Tracking COVID-19 with wastewater. Nature Biotechnology. 2020;38(10):1151-3. doi: 10.1038/s41587-020-0690-1 
4. Harvey WT et al. SARS-CoV-2 variants, spike mutations and immune escape. Nature Reviews Microbiology. 2021;19(7):409-24. doi: 10.1038/s41579-021-00573-0 
5. Starr TN et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science. 2021;371(6531):850-4. doi: 10.1038/s41579-021-00573-0