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Variants Vs. Lineages: How We Track SARS-CoV-2 Changes

By Allison Proffitt

March 30, 2021 | Color Health is adding its voice to calling for more granularity in how we name and track SARS-CoV-2 variants says Alicia Zhou, Chief Science Officer at Color. “There really is a difference between tracking variants versus tracking lineages,” Zhou told Diagnostics World.

“There’s a mismatch in the way [variants of concern] are being tracked in publicly-available data as compared to the way scientists are currently mapping those variants against some consequences like increasing transmissibility or immune escape by vaccine recognition,” Zhou said. “If the goal is to make sure diagnostic tests are able to recognize specific variants, and if you’re thinking about how antibodies induced by a vaccine recognize specific epitopes, [tracking] should also be variant-specific,” she argued.

The Color researchers aren’t the only ones concerned. In January, at a World Health Organization (WHO) meeting devoted to coronavirus variants, health officials and researchers started hashing out a new naming system, according to news published in Nature. “Terms such as ‘variant’, ‘lineage’ and ‘strain’ add to the confusion, because they have no unambiguous definitions and are sometimes used interchangeably,” the article points out.

Zhou agrees. “I like to take a moment to define those terms because I knew they get used somewhat interchangeably.”  

CDC (and Zhou) defines variants of concern (VOC) as those for which there is evidence of an increase in transmissibility, more severe disease (increased hospitalizations or deaths), significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.

A viral lineage is a group of viruses defined by a founding variant and its descendants, according to CDC. “Names are assigned to SARS-CoV-2 lineages using manual and automated methods. Lineage designations are based on phylogenetic grouping followed by the identification of shared, common mutations,” according to the CDC website.

Zhou elaborates that lineages are named according to the Pango nomenclature system and classified with the software tool PANGOLIN (Phylogenetic Assignment of Named Global Outbreak LINeages). The system was published in July 2020 in Nature Microbiology (DOI: 10.1038/s41564-020-0770-5). The tool takes the genomic sequence of a particular sample and algorithmically assigns it a Pango lineage designation based on a minimum number of matching defining variants. However, Color researchers claim that the Pango nomenclature does not prioritize variants in critical functional domains.

For example, the B.1.1.7 lineage first identified in the UK has 17 defining variants, Zhou said. Any sample belongs to the B.1.1.7 lineage if it has at least 5 of those variants. But some variants are more impactful than others and show up in many lineages, making lineage tracking an incomplete picture of the spread of some of the most harmful variants, she said.

In a research memo posted on the Color site last month, the authors warned: “By not tracking and reporting on VOC independent of lineages, scientific understanding of the effects of these VOC may be impeded.”

The situation calls for guidance from the World Health Organization and US Centers for Disease Control and Prevention, Zhou said.


Variant Validation

Color researchers observed the problem while looking at public SARS-CoV-2 sequencing data to continue validating the company’s test. “We are constantly surveying the sequencing data to make sure our diagnostic test continues to perform with high sensitivity across all emerging strains,” Zhou explained. They noticed that sequences classified as belonging to a certain lineage may not actually contain some of the functional phenotypic variants associated with that lineage.

“That was surprising to us, because it made us realize that the way that these things are being classified in public repositories may not be precise enough to really be tracking these specific variants that are causing changes to the viral properties,” she said.

For Color, a health technology company, this is concerning. Color works with health systems, employers, and national health initiatives around the world, including the All of Us Research Program. The company provides physician ordered genetic testing for common hereditary cancers and hereditary high cholesterol, and since the COVID-19 pandemic began, has rolled out high-throughput COVID-19 testing and partnered with more than 100 major employers and universities to provide critical testing programs including the State of California and the City of San Francisco.

The Color SARS-CoV-2 test is not a whole genome test, so it the test is not detecting variants itself. The company instead has FDA EUA approval for RT-LAMP technology, a real time reverse transcription loop-mediated isothermal amplification assay intended for the qualitative detection of nucleic acid from the SARS-CoV-2 virus collected in respiratory swabs. The company says their RT-LAMP test is as accurate as RT-PCR, about 50% faster, and relies on less constrained supply chains.

But Zhou said Color and other diagnostic test developers still want to keep tabs on emerging strains of the virus. “We are constantly trying to keep on top of what emerging strains are coming out of various geographies. Especially if the strain becomes predominant within an area, we want to make sure that our test is not affected by the emergence of that test.”


Long Live Lineages

Zhou is not arguing for a focus solely on variant tracking. Tracking lineages long term is very useful from an epidemiology and evolutionary biology standpoint, she said, and in the short term it is useful for contact tracing. “But if the goal is to make sure diagnostic tests are able to recognize specific variants, and if you’re thinking about how antibodies induced by a vaccine recognize specific epitopes, [tracking] should also be variant-specific,” she argued.

“The only way for us to be more precise about how to track the variant of concern versus the lineage for now is to track both of them,” Zhou said. “I think it will take a point of view from the WHO and the CDC to separate how should these variants be tracked, how they expect them to be named, and when do they want us to be tracking lineage versus variant, in order for everyone to get on the same page.”