Governments across the globe are struggling to keep pace with the SARS-CoV-2 virus’s impact on public health, but the new variants are presenting their own challenges. The next task facing governments across the globe is to sequence the latest mutated variants of the virus and keep track of any further mutations, all while validating new and revamped existing tests, a task that is likely to prove difficult to meet for at least the next few months.

Among the government agencies working to track and sequence mutations to the SARS-CoV-2 virus is the COVID-19 UK Genomics Consortium, or COG-UK. This consortium brings together a number of public- and private-sector entities and has developed several protocols for sequencing, such as one published in November 2020. The group is also working on projects to support the roll-out of vaccines, but this group’s work was critical in identifying the B.1.1.7 variant, which has been detected in other nations as well, including the U.S. The U.K. government ensured that this effort was well supported with a bolus of £20 million (US$27.66 million) that has allowed the participants to sequence more than 250,000 genomes to date, according to a Feb. 8 COG-UK tweet.

American government agencies are also at work on similar efforts, led largely by the CDC, which is sequencing samples contributed by state departments of health and other entities. However, the agency said it is able to process only 750 genomes per week as of Jan. 25, 2021, although CDC took a contract with Quest Diagnostics Inc., of Secaucus, N.J., to aid in the effort. Quest will randomly collect de-identified specimens and provide CDC with entire viral sequences from these samples. Quest said in a Jan. 18 statement that its facility in San Juan Capistrano, Calif., would be tasked with the sequencing work.

Meanwhile, the World Health Organization (WHO) revised its list of essential diagnostics to include antigen and molecular tests for the SARS-CoV-2 virus. WHO noted that the list also includes tests that should not be supplied for reasons such as lack of reliable performance or poor cost effectiveness. Much of the emphasis is on tests to be made available to the patient during primary care visits or to visits to community health clinics.

The European Medicines Agency (EMA) advised industry in a Jan. 21 advisory that sequencing programs are underway in several member nations. One example is a Danish study in which the U.K. variant was detected in large numbers, and which indicated that the B.1.1.7 variant could be the dominant strain in Denmark by the end of February 2021. The South African variant has been detected in much of northern and western Europe as well, but EMA indicated that there is little indication that the South African variant would substantially affect the majority of diagnostic assays. The bulletin includes a link to a technical guidance for sequencing the virus as well, which includes a recommendation that each EU member nation sequence at least 500 randomly selected samples each week.

The CDC indicated Jan. 28 that most reverse transcription polymerase chain reaction (RT-PCR) tests can still detect these novel variants because most of these tests pick up more than one target. However, not all of these tests will be able to retain sensitivity as indicated by the FDA’s Jan. 8 statement, a predicament that may force developers to conduct new validation studies.

The FDA’s director of the Office of In Vitro Diagnostics and Radiological Health, Tim Stenzel, expressed concern about the ability of antigen tests to maintain sensitivity with these new variants in the Jan. 27 COVID-19 testing town hall. These tests are playing a vital role in the pandemic thanks to the fact that they can be deployed in a fully at-home diagnostic such as was seen in the Dec. 15 FDA announcement for the Ellume test. The FDA’s device center has published several templates for the various test types, but may have to update each of the templates before more than a handful of developers will attempt to revise their EUAs. The agency has previously indicated that it may return EUA filings if they are visibly and grossly deficient, so these template updates are critical to avoid wasted time and energy.

Defense Production Act to be invoked

In the U.S., the Biden administration has promised to invoke the Defense Production Act for a number of purposes, including to increase production of at-home COVID test kits. At least half a dozen test developers have indicated that they will consequently be able to increase production by the coming summer season, but the plan has its critics. Michael Mina, the Harvard epidemiologist who has routinely criticized the federal government’s response since nearly the beginning of the pandemic, argued recently that low-cost lateral flow test kits could be inexpensively manufactured in bulk quickly enough to increase at-home testing in spring. Mina also continues to criticize what he sees as an unwavering belief on the part of the FDA that PCR testing performance metrics should be matched or at least approached by these other test types.

Frederick Nolte, who chairs the COVID response steering committee for the Association for Molecular Pathology (AMP), told BioWorld, “we have noticed that the U.K. variant may adversely affect the performance of specific molecular tests that include an S gene component because of mutations in the target site.” When asked whether all tests going forward will have to pick up on multiple variants to be of any use, he replied, “I would say that would be more than likely since the variants of interest do not seem to be geographically restricted.”

While sequenced samples of the new variants might not be as widely available as desired, Nolte said the test developer and/or manufacturer “should be able to use the genomic sequences to predict whether any given variant might impact the performance of a given test. If there is suspicion that it might impact performance, then that hypothesis must be tested.” However, he noted that AMP has received no word from the FDA as to whether the need to revisit existing tests will cramp operations at the agency. Nolte also serves as the director of the molecular pathology lab at the Medical University of South Carolina.

The American Clinical Laboratory Association has developed an FAQ regarding the impact of the new variants on LDTs, which says that many LDTs use multiple targets to pick up the virus, and hence many of these tests should still perform reliably. Tests that target two features other than the S gene would presumably offer a reliable result if both those alternative targets come back positive. ACLA said many of its member labs are also pitching in on the effort to sequence the new variants in cooperation with the FDA, the CDC and local public health labs.