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Illumina Strikes Back: New NovaSeq X Series Sequencers to Push Boundaries on Throughput, Cost

Illumina X

SAN DIEGO – Illumina is launching a new line of high-throughput sequencers called the NovaSeq X series, based on a reengineered sequencing-by-synthesis chemistry, now officially called XLeap-SBS. 

At its most powerful, the tech tandem will be able to put out 16 Tb of sequencing data in approximately two days, for a list price of approximately $2 per gigabase, according to Joel Fellis, VP of product management at Illumina. Moreover, the X series instruments will feature onboard secondary analysis from the firm's Dragen IT platform. 

At the inaugural Illumina Genomics Forum — a splashy meeting boasting CEOs, public health ministers from around the world, and even former President Barack Obama in attendance — Illumina employees suggested on Thursday that the new products will help the firm recapture some of the attention granted to startup competitors in the NGS market. 

After slow-playing the X series announcement by first revealing the NovaSeq Dx (a regulated, clinical high-throughput sequencer), Illumina Complete Reads (a technology for creating longer contiguous sequences using short-read sequencing previously referred to as "Infinity"), and the new XLeap-SBS chemistry, CEO Francis deSouza proclaimed to the crowd that Illumina was launching "the most innovative sequencing platform ever developed." 

Starting in the first quarter of 2023, Illumina will begin selling the NovaSeq X Plus, a $1,250,000 sequencer that can run two of its new 10 billion-read, or approximately 3 Tb, XLeap-SBS flow cells. That's comparable to what can be done with an S4 flow cell and a NovaSeq 6000. Later in 2023, Illumina will add the $985,000 NovaSeq X, which only runs one flow cell, along with two other flow cell configurations: 1.5 billion reads, or 500 Gb output, and 25 billion reads, or 8 Tb. 

After deSouza introduced the X series, Illumina Chief Technology Officer Alex Aravanis came on stage to provide details about the new chemistry. He called it "more than just a step change," noting that the research team "created new nucleotides, new bonds, new dyes," and even "new ways to make and break bonds." 

The chemistry will also be backwards-compatible, but only with the NextSeq 1000 and 2000 mid-throughput benchtop instruments, Fellis said. A new P4 flow cell with more than 500 Gb output will be available for those instruments in early 2024, although he declined to provide pricing.

Of all the features that triggered applause in the ballroom crowd, a 90 percent reduction in packaging weight and waste was arguably the most well received. 

"This is by far the coolest thing," said Molly Zeller, lab manager at the University of Wisconsin-Madison Biotechnology Center DNA Sequencing Facility, who attended the meeting. "Right now, it really is our biggest hurdle with the NovaSeq. My number one complaint with Illumina was always about the waste and the packaging and the shipping and the battles I go through recycling everything." 

"I think it shows Illumina is listening," she said. 

Not only is Illumina paying attention to its customers, but it seems to have learned from its competitors. One conference participant, who asked not to be named, remarked that the presentation, which featured an animated teaser trailer for the NovaSeq X series and professional stagecraft, had "'London Calling' vibes," referring to Oxford Nanopore Technologies' annual user group meeting. 

The new flow cells will feature individually addressable lanes, a feature that competitor Singular Genomics has been touting on its G4 instrument. And the cost per gigabase, which could be lower than the $2 sticker price with volume discounting, could be seen as a reaction to Ultima's promise of $1 per gigabase with its forthcoming platform. 

Illumina has been dropping hints about these product launches for months. At the JP Morgan Healthcare Conference in January, deSouza first mentioned what was then called "Chemistry X," noting that the firm was already building a factory to manufacture reagents for it.

NovaSeq Dx, also teased in January, will carry US Food and Drug Administration registration and the CE Mark. It will have both research-use only and in vitro diagnostic run modes and a dedicated Dragen server.

Illumina Complete Long-Reads will land in 2023 in two formats, first, a kit for human whole-genome sequencing in Q1 and, later, another for enriching the regions of the genome that are hardest to map. Illumina is regularly getting 6 kb to 7 kb sequences, deSouza said, with the longest sequences reaching more than 30 kb.

Many customers and stock analysts had expected a product announcement to accompany the launch of the chemistry, with an expected drop in sequencing costs. 

Illumina's reveal has mostly satisfied them. SVB Securities Analyst Puneet Souda saw Illumina as "largely meeting and beating most expectations for a new box and product updates," according to a note to investors following the announcement, calling it "a clear positive launch for Illumina." 

Cowen Analyst Dan Brennan suggested that pre-announcement research suggested Illumina would need to hit a price of approximately $233 per genome to keep customers happy. 

Already, Illumina has the Broad Institute Genome Platform and the Regeneron Genetics Center, two of its largest accounts, interested in the NovaSeq X series. They weren't the only ones. 

"I think it's good because you can do almost anything," said Zodwa Dlamini, director of the Pan-African Cancer Research Institute and a professor at South Africa's University of Pretoria. She's interested in getting one for her organization. 

But the instrument price could make some labs hold off. Whether Zeller's lab will get one will depend on how good the trade-in deals are, she suggested. "We still have to worry about depreciation," she said. "The price per gigabase is not too bad, it's the investment a core facility needs to put into it. We need to make sure the need, the want, and the demand is there." 

"The challenge from a clinical perspective is meeting the throughput," said Ken Eyring, director of lab operations at Intermountain Precision Genomics, who saw the presentation via webcast and echoed the sentiment about demand. "Obviously, the capabilities to generate a lot of data and test a lot of samples is there," he said. "You can drive down the cost of a whole genome, but for a smaller health system to have enough samples to test to make use of that full capacity, it could take some time to get to that point." 

Some specs of the new instrument and chemistry were not clearly addressed in Thursday's presentation. Illumina uncharacteristically did not focus on accuracy, and when it did, the messaging wasn't straightforward. Overall, Illumina officials have claimed it is twice as accurate as its predecessor, though deSouza claimed the new DNA polymerase at the heart of XLeap-SBS is up to three times as accurate as the old one at incorporating bases. 

"We're still optimizing our quality tables," Fellis said in an interview before the big reveal. "The way to think about this is as an overall reduction in error rates across the length of a read." After the announcement, Illumina published a spec sheet claiming accuracy of above Q30, or 99.9 percent per-base accuracy, for more than 85 percent of all bases in 2x150 bp mode, which is the same as what it claims for the NovaSeq 6000. 

And while it briefly flashed a diagram showing specs for metrics such as SNP precision, in response to direct questions about that and GC coverage, Illumina only said that the X Series was "highly concordant with NovaSeq 6000." 

In addition to the more accurate DNA polymerase, Fellis said that Illumina developed a new chemical block to help reduce sequence-specific errors. "It's more resistant to heat and stress," he said. "We can hit it with a high-output laser to boost signal-to-noise and scan flow cells significantly faster." 

After the presentation, Aravanis noted that a chemistry that ships at ambient temperatures has been a "long-term dream" for the company. This aspect could unlock sequencing for areas without reliable cold chain logistics, deSouza noted, improving accessibility. 

While it has taken approximately five years and loads of resources to develop XLeap-SBS, Aravanis said it's "dramatically" cheaper to produce the flow cells, thanks to fourfold higher cluster density and new nanolithography techniques that Illumina adapted for standard silicon wafers. This allows manufacturing to be automated and the larger wafer size to increase manufacturing yield. 

What value the on-board secondary analysis and waste reduction can bring to customers is yet to be quantified. Fellis suggested that the Dragen integration will "remove the bioinformatics bottleneck." 

"When generating 16 terabytes of data, it's important to streamline this," he said. 

Fellis said he expects the firm to release customer-generated data "in the coming months," but that the number of early collaborations would likely be limited.

Overall, the NovaSeq X Plus announcement seems likely to satisfy the highest-volume customers, who haven't needed to give a second though to purchase one. For anyone else, the launch timelines just might make them think very hard about buying elsewhere before the NovaSeq X and NextSeq XLeap-SB kits arrive.