After a long wait, Illumina has revealed a new series of sequencing instruments—the NovaSeq X series, designed to cement its position as the leader in next-gen sequencing in the face of intense competition.

The announcement was made during the Innovation Roadmap session of the company’s annual conference—the Illumina Genomics Forum—being held this week in San Diego, CA. The event kicked off on Wednesday with a headline interview with former President Barack Obama.

Illumina’s new sequencing series includes a pair of new instruments—the NovaSeq X and NovaSeq X Plus. The difference? The NovaSeq X uses a single flow cell versus the dual flow cells on the NovaSeq X plus. The two flow cells, however, do not run independently. Jason Johnson, VP and head of global product management for Illumina, tells GEN that they run simultaneously now, but that a stagger start will be enabled over time.

The NovaSeq X plus will start shipping in the first quarter of 2023. Although the instruments have the same footprint at the existing NovaSeq platform (the NovaSeq 6000), the NovaSeq X is a new system, featuring a new chemistry (that is not backward compatible with the NovaSeq 6000), new high-resolution optics and ultra-high density flow cells.

Nova Seq X [Illumina]
How does the NovaSeq X Plus compare to a NovaSeq 6000? A NovaSeq 6000 running at its highest output will generate six terabytes (Tb) of data in 44 hours. The new NovaSeq X will have 10B (10 billion clusters) flow cells. When run at 2×150 bp reads, it will also output six TB but in almost half the time (24 hours). In the second half of 2023, Illumina plans to launch a 25B flow cell (with 2.5x more clusters/flow cell) that will output 16 Tb of data (8 Tb / flow cell) in 48 hours.

The list price for the NovaSeq X plus is $1.25 million, while the NovaSeq X lists for $985,000, which is comparable to the NovaSeq 6000. Johnson asserts that the actual cost to the user will be less, with more flow cells per wafer and less reagents per run. With the highest output flow cells, he says, customers will see a 59% reduction in cost per gigabase (Gb) relative to the NovaSeq 6000 S4. At list price, that’s $2.00/Gb, which yields a roughly $200 human genome (including the clustering, the sequencing and the primary and secondary analysis.)

Kári Stefánsson, MD, founder and CEO of deCODE Genetics, said that “Illumina provided us with the first technology that allowed for the sequencing of thousands and then hundreds of thousands of whole genomes. The new NovaSeq X is going to allow us to sequence the genomes of whole nations.”

Chemistry X

The new platform may share the same name as an older platform, but Johnson says that that is where the similarities end. When compared to previous instruments, “probably the only thing that’s common is the Illumina logo!”

The new chemistry used by the NovaSeq X, which was teased early this year as “Chemistry X,” is now called XLEAP-SBS. XLEAP-SBS is the result of a five-year-old program. Johnson says that while it is still sequencing-by-synthesis (SBS)—the fundamental stepwise chemistry developed by the British company Solexa that Illumina acquired in 2007—it features a new polymerase, blockers, linkers, and dyes.

Starting in 2024, the XLEAP-SBS chemistry will be able to be used on Illumina’s NextSeq 1000/2000 instruments. Why the NextSeq line and not the NovaSeq 6000? “For the new chemistry to work as well as we’d like to, you need some of more of the advanced ultra-high numerical apertures and advanced optics. The NextSeq 1000/2000 has that,” Johnson explains.

Regarding the chemistry, Illumina still leaves much to the imagination. Johnson tells GEN that the company redesigned the blocker to reduce phasing. And it has “redesigned the linker and the dye, which allows it to be brighter and it makes it easier for us to cleave very accurately.”

Illumina says that both the sequencing error rate and the phasing are reduced by about 50%. The new polymerase is three times faster than the current enzyme. And those advances are incorporated with higher powered lasers and staging in the NovaSeq X series.

Johnson says that Illumina tested millions of different iterations while working to optimize the systems that led to XLEAP-SBS. In doing so, they called on the expertise of the team that designed the original Illumina SBS system from Solexa, many of whom are still employees at Illumina.

Longer reads

Illumina made some other announcements at the Forum. As anticipated, their longer read technology, known as Infinity, will be made available in the first quarter of 2023. How long are the long reads? The longest reads that they see are 30 kilobases (kb), but the majority are around 6–7 kb. Infinity can be used on NextSeq, NovaSeq 6000, and NovaSeq X. A targeted version will launch in the second half of 2023.

Illumina also announced the NovaSeq 6000 Dx as the first FDA-registered and CE-marked in vitro diagnostic (IVD) high-throughput sequencer.

Lastly, the company emphasized that the NovaSeq X series has thermostable reagents which can be shipped at room temperature. This eliminates the need for dry ice and reduces waste. The company notes a 90% reduction in packaging waste and weight and 50% reduction in plastic usage.

From the Forum stage, Illumina emphasized that customers will like the fact that DRAGEN (Illumina’s tool that allows analysis of sequencing data) is integrated on-board, the overall throughput and economics, and the sustainability elements of the new system.

Current NovaSeq customers may gripe at the lack of backward compatibility of XLEAP-SBS on the NovaSeq 6000. However, if they want to upgrade, Johnson points out that the company has a promotion, depending on the age and different aspects of the trade in, that they will negotiate with individual customers.

Skeptics may point to the absence of any early users. Indeed, the NovaSeq X has yet to be deployed to the field. Once it gets into users’ hands, the NovaSeq X will have to do something Illumina’s previous instruments have not had to worry about as much—it will have to compete.

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