In 2022, Zeng’s popular pathogen metagenomic sequencing (mNGS) has encountered unprecedented challenges.
The emergence of pathogen-targeted sequencing (targeted NGS, tNGS) has made the market competition pattern of pathogen metagenomic sequencing, which was gradually red sea, even more complicated.
On the one hand, pathogen-targeted sequencing has lower cost, easier operation, and shorter time-consuming. It has been favored by clinicians and patients as soon as it was unveiled. This is exactly what the commercialized pathogen metagenomic sequencing has been working on for many years. Unrealized goals.
On the other hand, unlike the relatively simple technical flow at the beginning of the commercialization of pathogenic metagenomics, the composition of players in the pathogen-targeted sequencing market is obviously more complex. It includes not only large-scale and highly capable third-party medical inspection institutes, but also leaders in the competition for pathogen metagenomics, and even testing service companies that focus on tumor genetic testing. This technology application with lower threshold and higher certainty is undoubtedly driving profound changes in the pathogen diagnosis market.
So, how big is the market capacity of pathogen-targeted sequencing? What opportunities will it bring to companies that have already participated or are preparing to enter the game? We try to answer.
Rapid fission from 0 to hundreds of thousands
The commercialization history of pathogen-targeted sequencing is short, but the potential is strong.
In a sense, the rapid popularity of pathogen-targeted sequencing products is the light of pathogen metagenomic sequencing (mNGS) products. Clinically, most doctors do not have sufficient judgment ability to determine the pathogen of infection, so the pathogen metagenomic sequencing product became popular as soon as it was launched. In the past few years, capital has poured in. They have promoted the rapid clinical application of this innovative product, and have also helped front-line doctors and patients to establish a market awareness of accurate pathogen diagnosis. Every year, hundreds of thousands of patients have passed the pathogen macro. Genome sequencing to identify the pathogens they are infected with.
However, metagenomic detection of pathogenic microorganisms is not without its shortcomings, and detection sensitivity is one of them. In pathogen metagenomic sequencing, host information accounts for more than 90% of the sequencing data, while the signal of pathogenic microorganisms is relatively weak, and there may be limitations such as host gene interference and difficulty in typing, so the requirements for detection sensitivity are high. In this regard, companies are also actively optimizing their technologies in improving microbial signals, which makes targeted sequencing technology useful.
Pathogen-targeted sequencing technology uses the combination of ultra-multiplex PCR amplification and high-throughput sequencing to detect dozens to hundreds of known pathogenic microorganisms and their virulence and drug resistance genes in the sample to be tested. In the process of commercialization, pathogen-targeted sequencing focuses on common clinical infectious pathogens. By designing specific primers and using an ultra-multiplex PCR library building system, targeted amplification and enrichment of target sequences are performed, and then high-throughput sequencing is used for amplification. Synchronous detection of increased products. Since only the nucleic acid of pathogenic microorganisms is sequenced during sequencing, the detection sensitivity of pathogenic microorganisms can be greatly improved.
Pathogen-targeted sequencing versus pathogenic metagenomic sequencing
This new detection product strives to “what you see is what you get, and the detection is infection”. The detection can be completed within 12 hours from sampling to reporting. It is a clinically more accessible and operable method. Pathogen diagnostic products. The detection sensitivity to special pathogens, such as Mycobacterium tuberculosis complex, Chlamydia psittacosis, Cryptococcus neoformans, etc., can achieve higher sensitivity than pathogen metagenomic sequencing products, and can take into account both DNA and RNA viruses. Pathogen subtypes and subspecies identification can also be more informative.
Another advantage of pathogen-targeted sequencing is its low cost. Compared with the well-known mNGS products, the cost of pathogen-targeted sequencing is only 1/4-1/3 of the cost, which is more valuable in health and economics. The first is the selection of gene sequencers. Pathogen-targeted sequencing can use relatively simpler and lower-priced gene sequencers. The amount of nucleic acid data of pathogen-targeted sequencing is 1/100 of that of pathogenic metagenomic sequencing, so the amount of sequencing data is smaller. For example, Golden Mile Medical uses low-throughput gene sequencers to complete pathogen-targeted sequencing, while pathogenic metagenomic sequencing often requires large-scale gene sequencers with higher throughput to complete. The second is the reagents configured when the sequencer is running, which is relatively simpler and the corresponding cost is lower. Finally, at the level of sequencing operations, pathogen-targeted sequencing does not have high requirements on the professional level of users, and the overall degree of automation is higher, which will reduce labor costs to a certain extent.
The main pathogen-targeted sequencing products on the market
For example, in October 2021, Illumina launched a broad-spectrum respiratory pathogen resistance gene detection kit using targeted sequencing technology in the United States, which can cover 282 DNA and RNA pathogens at one time, including some drug resistance related genes.
The pathogen-targeted sequencing products launched by Keyinga are also used for the primary screening of hospitalized infected patients. Developed in collaboration with hospitals. The Dano-seq multi-targeted detection of pathogenic microorganisms launched by Dean Diagnostics is characterized by real-time sequencing analysis of third-generation nanopore sequencing technology, combined with traditional microbial detection technology, to form an integrated “sequencing + smear” integrated report.
Obviously, for pathogen-targeted sequencing companies, although the commercialization time of this technology is short, it is not easy to obtain and maintain a competitive advantage for a long time.
Substitute or complement?
“Once the hospital has opened pathogen-targeted sequencing, it basically has only a few pathogenic metagenomes left.” A practitioner once described the influence of pathogen-targeted sequencing products. This makes people suspect that the rapid development of pathogen-targeted sequencing is eroding the market of pathogen metagenomic sequencing.
But in fact, rather than saying that pathogen-targeted sequencing has replaced the application space of pathogenic metagenomics in clinical practice, it is better to say that the two complement each other and jointly improve the efficiency of pathogenic diagnosis in the hospital.
In clinical practice, traditional microbial culture methods and empirical diagnosis are still the mainstream. As we all know, pathogenic infection is often easy to diagnose and treat, but difficult to diagnose. For example, according to the patient’s performance, it can be clinically diagnosed as pneumonia, urinary tract infection, cholecystitis, meningitis, endocarditis, etc., but from Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Baumannii, etc. It is very difficult to identify the causative pathogen among a large number of pathogens such as kinesiobacterium, Pseudomonas aeruginosa, and mycoplasma.
This is because the traditional pathogen diagnosis methods are not efficient. Bacterial culture takes a long time, and in clinical practice, it is not possible to wait until the pathogenic microorganisms are reported before taking drugs. In addition, the positive rate of microbial culture is relatively low, resulting in the inability to obtain microorganisms in many pathogenic infections. For example, the cultivation of pathogenic microorganisms of community-acquired pneumonia is difficult to succeed.
Therefore, empirical diagnosis and treatment is still widely used in antibacterial therapy. This pathogen diagnosis and treatment method often combines different infection sites, common pathogens and their corresponding antimicrobial drugs to formulate treatment plans. For example, the common pathogenic microorganisms for urinary tract infection are Escherichia coli and Staphylococcus saprophyticus. According to the practice of empirical diagnosis and treatment, cephalosporins and quinolones are recommended. As a result, the level of precision in the clinical application of antibiotics is relatively low.
The emergence of pathogen metagenomic sequencing has improved this situation to a certain extent. However, as mentioned in the previous section for the reasons of high cost and low accuracy, the clinical application of pathogenic metagenomic sequencing is still limited to a small scope, thus leaving room for synergy for pathogen-targeted sequencing.
On the one hand, this synergy is reflected in the sequence of time. In the process of clinical promotion, manufacturers often recommend that the application timing of pathogen-targeted sequencing be advanced. The reason behind this is that pathogen-targeted sequencing covers both DNA and RNA viruses, which can lock the pathogen in the early stage of infection, thereby making the treatment more targeted. For example, the tNGS detection technology deployed by Geinga targets the detection of specific target pathogens, reduces the background noise of human origin, increases the enrichment multiple by tens to hundreds of times, improves the sensitivity, and realizes the detection of Firmicutes, intracellular bacteria and RNA. Efficient detection of virus and drug resistance markers.
In most cases, through pathogen-targeted sequencing, the pathogen that a patient is infected with can be identified. According to the current data, there are only about 200 common pathogens in clinical practice. In the face of patients with suspected infection, targeted sequencing technology is used for one-time detection, and common pathogenic microorganisms and related drug resistance information are provided to the clinic. If a patient is infected with a pathogen that is not within the scope of the targeted sequencing kit used, it may be relatively rare, or even an emerging pathogen. At this stage, metagenomic sequencing is started again to carry out the identification of the pathogen in a haystack.
On the other hand, it is also reflected in the choice of application scenarios. From the current centralized application scenarios, pathogen-targeted sequencing is mostly used in the respiratory field, focusing on viral infections, while pathogenic metagenomic sequencing is mostly used in the field of severe infections, such as nervous system infections, bloodstream infections, etc., with comprehensive coverage Diverse pathogens such as bacteria, fungi and viruses.
In this sense, the clinical application goals of pathogen-targeted sequencing and pathogenic metagenomic sequencing are actually different. The former aims to promote the early initiation of more optimized antibiotic treatment, reduce wide coverage and long-term treatment, make treatment more targeted, and lower medical costs, while the latter can be used as the ultimate solution for difficult infectious diseases.
In the future, as the cost of NGS sequencing continues to decrease and the convenience of operation is further improved, in the field of microbial NGS sequencing, the two technologies of metagenomic and targeted sequencing will go hand in hand and complement each other. It is expected that the two will be combined in the form of products Going to serve the clinic will become a development trend.
Application scenarios need to be broken through
A fact that cannot be ignored is that if it is limited to the current application scenarios, the market ceiling of pathogen-targeted sequencing is not high. Based on the calculation of 1 million pathogen-targeted sequencing completed every year, the single charge is 1,000 yuan, and the overall size of this market is only 1 billion yuan, which is obviously not enough for the influx of pathogen-targeted sequencing companies.
For pathogen-targeted sequencing, the greater market opportunity lies in breaking the boundaries of existing application scenarios.
The first is the type of pathogen targeted. At this stage, pathogen-targeted sequencing is mainly for patients with respiratory tract infections, which cover more than 95% of clinical infection scenarios, and respiratory tract infections are mainly viral infections. But in fact, pathogens that cause nosocomial infections include bacteria, viruses, fungi, etc. Among them, bacterial infection is the most common, and over 90% of hospital infections are caused by bacteria, mainly Gram-negative bacteria, mainly Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Baumannii Acinetobacter. In other words, the existing pathogen-targeted sequencing products only cover the tip of the iceberg of nosocomial pathogens, and there is still more application space to be explored.
For example, using pathogen-targeted sequencing products to accurately diagnose the pathogens of bloodstream infections in advance, when bloodstream infections are suspected, targeted antibiotic treatment programs can be started as soon as possible according to the test results.
The second is the application scenario. At this stage, pathogen-targeted sequencing is still largely limited to hospitalized infected patients, despite earlier initiation. In terms of outpatient services, the penetration rate of pathogen-targeted sequencing is still very low due to the relatively long time for detection and reporting and the relatively high price. With the continuous maturity of technology and product design, the pathogen-targeted sequencing market that comprehensively covers patients with in-hospital and out-of-hospital infections is obviously a bigger blue ocean.
Overall, the emergence and commercialization of pathogen-targeted sequencing technology has provided a more efficient tool for the diagnosis of infectious pathogens, which is still inefficient, and we look forward to the continuous iteration of this tool to enable more diverse clinical scenarios landing.