With more strains of SARS-CoV-2 appearing in communities across the globe, there is a growing call for national and international collaboration to understand these variants, including whether any are more infectious and how they are spreading. While PCR is a very important and scalable tool that is being used extensively in labs across the globe for diagnosis of COVID, it cannot provide deep insight into the virus’s full genome – this is where the advanced technology of next-generation sequencing (NGS) comes into play.
In this Q&A, Garret Hampton, president of clinical next-generation sequencing and oncology at Thermo Fisher, discusses how NGS supports COVID-19 global surveillance efforts to track and understand emerging variants, other applications for this technology today, and how Thermo Fisher is enabling global access to rapid sequencing technology.
Last March, Thermo Fisher Scientific introduced the Ion AmpliSeq SARS-CoV-2 Research Panel to aid in COVID-19 epidemiological research and contact tracing efforts using rapid NGS. Labs around the world have been using the panel to study how the virus is transmitted and decipher changes in its genetic code. Now, recognizing the pressing need to ramp up efforts to identify and track the newly identified strains, as well as emerging variants, additional clinical laboratory directors are joining global efforts to identify variants among patients who test positive for COVID-19.
Q: How is genetic sequencing being used for the surveillance of COVID-19 and to track new strains of coronavirus?
A: Often when we think of tracking the virus, our minds immediately jump to diagnostics: does someone have COVID-19 or not. While this is possible to decipher through genetic sequencing, it is not the most efficient or cost-effective method to detect whether a sample is positive or negative for SARS-CoV-2 – the diagnosis is primarily being done through PCR or antigen testing. Where researchers are using next-generation sequencing is for genetic epidemiology – the ability to sequence a viral strain and compare it to the ones that are known and emerging, as well as those not yet known today.
When we sequence a genome of the virus, we can see any base mutations that occur and can map these mutations to specific functions of the virus. For example, when looking at the spike protein, which is how the virus enters a cell, sequencing has allowed us to determine that more infective strains have a tighter binding to human cells. This is incredibly valuable in assessing the risk of new strains, as well as better understanding those that are already circulating.
In the example of the U.K. variant, statistics show that it was originally infecting small numbers of people, but within a month was infecting the majority of people within certain communities. Through sequencing, we were able to learn that this is likely a more virulent strain, that the population is getting too close together, or that lockdowns aren’t working well. While the symptoms are not more severe, the sheer quantity of people infected reinforces the importance of identifying when someone may be infected with this strain versus another, and monitoring their transmission closely from a public health perspective.
As one example, MAKO Medical has been using Thermo Fisher’s TaqPath COVID-19 Combo Kit for COVID-19 PCR testing. The company provides testing services to 35 states and has been invited by the Centers for Disease Control and Prevention (CDC) to support their national surveillance efforts.
MAKO recently expanded its capabilities using one of our NGS platforms for surveillance, and announced it has identified 35 variant cases in six states, including 30 cases with the B.1.1.7 variant and one case with the B.1.351 (South Africa) variant. Across its facilities, MAKO sequenced nearly 300 samples.
Q: Why is there a growing urgency to ramp up SARS-CoV-2 sequencing efforts?
This urgency has come partly from realizing that here in the United States, we had only sequenced a fraction of the genomes necessary to identify and track strains. The combination of regulatory initiatives and proposed legislation to fund surveillance with up to $2BN has drawn growing awareness and demand for wider-spread sequencing.
Going back to last spring, the biggest focus in the U.S. was on testing – ramping up access to testing and ensuring contact tracing efforts were in place when someone did test positive. With these new strains, however, we were caught flat-footed. No one expected the virus to mutate to the extent that it did, or as rapidly as we are now seeing. Even within one variant, researchers are seeing as many as 17 mutations, which is highly unusual in this short amount of time.
While we could identify if someone was positive, in many cases we didn’t know who was being infected by these new strains or the extent of the spread. PCR testing only looks at specific regions on the genome to identify if a sample is positive or negative for coronavirus. Certain variants – including the U.K. strain – have a mutation within one of these regions, which can be flagged through the PCR test. The PCR test, however, won’t show other mutations in the viral genome, which is becoming more and more important – only sequencing can do that.
Other countries have committed to broader sequencing efforts, and the U.S. is beginning to follow suit. For example, Germany has said it will sequence 5% of all positive COVID patients in the population to better track virus spread and how the new strains are infecting its population, and has established reimbursement for the costs that labs incur when they do this kind of sequencing.
Despite the best intents of regulatory agencies, there are 250,000 viral genomes from COVID tests in global public databases, but only about 50,000 were sequenced here in the U.S. Researchers are working to increase this rate, and recent initiatives are greatly increasing the volume of genomes the U.S. is collecting.
Regulatory bodies have reinforced the importance of sequencing through their own initiatives. The U.S. Food and Drug Administration (FDA) is tracking how new variants are affecting molecular test performance, and have advocated for the importance of genetic sequencing. Similarly, the CDC is leading the SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology and Surveillance (SPHERES), a national genomics consortium to coordinate SARS-CoV-2 sequencing across the United States.
To support this program, CDC has partnered with labs across the country. While states have been empowered to forge their own paths with testing over recent months, this centralized leadership attests to the importance of sequencing on a national and global level. A great deal of interest remains among clinical lab directors to do variant sequencing in local and regional laboratories closer to the physicians and patients they serve. Doing so allows more labs to identify variants and quickly trace their spread. Once they have that information, they can alert local public health agencies to provide accurate and actionable information to those authorities.
Q: Many experts are calling for a national sequencing strategy in the U.S. and more global data sharing. What are some of the obstacles to more widespread adoption of genetic sequencing? What can be done to support global and national sequencing initiatives? How is Thermo Fisher stepping in?
We only recently received support from the FDA and CDC to move forward with broader sequencing efforts. Prior to their statements, most labs and institutes did not know whether sequencing would be important in tracking this virus. Now that we know that it is important, there is a question about how to implement this when, in many places, we are barely keeping up with testing.
Because the U.S. does not have a national healthcare system, there are also questions around who is going to pay for the sequencing. While some countries in Europe are offering reimbursement for these tests, there is no repayment or insurance payment model for next generation sequencing in the U.S.
Public health, academic, and independent labs are also interested in conducting their own sequencing to augment what is being done at a federal level and to offer faster, actionable results. These findings can contribute to the same national and global databases that support the CDC’s program, but also offer the more immediate insights into community transmission that are needed for contact tracing and making important local public health decisions.
Back in the spring, we launched our Thermo Fisher GlobalAccess program to make rapid next-generation sequencing available to labs conducting SARS-CoV-2 research. With the emergence of new SARS-CoV-2 strains, we have extended this program through June 2021, allowing more labs to access this technology. Our main goal is to enable labs to get results quickly so they can act on their data – in the case of COVID, this quick turnaround empowers labs to deliver insights directly to local or state health authorities, as well as to assist with local contact tracing.
Next-generation sequencing is viewed as a highly sophisticated, time-consuming process that is reserved for large academic medical centers. We wanted to make sequencing easy to use, fast and possible without the need for highly trained technicians. That was the thinking behind the Ion Torrent Genexus System, the first fully integrated NGS platform that features an automated specimen-to-report workflow to deliver results in one versus a few days.
Q: What are the other applications for rapid NGS beyond tracking SARS-CoV-2?
While the COVID pandemic is creating new opportunities for more widespread sequencing, NGS has seen increased interest and use over the last five years to help understand disease progression and treatment options. NGS is most pervasive today in oncology research, and one of the newest applications in this industry is in liquid biopsy. Previously, a slice of a cancer tumor would be needed to sequence and better understand tumor characteristics. Now, pathologists can use NGS assays and extract and sequence the DNA of a tumor from a simple blood sample of a cancer patient.
Another emerging area for NGS in oncology is in monitoring if a therapy is working or not – and if it is not working, understanding when the cancer comes back. Typically, this has fallen to radiology, but the challenge with radiology is that these images often only spot large tumors. Using liquid biopsy, you can go back months after an initial therapy selection and use a blood sample to see if you can identify tumor DNA fragments. This allows pathologists to detect if tumors are still present at a much earlier stage than what would be possible through traditional radiography. And earlier detection can lead to earlier and more accurate treatment.
Going back to our Genexus System, pathologists are now empowered to conduct genetic sequencing within their own labs in a decentralized model. Again, thinking about how things have traditionally been done in a more centralized approach, if a patient comes into a clinic and a slice of tumor is taken to be sequenced, that sample is sent to a central lab. From there, it can take 7-10 days to get a sample back, so in many advanced cancer cases, the patient would go on some kind of generalized therapy until the sample returns.
Researchers and providers in the oncology community know that NGS is the right thing to do to get the patient on the right treatment, it just takes a long time to get the data. With a Genexus system, however, labs can do the sequencing themselves and get the results between 24-48 hours after the sample is taken. This closer-to-patient testing allows the care team to get the patient onto the best therapy from the beginning without wasting days – or even weeks – waiting for results.
Thermo Fisher is committed to getting this technology into labs to fight this global pandemic, but we believe expanding access to this technology will also help advance science and medicine long after this public health threat is over. Labs may adopt NGS first and foremost to understand COVID, but as these labs bring NGS online for other applications, it will enable them to bring precision medicine to communities where it has never existed previously.
Take, for example, Baylor School, a high school in Chattanooga, Tennessee. Following the lead of two of their scientists, Dr. Dawn Richards and Dr. Elizabeth Forrester, the school built up its scientific lab capabilities with professional-grade equipment for educational purposes over the last few years. In March, when school shut down and students were sent home, they repurposed the school lab to conduct PCR testing to support COVID efforts in their rural county.
Recently, they installed the Genexus System to start sequencing local COVID samples to better understand specific strains in their region. They are the only facility within two hours that has this technology and are naturally thinking about other ways they can continue to use it in a post-COVID world. Dr. Richards and Dr. Forrester have already started talking with their local medical center and oncology practices to see how NGS may be used in these settings, offering extended support for their community beyond their initial COVID focus.
Q. Anything else you’d like to add?
We need more labs at the local level participating in ongoing national and global surveillance of emerging COVID-19 strains. This task is too much for public health labs to take on alone. Through a collaborative approach that includes open data sharing, we can hope to better track and monitor new strains of this virus and how they are moving through our communities.