Genomic sequencing is yielding critical insights into how the SARS-CoV-2 virus mutates, which variants are the most infectious and how it travels from place to place. Yet sequencing is still rare in most countries, and more than a year since the virus made its deadly debut much about it remains a mystery.
Great Britain has emerged as an international leader in the effort to decipher the coronavirus’s genetic code: as of the end of December, British scientists had sequenced 7.4% of the country’s COVID-19 positive samples vs. the U.S.’s 0.3%.
A new government regulation will accelerate the pace of genomic research into the virus and cement the U.K.’s leadership position in the field. As of February 15, all international travelers to Great Britain from so-called “red list” countries are required to quarantine for ten days and undergo a polymerase chain reaction (PCR) test, the gold standard for coronavirus detection, on days two and eight. If the traveler tests positive, the sample must be sent to a government-approved lab for genomic sequencing. The rule was prompted by fears about the introduction of coronavirus variants that might prove resistant to vaccines. (The infamous B.1.1.7 variant, which was first identified in the U.K., does not appear to be vaccine resistant.)
To find out more about the U.K.’s sequencing work, we spoke with Dr. Marco Loddo, PhD, and Prof. Gareth Williams, MBChB, PhD, co-founders of Oncologica, a government-approved provider of COVID-19 testing and genomic sequencing. The pair discussed the company’s COVID testing and SARS-CoV-2 sequencing work to control the spread of the coronavirus.
Q: Oncologica, as its name suggests, is a precision oncology services laboratory, focusing on molecular profiling of cancer patients to enable targeted therapies. How did you get into the COVID-19 testing space?
Dr. Loddo: It has been an interesting transition for us. We founded our company in 2014 with a focus on applying genomic sequencing to identify patients more likely to respond to certain targeted cancer therapies. When the pandemic began, our initial rationale for getting involved with COVID testing was to offer it to vulnerable, immunocompromised cancer patients. Subsequently, we were invited by the British government to take part in its national testing program. Who we are testing has expanded over the past year, and now we’re testing for private companies, educational institutions and others. More recently, we’ve become one of the companies testing international travelers.
The government’s new test-and-sequence program is probably the strongest strategy for protecting the borders from new variants of concern.
Q: Has the TaqPath test been your main tool for COVID testing?
Dr. Loddo: We have been using the TaqPath COVID-19 CE-IVD RT-PCR Kit exclusively. TaqPath’s huge advantage is that it’s a multiplex assay — which means that it targets multiple areas of the SARS-CoV-2 genome, enabling it to detect the presence of the virus even when it’s a mutated version. We’ve found that other company’s tests can struggle, particularly if they’re single- or double-target assays, to pick up some of the new variants. With the TaqPath kit, we’re able to identify all the variants. In fact, part of the new government regulations is that single target RT-PCR tests are no longer allowed for international arrivals; labs must now use a multiplex test that targets at least two genes.
Q: I understand that you haven’t embarked on sequencing yet under the new travel regulations,* but you have been validating the Ion AmpliSeq SARS-CoV-2 Research Panel. Why did you choose it for this work?
Dr. Loddo: In genomic sequencing, there are two parameters, “coverage” and “depth,” which determine the accuracy of the sequencing. The coverage we can achieve with AmpliSeq, compared to other sequencing technologies, gives us more accurate data that we can use to more precisely identify new variants, which was very important to us. On a side note, the minimum coverage requirements set by the government are quite low—50%—while Ampliseq covers more than 99% of the SARS-CoV-2 genome, including all serotypes. It’s really important to quickly link information about new variants to the test and trace program.
Q: Do you anticipate you’ll be testing a lot of samples in coming weeks through the international arrivals program?
Dr. Loddo: Our current capacity is around 30,000-35,000 tests per day. We had consistent volume of between 15,000-17,000 tests per day until a few weeks back, as the lockdown has caused a drop in testing. With the new requirements, we’re expecting an extremely high volume of samples from international arrivals, so we are getting ready to fill up our capacity in the next week or so as we start this program. Scaling testing will involve further infrastructure expansion and automation, which will enable us to process in excess of 35,000 tests per day.
Q: What is the current state of knowledge about the coronavirus variants in the U.K.?
Dr. Loddo: As you know, we had the emergence of the B.1.1.7 variant which spread very rapidly. It’s now by far the most prevalent strain in our country. We have even picked up the new B.1.1.7 cluster with the E484K mutation, a mutation in the spike protein. This is a variant of concern because, particularly when coupled with the 501Y mutation, it is associated with antigenic change and vaccine bypass.
When the B.1.1.7 variant was first characterized last year, it had around 26 mutations. Now we’re picking up between 31 and 36 mutations, so the virus is continually changing. It’s so important to pick up these small mutations, which can make a big difference in terms of antigenic change. These changes in the antigens, the virus’s surface proteins, are concerning because a vaccine may no longer recognize the antigens once they’ve changed, and it’s that recognition of the antigens that triggers the immune response to fight off the virus.
Testing and sequencing must be a global endeavor. That’s the only way we can protect our communities from variants traveling around the world.
Q: Once large numbers of people are vaccinated against the coronavirus, is there still a role for genomic sequencing?
Prof. Williams: As more people are immunized, the selective pressure driving these emerging variants will increase. Natural selection will determine which strains become prevalent in the population, as mutations that increase the virus’s transmissibility or ability to evade immune response are most likely to persist. That’s why sequencing is needed to track these strains as they emerge. And again, it’s really important to have full sequencing coverage because the mutational clusters are distributed along the whole of the coding sequence.
Q: What does the future hold for testing and genomic sequencing as a pandemic containment strategy?
Dr. Loddo: This pandemic has really put testing and sequencing on the map, highlighting the importance of both. We have learned how the variants can come across borders very rapidly, often undetected with asymptomatic individuals. I think testing and sequencing are definitely going to be a part of protecting ourselves from future pandemics— being able to identify not just the pathogen and its variants but also the individuals most at risk using immune analysis.
A Look Ahead
Over the coming year, NGS will play a critical role in enabling immune repertoire profiling to determine vaccine response, assess vaccine efficacy and guide the development of more effective, targeted vaccines. Already, clinical researchers are using NGS to better understand immune response to vaccines and efforts are underway to create a repository for COVID-19 patients’ immune repertoires to advance global research and vaccine discovery efforts.
*Editor’s note: the U.K.’s genomic sequencing requirement began March 1, a week after this interview was conducted.
The TaqPath COVID-19 CE-IVD RT-PCR kit is labeled “For In vitro Diagnostic Use”.
The Ion AmpliSeq SARS-CoV-2 Research Panel is labeled “For Research Use Only. Not for use in diagnostic procedures.”