Although the initial U.S diagnostics response to the monkeypox outbreak mirrored early failures of the COVID-19 pandemic, monkeypox testing has quickly scaled up and aided in effectively controlling the disease’s spread. We sat down with a director of a major U.S. lab to understand lessons learned from the COVID-19 pandemic, the launch process for testing monkeypox in his lab, barriers to in-house hospital testing, and more.
• With vaccines and FDA-approved tests already available, the American healthcare infrastructure was more prepared to contain the monkeypox outbreak than SARS-CoV-2
• Open communication and partnerships between labs and the CDC that were forged during the COVID pandemic facilitated the rapid scaling of monkeypox testing
• Supply chain issues persist, however
• The urgency to begin testing led most labs testing monkeypox to adopt the CDC’s monkeypox assay, sometimes with modifications (e.g.,increasing throughput)
• Adopting new assays involves multiple stakeholders and becomes possible once the clinical need for the novel test is established
• Recent relationship-building between reference labs and diagnostics manufacturers in product development has enabled manufacturers to develop products that meet labs’ diverse throughput and turnaround time needs.
• Lack of technical expertise, poor awareness of biosafety measures, and lack of assay standardization remain barriers to in-house hospital testing during outbreaks
How would you characterize the U.S. diagnostic response to the monkeypox outbreak and how does this compare to our COVID-19 response?
Monkeypox was not as challenging as COVID-19. The monkeypox virus was discovered in the 1950s and the first human case was around 1970. Moreover, an FDA-approved vaccine existed for monkeypox before this year’s outbreak. However, until recently, monkeypox was mostly limited to Africa, more specifically centralWest Africa. It was rare in the U.S., with occasional cases due to imported animals or international travel, but now we have ~25,000 confirmed cases in theU.S.
Conversely, SARS-CoV-2 was a novel virus with no vaccines or drugs. We failed in our response because of the novelty of the virus, asymptomatic spread, and lack of interventions. Although the most important component of outbreak response is testing, it took a while to ramp up ourCOVID-19 testing. While our monkeypox testing response was slightly delayed, it was more robust than our COVID-19 response.
What are some of the lessons we were able to learn from the COVID-19 pandemic and implement successfully in our monkeypox response?
Most importantly, a partnership emerged during the COVID-19 pandemic between reference labs, AMCs, and public health departments, including the CDC. This continued partnership gave rise to a coordinated response that we can leverage for future outbreaks and was important for the monkeypox response.
For communication, the CDC is better at disseminating findings than before COVID. This exchange of information also helped manufacturers evaluate whether assays could be performed on their platforms.This was critical because during the COVID-19 pandemic the CDC believed they could perform all testing through their laboratory response network, and we were siloed early on. This prevented other labs from building capacity and delayed development timelines from manufacturers.
Additionally, the COVID-19 pandemic allowed diagnostics manufacturers to scale up production. Big players, such as Roche, spent hundreds of millions of dollars to enhance their manufacturing process and reaped the benefits this summer.
We also started to think about how to deliver healthcare, and innovation accelerated. For example, self-sample specimen collection, where you collect the sample yourself and ship it out to a lab, reducing the need fora healthcare provider to do it for you, helped us better combat the monkeypox outbreak.
What was the decision-making process for your lab to begin testing monkeypox? Were there any specific signs and signals that you look for to begin adopting a new test in-house?
We had ongoing conversations with the CDC as well as internal conversations tracking the emergence and spread of cases in Europe and then the US. Right from the get-go, we received inquiries from state health departments and other public health departments at various levels.
In parallel, we forayed into test development with the CDC. We began shopping around with different vendors to see their versions of the monkeypox assay. And of course, the challenge with running an LDT is that you must have a certain number of positive samples, which were not readily available. We ultimately decided to go with the CDC assay as it was the best option for FDA clearance. We did, however, raise the throughput of that assay by automating pre-analytical extraction.
Additionally, there was an urgency to release the monkeypox assay. This was an unusual case and although we hadn’t even worked out the cost of the test, this was a public emergency and we had to quickly ramp up testing capacity to about 10,000 tests per week.
Who makes the decision to either adopt a certain test or develop a new test?
There are multiple stakeholders – no one person decides.Whatever the disease is, we need to first establish a clinical status for the test. Is there a clinical need? Does it improve patient outcomes? At this point, we’re not even considering profit – the clinical need must be established before the Chief Medical Officer approves.
Once the CMO says it makes sense, we consult with KOLs and peruse available literature. There are also other factors, such as the expected volume, end user of the test, which providers will order the test, or whether it’s primary care or specialties that will use the test. We also look at the complexity of the assay and the technological options available. When the testis ultimately developed and validated in-house, the Science and TechnologyGroup signs off on it before it reaches the Chief Scientific Officer, and he signs off to enable use.
What factors, other than the complexity of assay development, did you consider before choosing the CDC assay? And can you also explain the pros and cons of the CDC orthopox assay?
FDA approval was the assay's biggest advantage. Our policy is to, if possible, have an FDA-approved assay, and given the time sensitivity, it made sense to use this assay. We did, however, modify the pre-analytical workflow to improve the throughput. It also conveniently allowed the CDC to leverage our relationships with healthcare providers. But we did explore many options, and many vendors reached out to us to develop an LDT. We are still considering developing a novel assay with multiplex capabilities including herpes or VZV, but this is dependent on demand.
Going back to COVID-19, we started testing via partnerships with Roche and Hologic; however, they could not guarantee us kits, so we had to develop our own tests. However, I don’t envision this happening in the case of monkeypox. There may be ways to reduce costs and improve turnaround time, but this will depend on the future of this outbreak.
You mentioned that certain diagnostic manufacturers were unable to fulfill your testing needs. What should these manufacturers know from the reference lab perspective to best serve you and work alongside you in an outbreak scenario?
It is challenging to predict future outbreak needs, as you can only prepare for what you know. Nonetheless, I think that communication is paramount and the communication between us and major vendor partners has improved tremendously compared to early COVID. We are now more conscious of their development pipeline, and they seek our input as the end users of the instrumentation.
Additionally, even within our network of labs, not every location has the same kind of throughput or turnaround time needs. We have hospital clients that require a much faster turnaround time but have lower throughput requirements. So our clients have totally different requirements, and this is something we’ve conveyed to vendors when we explore partnership options.I am pleased that we are talking a lot more with vendor partners about pipeline development and they are anxious to hear from us about what kind of assays make sense.
What barriers, other than the lack of commercial kits, do you see to in-house hospital testing? Now that the FDA has enacted an EmergencyUse Authorization (EUA) for the Quest monkeypox assay, what implications do you see this having for commercial assays such as Roche, BD, and Qiagen?
Inevitably, there will be other manufacturers submitting EUA requests. There are smaller companies like Biomeme and larger companies like ThermoFisher which will have developed these assays. But as I mentioned, hospital needs vary. AMCs have molecularly trained personnel and the infrastructure to handle it. You, ideally, want tests that can be performed at point of care for a faster turnaround time; when you have a hospital in the middle of a cornfield, there are different requirements to handle testing. There’s also the issue of the footprint for instruments, the ease of use, and awareness of biosafety practices. We are BSL-2 at a minimum, and often BSL-3, and employees are advised to be vaccinated for monkeypox testing.
Additionally, the limited supply of kits meant that hospitals were sometimes forced to use more than one system. The problem here is that when you do validation or cross-validation, different assays have different limits of detection (LOD). This meant that some samples came up positive on one system but negative on another. The implications of these patient test results confused several medical directors at hospital labs, and we had several conversations trying to explain this difference in LOD between assay systems. So, standardization of assays is a critical barrier to in-house hospital testing.
Do you have any final thoughts for our readers regarding the monkeypox outbreak?
I want to reiterate that our response to the monkeypox outbreak was better than the COVID-19 pandemic and that we are now more capable of mounting a robust response to future outbreaks. By working closely with theCDC, we rapidly ramped up testing to meet demand and we will be able to leverage this infrastructure for future outbreaks. However, to ensure we are fully prepared for future outbreaks, we must strengthen the partnership between the CDC, manufacturers, and diagnostic labs to drive innovation and address key issues, such as the supply chain.