I’ll begin by stating the obvious: Virtually everything about testing for COVID is an unacceptable mess at the moment in the United States.
With that very clear fact out of the way, I’m going to focus today’s blog post on delivering solutions to the problem. As we all know, America is a capitalist society, and the free markets are designed to ultimately create greater efficiencies than government directives. As such, we must outline the key factors that are currently not allowing for these efficiencies to be achieved and work on solutions to overcome the barriers. The first and most important thing to understand about applying capitalism to this very real public health crisis is that CLIA certified laboratories, rapid test manufacturers, retail suppliers such as CVS/Walgreens and physicians prescribing the tests are all doing so because they make money for their corporations. All initiatives start with the goal of making money by fulfilling a specific need. Only after an organization’s profit model is secured will they look to accommodate other altruistic motivations that end up in the marketing campaigns we all see on TV and social media. The challenge from the outset has been how to seamlessly mesh a societal imperative into an efficient profit model.
A little history regarding COVID testing
Everyone remembers the first quarter of 2020, when getting a test result for COVID-19 was nearly impossible. The issue at that point was very simple: there was no testing capacity. There were virtually no PCR tests approved by the FDA, very few labs outside of large central labs owned by Quest and LabCorp able to run the limited PCR tests that were approved due to lack of equipment and staffing, rapid antigen tests were not even on the FDA’s radar, it was still unclear who was going to pay for those PCR test results and antibody testing held the key promise for giving a good understanding of population-level immunity that could guide local policy based restrictions based on local population immunity levels. Within 6 months by the end of September 2020 several new PCR tests were authorized by FDA, virtually every CLIA lab transitioned into COVID testing because all other testing revenues had dramatically dropped due to stay-at-home orders, the Trump administration guaranteed payments for COVID testing with various programs such as the CARES Act that allocated funds specifically for COVID virus testing and antibody testing was discarded due to the tests at the time focusing on prior infection rather than acquired immunity because it was determined that overall antibody levels had insufficient correlation with protection from re-infection. Despite the testing funding programs’ availability, adoption didn’t take root in schools and other places due to the lack of cohesive plan and instructions on how to implement testing programs. The main issues that remained at the time were:
- Logistics of shipping samples via FedEx and UPS created a major increase in volume through those channels and delays in simply getting samples from the collection site to the lab;
- Automation for smaller decentralized local labs was needed to be able to process the large numbers of samples needed to be able to more closely monitor asymptomatic people who were likely being exposed to the virus;
- Ultra-fast turnaround time (TAT) testing needed for Return to Work and Return to School programs so people could be screened before congregating indoors for normal daily activities;
- Identifying improved ways of tracking immunity, rather than prior infection, as vaccines were readying to come to market.
If we paused at that moment in time and fast-forwarded to today, these exact same problems persist. We also now have new issues that are popping up as most people are returning to normal daily life:
- With new COVID strains circulating that have different biological properties that express themselves differently in people, are we taking samples the right way to maximize sensitivity?
- With multiple COVID strains circulating at the same time that each has different treatment paradigms, should patients and physicians know which variant they have?
- Does the CDC have accurate data regarding how many people actually have COVID, and can we track individuals’ COVID history so that we can fine-tune vaccine recommendations?
From here we need to talk integrated solutions and what can be done both in terms of top-down policy from government and enterprise level systems to address all of the above problems.
Solutions to address our COVID testing misery
Based on our real-world experience, there are clear solutions that could be enacted NOW that would dramatically improve upon the current ‘paradigm’ of COVID testing in the United States. What makes this different from prior testing crises is that we now have better technologies available to us than we did before. We understand all of the problems and the bottlenecks in the testing business. I believe if we are proactive, there will be more money and less headaches for everyone involved. This means patients getting results faster, more robust information shares with the government agencies, breaking the chain of infection to help save lives and livelihoods, and more overall profit for companies.
First and foremost, COVID testing is here to stay. The Biden administration came into office prioritizing vaccines at the expense of testing. The prioritization of getting a robust vaccination campaign was absolutely the right move to increase overall immunity levels in the population and I must commend the current administration for the early success of the vaccine campaign. In doing so, President Biden calculated that the loss of testing infrastructure was a worthwhile sacrifice in order to save the country’s healthcare infrastructure by reducing hospitalizations, especially from those at high risk of bad outcomes such as the elderly and the immune-compromised. And they made this decision because there were not enough resources to focus on both.
With that said, once the vaccine campaign began to slow in the second quarter of 2021 with those at highest risk largely vaccinated, the re-establishment of the country’s COVID testing infrastructure should have been re-prioritized in order to be able to surveil community spread. Given the challenges the country is now experiencing with COVID testing that is the direct result of seasonal holiday demand combined with the Omicron variant that seems to easily overcome most vaccine and infection acquired immunity, I expect that the current administration understands the need to fulfill its campaign promise to fortify testing heading into the 2022 midterm election. With this in mind, COVID testing outfits such as Todos’ CLIA/CAP lab Provista Diagnostics or our COVID testing supplies subsidiary Corona Diagnostics can confidently make strategic investments to meet the cyclical demand that underlies the nature of COVID testing. The administration needs to take concrete actions to increase lab industry confidence.
With this greater certainty of demand now assumed at the corporate level among testing executives, we are now able to address the challenges of giving fast accurate information to patients and healthcare providers. The government needs to implement more comprehensive COVID testing standards in order to guide individual decisions. Below I note the key points we need to focus on to solve our problems:
Rapid antigen tests (RATs) and PCR testing are complementary tests that work together as part of a testing scheme to improve access. RATs were designed to test people who are exhibiting symptoms of COVID-19, and that is where they have the best sensitivity and give the smallest likelihood of a false negative result. They should be used for anyone who has COVID symptoms so they can get fast results and make a rapid decision with regards to isolation. PCR testing is best suited for screening asymptomatic individuals, and to confirm a negative RAT in an individual strongly suspected of COVID-19 despite a negative RAT. Tests should be used for the acute need of testing for an onsite event such as a family gathering; the preferred test to be used is the PCR test because it will identify someone who is asymptomatic and likely contagious much sooner than a rapid antigen test. With all this said, given the relative scarcity of available tests of any kind, especially PCR tests, people are using antigen tests for purposes not initially intended. With this in mind, point of care (POC) or at-home PCR tests provide the ultimate certainty that someone at an event is negative and this should be the method pursued in the medium term until better technologies emerge. If that isn’t possible in the short term, then the next best option is to have two consecutive negative RATs with no known exposure in between to reduce the risk of positivity given that RATs are able to identify asymptomatic individuals in about 50% (pre-Omicron) of cases when used as a single test in the real world. It’s clear that screening people for COVID at the point of care remains one of the biggest challenges with COVID testing today, and it is one of the main reasons Todos is continuing to work with NLC Pharma in developing TolloTest, a 3CL protease test that is a potentially more sensitive than the PCR test with results in under 5 minutes with the same convenience as RATs. One of its biggest advantages is it is designed to evaluate infectivity, and so also could overcome both the failure of qualitative PCR results and RATs, and so is also well-suited for quarantine/isolation release criteria. Given the scarcity and pricing of POC & At-Home PCR tests, RATs are the most in-demand tool right now and we should continue to scale-up their availability while continuing to bring more sensitive tests to market.
- PCR testing needs to be done primarily locally, close to where samples are collected, in order to reduce turnaround time (TAT) and make PCR a more sensitive alternative to RATs. FedEx and UPS are bottlenecks that cost significant time and expense in getting samples to labs in different states, and this can be largely cut out if samples are processed close to where they are collected, including at-home COVID PCR sample collection such as the ones Provista is offering to Atlanta-area customers. By using at-home sample collection for local labs, FedEx and UPS can keep the samples at local hubs and drastically reduce costs and potential shipping delays due to weather or other disruptions. This also has the benefit of improving the local economy with jobs being created in the place where the patients are. This gives an additional incentive for local governments to encourage COVID testing, because local labs will be able to expand their operations into other types of diagnostic testing needed to improve and fortify the local healthcare community while improving their tax base. Rapid TAT is critical to increase the value of the information provided by PCR tests and to make them compelling alternatives to the less sensitive but more accessible RATs. With rapid TAT PCR testing, we give ourselves the best chance at cutting the ever growing chains of infection.
- The local labs in many communities that could support local communities are often owned by individuals who do not have the means to buy the expensive robotics needed to automate/scale PCR testing to be able to conduct the thousands of tests needed every day to keep up with the surges in demand that are inherent in COVID testing. As such, the best way to ensure that CLIA labs are able to acquire the necessary infrastructure needed to meet their communities’ demand is to provide loans to those labs secured by the revenue associated with the contracts that underlie the need for the testing in the first place. The great benefit of doing this is that the robotics used in COVID testing can also be applied to many other types of tests that are needed by local healthcare systems to improve diagnoses and monitoring of disease. Given the recent massive $1 trillion infrastructure package recently signed into lab, the resources needed to improve the overall lab testing infrastructure in the United States should now available, and should be used right now to accelerate the automation of local labs to meet the PCR testing demands of the community.
- With local testing infrastructure in place, surveillance testing when appropriate under circumstances of low positivity rates can be done with PCR pooling, providing the greatest chance to break the chains of infection that lead to mass disruptions to local industries such as healthcare services, schools, hospitality, sports, travel and the workplace so that life can continue without mass disruptions. PCR pooling standards need to be upgraded to keep up with the biology that we are now witnessing, with high viral loads leading to a better ability to pool such as 10 to 1, or 20 to 1. With Omicron producing so much higher viral loads than previous strains, pooling can in fact be highly sensitive. With the current positivity rate of 24%, pooling is not an option, but when rates get to the 2-3% range in the future, it will be important to get pooling established broadly so that surveillance testing can continue uninterrupted in a way that is still profitable for businesses and could ultimately lower the cost per test for payers.
- We have seen that while 63% of the US population is ‘fully vaccinated’ only 33% of those individuals have received booster shots (so nationally only 21% boosted), underscoring the challenges of public health messaging around the need for 3-4 COVID-19 inoculations annually. With Omicron clearly overcoming much of the immunity wall built-up through vaccination, it is becoming critical to reassess our understanding of community immunity within the context of a variant that requires much higher titers of ancestral neutralizing antibodies to improve the likelihood of overcoming SARS-CoV-2 exposure and preventing infection. In order to assess this, we should focus on using the FDA authorized cPAss neutralizing antibody (nAb) test to assess titers in the at-risk, the elderly and immune compromised, because those are the populations that are most likely to take the additional booster shots that will keep them out of the hospital. Given that data out of Israel has shown that Pfizer’s booster shot increases nAb titers for approximately 10 weeks, after which an additional booster will likely be needed, we need to address the glaring lack of tests (variant-specific neutralizing antibody test, we well as T-cell & B-cell tests), that asses immunity so as to be able to provide a clearer picture to public health officials making policy. Israel has now authorized, and begun administering, 4th jabs (the second booster shot) to the immune compromised and individuals over 60. We expect this will ultimately be the same here in the United States given that we have implemented every single vaccine guideline initially adopted in Israel. As such, closely monitoring immunity titers in these individuals is critical to give ‘just in time’ boosters and minimize the potential for immune exhaustion in these key populations that are at highest likelihood of requiring hospitalization that puts strains on our healthcare infrastructure. Additionally, those who have been recently infected, which will be a large swath of the US population in the next few months given the rapid spread of Omicron, should not be required to vaccinate if they have nAb titers equivalent to those who have been vaccinated. The advantage of getting these individuals to monitor their nAb titers is that it will ultimately provide clear quantitative evidence of waning immunity that will drive a larger percentage of the unvaccinated to ultimately get inoculated when needed. The cPass test can be implemented at scale on the same automation platform as PCR testing, with different readers at the end of the process, and thus multiply the value of the infrastructure investment outlined above.
- Despite what CDC Director Dr. Rachel Wallensky recently said, PCR tests are in fact best suited to identify infectiousness with quantitative resulting. The problem Dr. Wallensky outlined is not with the PCR test itself, but with what CDC allows labs to routinely report to patients. PCR tests work by amplifying the amount of virus through amplification cycles. The number of cycles, also known as cycle time values (ct values), is inversely correlated with the quantity of virus sampled. For example someone with a huge amount of virus may only need to amplify the virus 12 times (ct = 12) in order to identify the presence of the virus. Conversely, if someone has very little virus left in their system, then one would need to amplify the amount of virus 30+ times (ct = 30) in order to identify the presence of the virus. There is a significant body of evidence in the published literature that ct value above 30 are generally associated with very low rates of infectiousness, especially when combined with time from initial positive test. At Todos, have confirmed this theory with our TolloTest data that shows high ct values are associated with below-threshold quantities of 3CL protease. As such, if labs are allowed to report ct values, then the PCR test should be used to make quarantine-ending decisions. While some rapid antigen tests also correlate with high ct values and low infectiousness, the limit of detection of antigens varies widely among manufactures, and its lack quantitative values reported makes it very difficult to make distinctions related to infectiousness. RATs are best used for their authorized intended use: symptomatic infection identification and when PCR testing is in short supply to be used in a serial testing scheme to reduce the risk of asymptomatic spread. Ultimately, we think TolloTest will be the best tool, but until the 3CL protease test is in the market, PCR ct values should be used to determine quarantine ending decisions.
- PCR testing also has significant value by using a different type of assay, a SARS-CoV-2 point-mutations variant assay (PCR Variant Kit), to determine the variant lineage of positive COVID samples. While variant monitoring has largely been a public health concern monitoring exercise for the majority of the pandemic, the Omicron variant has dramatically increased the need to understand which variant someone is infected with because while the Regeneron and Eli Lilly antibody treatments work against Delta, only the Vir/GSK monoclonal antibody treatment works against Omicron. As such, physicians need to know which variant a patient is infected with in order to know which treatment to prescribe. The way public health officials are used to identifying the prevalence of variants circulating is through genetic sequencing. Unfortunately, genetic sequencing is a relatively expensive and extremely slow process, which means that a physician may have to wait one week or more to prescribe a treatment. This is not feasible within the context of an aggressively advancing adversary such as COVID-19, and so the next best option is the PCR Variant Kit that is used on positive samples and can give a quick (2 hours or less) answers on the variant lineage of the positive sample so that physicians can make correct treatment decisions. 80%+ of PCR testing lab in the US are able to implement this type of testing very quickly into their workflows, and local centers of excellence could be established to reference positive test samples to on a daily basis in order to take the burden off the individual lab, if needed. Shockingly, the CDC has sent out a notice to all CLIA labs precluding them from telling physicians and/or patients which variant the patient has. This major misstep needs to be corrected immediately in order to empower physicians with the information needed to help them properly treat patients, which is the primary purpose of CLIA labs. As such, I call on the CDC to reverse this guidance and encourage labs to perform PCR variant testing and report the information for patients and physicians so they can make better decisions NOW about patient care AND give the CDC better information on the prevalence of circulating variants given that current data is highly biased by the location samples come from. We recently saw a correction on reported variant prevalence data over the holidays (originally reported 73%, revised down to 59% and most likely still inaccurate) that almost certainly impacted physicians’ treatment decisions based on the false information reported by CDC. Doctors should not have to eyeball or guess which disease their patient has. Just like labs don’t tell a patient they have ‘breast cancer’, they have Her2 positive or EGFR negative cancer, we need this information on SARS-CoV-2 variants because the targeted monoclonal antibody therapies currently authorized for COVID will only work in a personalized way for the variant the patient has. It won’t work 73% as well. It will work or not, and so that decision process by the physician needs to be made with data.
- We have been taught since the beginning of the pandemic that nasopharyngeal samples are the gold standard for sample collection of SARS-CoV-2 specimens. Unfortunately, studies have found while it is sensitive when done properly, nasopharyngeal collection is especially prone to variability because it is extremely uncomfortable and difficult to perform on oneself, or even by trained professionals. While other nasal sampling methods have become more standard, such as nasal mid-turbinate (NMT), it appears that the Omicron variant is much better detected in the oral cavity. As such, we need to establish a new testing paradigm that is a catch-all for the different variants. Oral swabbing, when conducted prior to nasal sampling with the same swab or different swab and then added to the same collection tubes, appears to be the preferred method for detecting Omicron, Delta and the other variants currently circulating. Saliva sample collection also seems to be very sensitive and consistent, although education is needed about eating/drinking before collection. We need to bring greater awareness to the sampling method potential source of false negative tests, and further study the emerging sample collection problem so that we can create new standardized guidelines to maximize test sensitivity. This is of paramount importance to cut the chains of infection.
While still other issues persist, including data transfer from lab to lab, or data gathering at the point of sample collection that has HIPAA implications for data reporting, I believe the issues noted above are the most critical ones to improve the likelihood of catching asymptomatic carriers early in order to break the chains of infections, delivering fast turnaround times that improve the relevance of the highly sensitive PCR test, prioritize RATs where they will add the most value to the national testing infrastructure, and give patients and physicians the information they need to make timely and accurate treatment decision and rationalize the use of scarce monoclonal antibody resources to help the patients who stand to benefit the most.
I thank you for taking the time to read this blog and I hope that public health officials will reflect on what can be implement NOW to improve testing in the United States.