Pandemic preparedness requires long-term investments in disease surveillance, diagnostics, therapeutics, and vaccine research.
By Jack Regan, PhD
The United States’ COVID-19 response was ineffective at containing the spread of the virus, leading to high case counts, hospitalizations, and deaths. Beyond basic preparation, planning, education, and leadership, there remains a profound technology gap, posing a risk for the remainder of this pandemic and for the management of the next one. The technology exists to help us better mitigate the risk, but supporting the development and deploying these advancements will require the support of the federal government.
Pandemic preparedness requires long-term investments in disease surveillance, diagnostics, therapeutics, and vaccine research. Diagnostics is an area that has been largely underfunded, despite the repeated and consistent warnings from virologists, microbiologists, epidemiologists, and other public health stakeholders. Years of underfunding diagnostics and inadequate testing policies have left us vulnerable to microbial attack, and SARS-CoV-2 has been just that sort of reckoning. Even though we are not through fighting COVID-19, we must recognize that a similar threat will likely emerge in the not-too-distant future, and we must take steps now to prevent such a catastrophe.
Pandemic Preparedness 101
The lack of financial support for key technologies left the United States and the world vulnerable to a novel pathogen. The grim statistics illustrate the full weight and measure of this failure far beyond budgets and dollars. Every country needs serious investment in pandemic prevention, specifically to support rapid point-of-care tests that are able to quickly detect new pathogens, including variants of SARS-CoV-2. New diagnostic capabilities must provide the most economical, efficient, and effective path forward in global disease management to meet the needed defense and surveillance infrastructure required in this shifting microbial world.
It is also important to note that SARS-CoV-2 will not be the last pathogen to cause a global pandemic. A CDC report summarized that nine new pathogens were introduced or emerged in the U.S. between 2004 and 2016.1 There have been several examples of similar respiratory threats in recent history (e.g. SARS, MERS, and avian influenza H5, H7, and H9 subtypes).2 The rise of SARS-CoV-2 in December 2019 forced China and other countries to lean on lessons learned from previous respiratory viruses. However, one of the key differences in this latest pandemic is the high incidence of asymptomatic spread. The degree to which asymptomatic transmission was so prevalent (59%) was not initially known and played a significant role in the rapid spread of SARS-CoV-2 across the world.3
The end of the COVID-19 pandemic is uncertain. This harsh reality is true despite the historic pace of vaccine development and deployment. Fortunately, there are concrete actions we can take now to improve our defenses against prolonging this pandemic and preventing the next pandemic. The goal herein is to outline some measures that will begin immediately to put humanity in a stronger position to better fight the microbial world when it next attacks.
Pandemic prevention cannot be adequately addressed without some mention of vaccines. While vaccines are a vital part of halting a pandemic, overreliance on a magical shot represents a dangerously incomplete pandemic response strategy, this is because vaccines are only developed against a new pathogen after all other measures have failed and a significant number of deaths have occurred.
Also, it is impossible to accurately predict the unknown (i.e., what pathogen will next cause a high number of deaths). Prior to SARS-CoV-2, avian influenza was viewed as the pathogen most likely to cause the next pandemic, despite the emergence of SARS and MERS. To prepare for this, Anthony Fauci, MD, the Director of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), championed efforts to develop a universal influenza vaccine. Traditional human influenza kills up to 61,000 Americans annually and a newly emergent avian influenza strain would likely kill a similar number to SARS-CoV-2, if not more. As such, the seasonal threat and the threat of a new avian strain more than justifies allocating considerable resources toward developing a universal influenza vaccine to protect against human and avian influenza. Although good progress has been made, this universal vaccine has not yet been approved for widespread use.
The limitations on existing diagnostics and the poor infrastructure supporting them have allowed for the current pandemic to happen. In principle, the successful use of high-quality, rapid diagnostics should greatly increase the chances of halting the spread of a novel pathogen, before it explodes into a pandemic. It is not just the slow turnaround times for diagnostics that is a problem, but also the underutilization and/or lack of multiplex tests, especially for symptomatic patients, that contributes to the difficulty in managing the care of sick individuals. Multiplex testing improves the likelihood of an informative test result, as they screen for not only the most likely pathogen (e.g., SARS-CoV-2 in 2020-21), but also screen for ~ 20 other respiratory pathogens that can cause similar early symptoms. In contrast, a singleplex test that returns a negative result on a symptomatic individual is troubling, as it is unknown as to whether the test returned a false negative for the screened pathogen or if the individual is sick from a different pathogen.
Notably, a negative result on a multiplex test is also troubling, as the result indicates either a false negative result or that the illness could be caused by a novel pathogen, the latter of which is a greater concern. For proper surveillance of newly emerging pathogens, a multiplex test that returns a negative result on a seriously ill person should always be sequenced to determine whether the illness is due to a novel pathogen, a mutation of an existing pathogen, or a false negative due to poor sensitivity. The point here is to highlight how important it is to be able to rapidly respond to a new threat detected via sequencing. The response is not reliant on sequencing, which is slow, expensive, and only done in reference laboratories, but instead to take the information learned from sequencing and develop new PCR tests that can be quickly deployed to clinics and hospitals operating easy-to-use automated systems that are fast, accurate, and affordable.
The Need for Point-Of-Care
Improving the capabilities of reference laboratories alone is not adequate to address our infrastructure needs, especially given their historically slow turnaround times. If a reference lab is processing hundreds of samples a day for a novel virus, then initial containment efforts have failed. The solution should not be to continue to expand the capacity of these reference laboratories to handle tens of thousands of samples daily, but instead, to support the deployment of more point-of-care (POC) tests that can rapidly return actionable results. The faster accurate results are returned at the POC, the better the chances of limiting additional viral spread.
There are a range of technologies for point-of-care testing, however, the majority are antigen based with lower sensitivity. Even the best antigen tests are roughly 80% sensitive for symptomatic and 41% sensitive on asymptomatic patients. Both are inadequate for pandemic prevention.4,5 Cheap and portable tests are not good enough to flatten the curve of new infections. To successfully contain a novel viral pathogen, we need a decentralized testing system, at the point-of-care, with the sensitivity of laboratory-based tests.
Because of this, priority must be given to molecular testing, given its improved sensitivity and specificity over antigen tests. Fortunately, microfluidic advancements have led to the development of PCR-based technologies that are capable of processing samples at the point-of-care. These technologies return results in 45 minutes to 3 hours, which is a dramatic improvement over distant reference laboratories that often take days to return results.6,7
The most valuable change we can make to modernize our point-of-care testing solutions is using “open-access” testing. Open-access PCR machines are microfluidic and draw reagents from bulk reservoirs capable of performing multiple tests utilizing the highly sensitive and specific real-time PCR chemistry. Real-time PCR chemistry is manufactured globally by many vendors who supply these reagents to all laboratories performing molecular analysis. Real-time PCR chemistry is considered a gold standard and can be synthesized at scale quickly and shipped at room temperature to any location that needs new tests. This permits new tests to be shipped to clinical facilities within a 1 to 2 weeks of initial pathogen sequencing compared to the 6 to 8 weeks it takes to configure “closed-access” systems with a new test, as these are generally manufactured in a single plant, which can cause a manufacturing bottleneck. As such, closed-access testing systems cannot be quickly configured to detect a new pathogen at the point-of-care. The difference in time between deploying a new open-access test versus a new closed-access test is massive in regard to having a better chance of successful containment, because as each week of failed containment passes, it generally means that there is exponential growth in new infections, making successful containment nearly impossible. Because of this, continuing to support the status quo for closed access point-of-care systems leaves us in the same vulnerable position for combating the next pandemic.
When it comes to pandemic prevention, only the federal government, which is tasked with protecting the well-being of its citizens, has the responsibility, the money, and the resources to implement meaningful change. During this pandemic the government has admirably spent tens of billions of dollars on testing and vaccine development, but sadly these investments do not address the lack of open-access, point-of-care, multiplex PCR testing solutions in our hospitals and clinics. As such, these massive investments have done little to protect us from the next pathogen capable of causing the next worldwide pandemic.
The likely reason for the lack of government support for open-access technology is due to their unfamiliarity with this technology and its benefits for pandemic prevention. Their unfamiliarity is excusable since open-access technology capable of addressing this infrastructure weakness has just now become commercially available, but is not yet through the FDA EUA process.
Another area where the federal government can make meaningful change is in test reimbursements. The Centers for Medicare and Medicaid Services (CMS) sets test reimbursement rates and the circumstances under which reimbursements should be paid by insurance companies. As such, CMS can greatly increase the frequency of when multiplex PCR tests are used and when negative tests are sent off for sequencing. Modest changes to current CMS policies would greatly improve the frequency and quality of tests run on clinical samples. Also, additional government economic incentives through grants and/or contacts would further spark innovation and additional commercialization to increase access to enhanced testing capabilities. These changes in government strategy and policies will ultimately make testing more widely used, which is critical to guard against future threats.
Tomorrow’s Testing Strategy Today
We need decisive and assertive efforts at the federal level to modernize our disease surveillance capabilities to better combat microbial threats that can cause millions of deaths. This is not just for SARS-CoV-2, but also for avian influenza, anti-microbial resistance (aka superbugs), and disease X. To address our greatest weakness, the government should incentivize diagnostic companies to develop open-access, point-of-care, multiplexed systems. The government should require that these point-of-care molecular testing solutions automatically report de-identified data to surveillance networks to avoid manual reporting logjams and improve real-time disease monitoring. The objective is for automated open-access, multiplexed point-of-care testing solutions to be omnipresent. The CDC and FDA must “stress test” the entire surveillance system via simulation exercises to test our ability to bring new point-of-care testing capability across the country in a sufficient time frame. This will spot weaknesses that need to be fixed to improve our chances of containing the next novel pathogen that has the capability to cause a worldwide pandemic.
ABOUT THE AUTHOR
Jack Regan, PhD, is the CEO and Founder of LexaGene, which has recently commercialized the first ever fully automated open-access, highly multiplexed, point-of-care PCR instrument. The company is currently performing studies to submit to the FDA for point-of-care testing for SARS-CoV-2.
- Illnesses from Mosquito, Tick, and Flea Bites Increasing in the US. CDC VitalSigns. May 1, 2018. https://www.cdc.gov/media/releases/2018/p0501-vs-vector-borne.html
- Influenza Type A Viruses. Centers for Disease Control and Prevention. April 19, 2017. https://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.htm
- JAMA Netw Open. 2021 Jan 4;4(1):e2035057. doi:10.1001/jamanetworkopen.2020.35057
- Ian W. Pray, et. al. Performance of an Antigen-Based Test for Asymptomatic and Symptomatic SARS-CoV-2 Testing at Two University Campuses — Wisconsin, September–October 2020. MMWR. January 1, 2021. https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm695152a3-H.pdf
- Gan, Nectar; Renton, Adam; Fox, Kara; and Clarke-Ezzidio, Harry. The latest on the coronavirus pandemic and vaccines. CNN. December 31, 2020. https://www.cnn.com/world/live-news/coronavirus-pandemic-vaccine-updates-12-31-20/h_1f88b08c1f45c6b04647f27fae73618b
- Quest Diagnostics Media Statement About COVID-19 Testing. Quest Diagnostics. June 6, 2021.https://newsroom.questdiagnostics.com/COVIDTestingUpdates#:~:text=The%20average%20turnaround%20time*%20for,homes)%2C%20and%20presurgical%20patients
- Testing Turnaround Time. Michigan.gov. May 28, 2021. https://www.michigan.gov/coronavirus/0,9753,7-406-98163_98173-545615–,00.html