As diagnostic technology evolves – we will still need answers
Evan Lee, Gerd Michel & David Bell*
As countries around the world start easing lockdown measures, there are many unknowns ahead. Questions about possible recurrence, the feasibility of reaching herd immunity, and the effectiveness of measures that will be implemented across varied settings and geographies loom ahead, but answers won’t be available for weeks or months.
It’s widely recognised that testing will be central to tackling this next phase. We’ve covered the types of tests and the importance of widening the innovation ecosystem to expand the range of organisations (established commercial companies, startups and smaller companies, and academia) in our previous post.
Since then, the science has continued to evolve. While the widely accepted standard for diagnosis relies on a technique called RT-PCR, there may be a role for testing of blood (serology) for a class of antibodies called IgM, as these can start to appear as soon as five days or less after the onset of symptoms, while the presence of actively replicating virus (as detected on RT-PCR), starts to diminish. This could help increase accurate detection of patients who experience delays before they seek medical care for the increasing list of symptoms that are are associated with COVID-19. The original list of three: fever, cough, and shortness of breath now includes chills, shaking with chills, muscle pain, headache, sore throat and loss of taste or smell As symptoms are so varied, there is a risk that people will initially dismiss some as irrelevant and put off seeking care. As the illness resolves, levels of IgM may diminish while IgG antibodies – which are more persistent, will persist and could serve as markers of immunity.
While the potential of serological tests could be critical to navigating the post-lockdown phase successfully, these are proving challenging to develop. A recent review confirms that many of the tests that were rushed to market fall far short of the sensitivity and specificity required to provide the conclusive answers needed. Even as these will continue to evolve and improve in performance and reliability, questions persist regarding whether the presence of detectable antibodies confers functional immunity. For other coronaviruses, such as those that cause the common cold, immunity appears to wane after a year or two – which is why we still catch colds. There simply has not been sufficient time to provide an answer to this question.
As such questions continue to be studied, technical innovation in testing is also continuing, with promising approaches using saliva for diagnosis, or devices that work with a smartphone, under development. There’s also a novel test that offers the possibility of testing the degree of immunity provided by antibodies by measuring the ability of these to actually inhibit viral entry into target cells.
Regulatory authorities are also catching up, working to stay on top of the innovation as tests evolve and more options appear on the market. There have been reports of fraudulent tests being sold on-line . With home testing – there is concern that incorrect technique for self-sampling that requires swabs may lead to false negative results. The current EU CE marking system may not be rigorous enough since test providers can self-validate their productions, and this will not change until May 2022, when new regulations come into force. Fortunately the FDA has tightened scrutiny, now requiring validation data to be submitted within 10 working days for companies applying for Emergency Use Authorization.
While the tests evolve, it’s important to be thinking about how to use the results. These touch both individuals (“have I been infected”, “is it safe to go back to work”), and populations (“are current control measures working”, “has a defined population - workplace, city, region, country – safely reached herd immunity”).
For example – with a home test, what guidance should be in place if the results confirm a diagnosis of COVID-19? Should self-quarantine be automatic? should the healthcare system be informed? Should this be mandated? And what recommendations should there be for management? And as testing for immunity becomes more reliable and available, should immunity passports be issued? And if these are used, would that create a new type of social inequality between those who are presumed safe to move around and those of us who are not? And would a new clandestine market develop, catering for people who would actually pay to get infected so that they can resume their normal lives? There is historical precedent for this approach: variolation, or inoculation with smallpox material, was regularly practised in the 1700s and even earlier,.
For the majority of people who seek testing services outside the home, access to these will be critical, and it will be imperative to provide results promptly, even as the technical state of the art in diagnostic testing continues to evolve. As these events unfold, however, it’s important not to lose opportunities to bring further innovation to the delivery of testing. By now, the “drive-in testing” pioneered in China and South Korea is being introduced more widely. In settings with low levels of car ownership, this won’t be feasible – but our experience in global health has shows that other approaches might work. For example, large cadres of community health workers – non-medical people with basic health training and tools, exist in most low income countries. They have a pivotal role in delivering maternal and child health care, helping communities to combat HIV, and more recently, addressing diabetes, cardiovascular and other non-communicable diseases.
With a point of care test for COVID-19 and proven software platforms to support this, resource-limited countries have a chance to fight COVID-19. Ideas derived from these countries also have applicability in wealthier ones - a partnership between the City of San Francisco and DiMagi to utilise CommCare - a mobile platform that was originally developed in the global health world for regions such as SubSaharan Africa – to support this US city’s efforts in contact tracing. Drones, which have been deployed in countries such as Rwanda to deliver essential medical supplies may also have a role, such as in delivering tests to rural areas in the US.
As the world continues to mobilise and to live with COVID-19, the complexity of the multi-dimensional challenge is increasingly clear: this pandemic cannot be addressed solely through technical innovation – even as the boost to innovation that we’re seeing is perhaps analogous to previous large-scale pushes to innovation, such as the US-Russia space race from the 1960s. Unlike this example though, the technical advances that are being driven by the COVID-19 pandemic will have immediate implications for all of our lives, and that will have to be addressed through a ‘systems’ lens that accounts the economic and sociological impact of the new technology.
 CDC. Coronavirus Disease 2019 (COVID-19) – Symptoms. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Published April 27, 2020. Accessed April 27, 2020.  Whitman JD, Hiatt J, Mowery CT, et al. Test performance evaluation of SARS-CoV-2 serological assays. medRxiv. January 2020:2020.04.25.20074856. doi:10.1101/2020.04.25.20074856  Tyrrell DAJ, Myint SH. Coronaviruses. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 60. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7782/  l’Obs. Un laboratoire français affirme avoir mis au point un test du Covid-19 mesurant le degré d’immunité. L’Obs. https://www.nouvelobs.com/coronavirus-de-wuhan/20200427.OBS28030/coronavirus-un-laboratoire-francais-affirme-avoir-mis-au-point-un-test-mesurant-le-degre-d-immunite.html. Published April 27, 2020. Accessed April 27, 2020.  https://www.fda.gov/consumers/consumer-updates/beware-fraudulent-coronavirus-tests-vaccines-and-treatments  à 06h19 PDR 27 mars 2020. Dépistage du Covid-19 : «J’ai besoin de savoir si je suis contaminée». leparisien.fr. http://www.leparisien.fr/societe/sante/depistage-du-covid-19-j-ai-besoin-de-savoir-si-je-suis-contaminee-27-03-2020-8288862.php. Published March 27, 2020. Accessed April 27, 2020.  https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.html  https://www.sciencedirect.com/topics/immunology-and-microbiology/variolation  https://www.dimagi.com/blog/sf-ucsf-contact-tracing-announcement/  https://www.theguardian.com/global-development/2018/jan/02/rwanda-scheme-saving-blood-drone
Evan Lee is a Geneva-based consultant and an expert in global health policy. He has previously worked for pharmaceutical company Eli Lilly, the Foundation for Innovative New Diagnostics (FIND), Management Sciences for Health and Medicines Sans Frontieres. A medically qualified doctor by training, he has a BA in chemistry and physics from Harvard University, a medical degree from New York University School of Medicine and an MBA from Massachusetts Institute of Technology.
Gerd Michel is a diagnostics expert based in Heidelberg, Germany. Having worked for more than 30 years in the diagnostics industry leading highly successful R&D units he focused on commercial products mainly in infectious diseases. His expertise is both in immunoassay and molecular assay development. He also spent several years in global health at FIND and has been an advisor to a number of international NGOs, e.g. the Wellcome Trust and The Global Health Technology Innovation Fund. He also served on the German National Blood Advisory Board at the Robert Koch Institute.
David Bell is an Australian-born and US-based public health physician, consulting in the development of global health technologies for community and point of care use. He previously led programs in product development and use at the WHO, Foundation for Innovative New Diagnostics (Geneva) and Global Good Fund (USA).