Recommendations for an Effective COVID-19 Testing Strategy:
A White Paper on the Need to Implement
a Large-Scale Serological Analysis for SARS-CoV-2 Antibodies
PlantForm Corporation, Canada
April 20, 2020
Our first priority in the response to the current COVID-19 pandemic should be to minimize deaths due to the disease, but it is also important that we limit the impact of COVID-19 on other health concerns, as well as on broader societal and economic interests. COVID-19 is associated with considerable morbidity in many patients who survive and may result in other patients with acute illnesses or chronic disease being denied access to timely clinical care (such as cancer patients awaiting surgery). The impact of social isolation, stress and job insecurity on mental health is increasing. The disruption of daily activities is prompting rapid societal change, economic uncertainly and upheaval. A significant percentage of the population is unable to work because they are infected, or because they are under quarantine or because they harbour pre-existing health conditions that require them to take special precautions to avoid infection.
Much of this impact can be mitigated by a better understanding of the epidemiology of viral spread and a better ability to identify those who are susceptible to COVID-19, those who are infected, and those who have recovered.
The current difficulties are compounded because there is no cure and there is as yet little inherent immunity in the population (current available data suggests less than 10%).
COVID-19 infection can be transmitted before the infected person displays symptoms (asymptomatic but infectious). Many infected (and infectious) people show few symptoms and will recover without being counted in the clinical caseload (the numbers are not known due to lack of testing among asymptomatic persons for research purposes).
The current management strategy is social distancing to reduce the transmission of the virus in the population and to isolate and quarantine possibly exposed persons. This policy is having a dramatic effect on the global economy and society. It raises the question as to when it is possible to release people back to normal daily activities and workers back to productive employment. The answer to this question can be approached using methods of epidemiology and public health. To conduct the proper studies, we need to have ability to test for current infection and for past infection. We need to ensure that those who have recovered are no longer a risk to others in their environment and have developed immunity to further infection, despite ongoing exposure. An effective response demands that both tests work in synergy.
Testing for current COVID-19 infection to limit the spread of the disease
The ideal test for current infection should have three properties:
First, it needs to be highly sensitive – that is, nearly 100% of those who are infectious need to be identified, both to prevent future transmission and to direct appropriate clinical care. Also, the false positive rate should be low (ideally below 2%).
Second, the turn around time for testing should be as rapid as possible – a matter of hours, not days. This would allow us to identify persons who are non-infectious and release them from 14-day quarantine. We could ensure safe workplaces by admitting only those who have a recent negative test.
Third, the test and the testing process should be large-scale and efficient. We require the capacity to test tens of thousands per day at an acceptable cost.
Consider the ideal circumstance: all people are tested for COVID-19 infection and the results are delivered within four hours. We could then triage people to safely rejoin the workplace or require further clinical evaluation and strict quarantine. We would no longer be required to quarantine people based on suspicion of infection because of a low probability that they are carriers. We would also acquire the data to evaluate the impact of any public health measure in real time. This should be our goal.
At present the prevalence of infected and recovered people is unknown. The decision to exit from lockdown, if driven solely by a decline in the daily number of patients testing positive for virus RNA, carries the risk that secondary waves of transmission will occur and will have further and unnecessary economic consequences.
Testing for past COVID-19 infection as a sign of immunity
The second testing objective is to identify those in the population with a past history of infection. In combination with the first test for infection, the second test for the presence of antibodies to COVID-19 can be used to identify those who are no longer infective. With widespread and sequential testing, this will allow us to identify a reservoir of those in the population who are considered immune and no longer susceptible to infection. Historically, as the number of susceptibles in the population drops to a critical proportion, there is a general decline in the transmission rate. At present, it is unknown what size of reservoir of immunity in a population is necessary to provide widespread protection from COVID-19. The PCR-based test for the presence of active virus is not helpful here as it does not identify recovered patients.
As recovered patients will have developed an immune response to eliminate the virus from their systems, there is a critical need for a diagnostic test to identify the presence of SARS-CoV-2 specific antibodies in serum samples. The development of such a test is complicated because of the nature of the coronavirus family. The key pathogenicity factor is the spike (S) protein, though other surface-expressed proteins may be immunogenic. There is significant sequence homology between proteins for different members of the virus family. There are several other coronaviruses which circulate in the human population that have few or minor symptoms and it is essential that a serological test can discriminate between the common forms. In addition, for a virus with unknown pathology, the nature of the immune response is yet to be fully understood. An antibody-based response (IgM followed by IgG) is observed in the majority of tested subjects. However, there are reports of patients who do not present a robust antibody-based response and may have developed protection through cell-based mechanisms.
A second challenge is introduced as the virus adapts through mutation to the human host. High mutability of the virus across a population may make a specific test obsolete. Indeed, there are reports from the UK where a serology test for SARS-CoV-2 was introduced for home use (similar to a pregnancy test), but has been withdrawn due to unacceptable performance. An unacceptable level of false results (positive and negative) is ascribed to lack of specificity (cross-reaction of the test kit antigen with antibodies against other coronaviruses) or sensitivity (inability to detect very low levels of antibodies, which may be the case either due to a transitory nature of the response, or a consequence of the observed very mild disease severity noted for some subjects).
There is a massive mobilization underway within the scientific community to develop vaccines and therapies for this new virus, but there is also a need to identify the components required for a diagnostic test. There is therefore a powerful argument to dedicate resources to the development of a robust diagnostic kit that is simple enough for self-administration and can be implemented on a massive scale. This critical diagnostic tool would permit a reliable and accurate determination of the number of recovered and immune members of the population of any given country. With this knowledge, epidemiologists can follow the actual transmission patterns of the virus within the population (as opposed to theoretical models) and permit an effective public health-based response to identify changes in incidence and transmission as quickly as possible.
Trouble in testing land, Professor Sir John Bell, GBE, FRS, Regius Professor of Medicine Oxford University, Government Advisor on Life Sciences, University of Oxford website, April 5, 2020
Why it’s too early to start giving out “immunity passports,” Neel V. Patel, MIT Technology Review, April 9, 2020
Prominent scientists have bad news for the White House about coronavirus antibody tests, Elizabeth Cohen, Senior Medical Correspondent, CNN Health, April 15, 2020