Even with promising recent news on vaccine development for COVID‑19, it will be some time before vaccines can be delivered to the general population. Thus, testing, tracking, tracing and isolating (TTTI) quickly, massively, and smartly will continue to be essential to prevent future rebounds of infections following lockdowns. Quick suppression of infections requires testing suspected cases and all their contacts to identify in a timely fashion who is infected and isolating those who are; tracking them effectively to make sure they do not spread the disease further; and tracing exhaustively with whom they have been in contact. An overview of available testing technologies has been provided in the OECD policy brief titled Testing for COVID-19: A way to lift confinement restrictions, published in May 2020. Since then, progress has been made in the development of new testing methods and repurposing of existing technologies for COVID‑19 including, among others, rapid antigen tests and other molecular diagnostic techniques (mainly CRISPR1-based tests and RT-LAMP2).

As opposed to RT-PCR, which has been used most widely up to now, new rapid antigen tests can be easily deployed at point-of-care and provide almost immediate results. These features are very useful for improving TTTI strategies but, as described below, rapid antigen tests are less sensitive than RT-PCR, and this can limit their utility in some scenarios. Point-of-care RT-LAMP and CRISPR-based tests are gaining a lot of attention and could become useful complements to the “testing tool box” in the medium term.

This note provides an update to the earlier OECD brief in the light of these recent developments in testing technologies, and discusses implications for more effective containment and mitigation strategies until vaccines become widely available. The main technologies currently available or expected in the short/medium term are described in the next section and summarised in Table 2. The subsequent section discusses testing strategies and the appropriate use of the various technologies to support these.

RT-PCR is a diagnostic technique to detect viral genetic material (viral RNA) in a biological sample after having amplified it to allow for its detection. It is the current reference for detecting presence of the virus in the respiratory tract, i.e. for identifying active infections. This technique has very good sensitivity and specificity, meaning that it is very reliable (see Box 1). However, in some situations positive results can be difficult to interpret (see Box 2). Some more general limitations of this method also complicate its use on a massive scale. First, some essential testing materials (e.g. reagents, nasal swabs, transport media, etc.) are in limited supply. In addition, even if this technique can return results within hours, the logistics of sample collection, transport to a central laboratory, analysis of the sample and return of results cause a long lead time between when a sample is taken and when the results are available and communicated. This can make RT-PCR testing a bottleneck in TTTI strategies, which hinge on identifying and isolating infected people as quickly as possible. Lastly, the relatively high cost of RT-PCR is a constraint in some countries (Carter et al., 2020[1]). For the sake of simplicity, techniques that share the same general characteristics as RT-PCR, in particular transcription-mediated amplification (TMA) and standard RT-LAMP, are not discussed separately. References to RT-PCR below cover these three techniques.

RT-LAMP is a technique similar to conventional RT-PCR tests, with the exception that the nucleic acid amplification occurs at a constant temperature,3 and thus equipment such as expensive thermal cyclers used to regulate sample temperature in RT-PCR are not required.

Until recently, RT-LAMP tests were performed predominantly in full-fledged laboratories and provided an alternative to RT-PCR with similar characteristics, but some point-of-care and near point-of-care test kits using this method have recently been commercialised and approved for use, including several in the EU and the United States.4 These tests report high levels of sensitivity and specificity against RT-PCR (Thompson and Lei, 2020[2]; Dao Thi et al., 2020[3]). It remains to be seen how quickly use of point-of-care RT-LAMP can be scaled up. However, depending on the cost, the technology may prove to be a more viable option for use in the context of, for example, pre-travel testing than antigen testing.

CRISPR-based tests work by identifying a sequence of viral COVID‑19 RNA and cutting apart any nearby single-stranded RNA. These cuts release a separately introduced fluorescent particle in the test solution. When the sample is then hit with a burst of laser light, the released fluorescent particles light up, signalling the presence of the viral genetic material. The current prototypes relying on this technique provide results within 30 minutes, with performance levels comparable with RT-PCR, and could also be performed at point-of-care.

In addition, this technique has another key advantage – it can quantify the amount of virus in a sample. This feature could, for example, help in estimating how contagious a patient is. Molecular tests, on the other hand, amplify the viral genetic material in order to detect it. This, by definition, changes the amount of genetic material present, thus precluding any chance of precisely quantifying how much virus was originally contained in the sample (Fozouni et al., 2020[4]; Ramachandran et al., 2020[5]).

Antigen tests detect another portion of the SARS‑CoV‑2 virus, the protein coat that surrounds the RNA genome. Like molecular tests, antigen tests are intended to detect the viral presence in symptomatic or asymptomatic individuals and are performed on samples obtained from the respiratory tract. The main advantages of rapid antigen tests5 over RT-PCR include their simplicity of utilisation: they can be performed at point-of-care; a simple swab is put in contact with the reagent. They are also much cheaper, from USD 15 to less than USD 50.6 But their main advantage is the rapidity of the result: most produce a result in 15 to 30 minutes, while as mentioned above, RT-PCR requires several hours to be performed, and even more time until results are available because of all the pre- and post-analytical work. Therefore, rapid antigen tests could allow for an increased volume of testing and faster isolation of people who test positive, which would contribute to breaking chains of transmission sooner.

Yet, compared to RT-PCR, these tests also have drawbacks: most rapid antigen tests achieve good specificity compared to RT-PCR but only moderate sensitivity (see Box 3), although these numbers may vary depending on how performance is assessed. This lower sensitivity of rapid antigen tests needs to be qualified by the possible over-sensitivity of RT-PCR with regards to detecting people who are contagious in some scenarios (see Box 2). Indeed, some evaluations of rapid antigen tests report sensitivity close to RT-PCR at high levels of viral concentration (see, for example, Corman et al. (2020[6]) and Public Health England and University of Oxford (2020[7])). This may allow for reliable detection of the most problematic cases for transmission of the virus.

Serologic tests look for the presence of disease-specific antibodies in someone’s biological fluids (usually blood). Such tests determine whether a person has developed antibodies against a given pathogen as a result of exposure or infection. These tests come in many forms: some require complex machines installed in laboratories (e.g. ELISA tests), others use less complex hardware and can be used at point-of-care (rapid tests). Serologic tests play an important role in epidemiology and vaccine development. However, they are not suited for diagnosis of new infections in exposed or symptomatic patients, and as a result, have no role in the implementation of TTTI strategies.

In general, the strengths and limitations of the various testing technologies discussed above mean that the selection of the most appropriate technology should depend on the objectives of the testing strategy, and not the other way around. In practice, there are three main objectives of testing:

  1. 1. The accurate diagnosis of patients to inform decisions in clinical care;

  2. 2. Confirming or disconfirming suspected cases, e.g. because a person shows symptoms or was in contact with a confirmed case, to inform TTTI strategies; and,

  3. 3. Monitoring specific population groups, in which infections are suspected to occur (e.g. nursing homes, companies, schools and universities, geographic areas with suspected clusters, etc.).

None of the testing technologies currently available is suitable in all three scenarios and the different implications in terms of costs and logistical requirements need to be taken into account when deciding which tests to use for what and on whom. Table 3 summarises which tests should be used primarily in each of the three scenarios. Testing technologies can also be combined to achieve the objectives of testing strategies and tests can be repeated to compensate for lower testing accuracy. As explained below, for example, RT-PCR can be used to confirm uncertain results of rapid antigen tests, and repeated rapid antigen tests increase the probability that their results are accurate.

While point-of-care RT-LAMP and CRISPR-based tests may ultimately overcome some of the limitations of RT‑PCR and rapid antigen tests, their development is still ongoing and they are not yet widely available. Also, the logistical implications of using these tests are not clear yet.

RT-PCR tests (and similar molecular tests) remain the reference in this scenario because of their higher sensitivity and specificity. In the medium term, point-of-care RT-LAMP tests and CRISPR-based tests could complement RT-PCR because their performance is very close. In the clinical setting, the objective is to minimise the risk of misdiagnosis and an incorrect management decision, which could have serious adverse consequences for patients. This is particularly important in winter when other respiratory pathogens are circulating. The most reliable test will therefore always be favoured.

This scenario includes confirming or disconfirming infection in people who show symptoms in the outpatient setting (as a first diagnosis step) and people who were in contact with a confirmed case to inform TTTI strategies. RT-PCR tests (and similar molecular tests) are also appropriate for this purpose and, for now, remain the reference in such scenarios. Yet, cost and capacity constraints may limit their suitability for confirming suspected cases, especially when their number is very large. Point-of-care rapid antigen tests constitute a possible alternative here if RT-PCR cannot be used (European Centre for Disease Prevention and Control, 2020[11]).

The utility of point-of-care rapid antigen tests in TTTI strategies derives from increased speed and lower costs, which can outweigh lower sensitivity. Models that have tried to estimate the possible impact of rapid antigen tests (HAS, 2020[9]) suggest that:

  • Lower sensitivity can be compensated by performing a higher number of tests. But assuming a sensitivity of 70% (see Box 3), the number of tests needs to increase by at least 50%.

  • Lower sensitivity can be compensated by getting results faster. The effect of this gain in time will of course depend on the point in time at which the person is being tested after the onset of symptoms (the closer to it, the higher the impact will be), but receiving a result instantly (as opposed to 2 days after taking the test) may reduce the possibility of transmissions by roughly 30%. This means that the main utility of these tests could be for symptomatic patients, shortly after symptom onset, to provide results more quickly and lead to quicker isolation.

In sum, if RT-PCR results cannot be accessed in less than 24 to 48 hours or the number of people to be tested exceeds RT-PCR capacities, point-of-care rapid antigen tests can be used for rapid diagnosis of symptomatic and asymptomatic patients in outpatient settings as a second best option. Given that sensitivity of currently available rapid antigen tests varies widely (see Box 3), it is important to use the best-performing antigen tests.7

Early detection of clusters in some specific population groups will be key when current containment and mitigation measures, including a second round of general population lockdowns in some countries, will start being lifted. This can contribute to preventing yet another round of costly containment measures while a vaccine becomes available in the needed quantities.

For monitoring of specific population groups such as nursing homes, universities, schools, companies, or any population group in which a new cluster of infections is suspected to occur, point-of-care rapid antigen tests constitute the most appropriate tool but may require repeated testing. First, this is because new infections can occur at any time, leading to the random emergence of new clusters, so that tests have to be performed regularly in order to increase chances of detecting them. Second, repeating tests on a regular basis improves testing precision (see Box 4).

Yet, it is important to bear in mind that positive results obtained in such circumstances might still need to be confirmed by RT-PCR. Whenever prevalence is low, a high number of false positives can be a significant problem (see Box 3).

For some purposes, wastewater surveillance can be used for location-specific surveillance of large population groups. It is now convincingly demonstrated that COVID‑19 infected persons shed virus in stool, even before symptoms manifest. Wastewater-based surveillance of nursing homes, companies, campuses, certain neighbourhoods, etc. would detect COVID‑19 appearance and fluctuations over time, possibly offering actionable evidence to guide “reopening” or to initiate more intensive testing.

Rapid antigen tests are increasingly being used in association with air transport, to ensure that only people who have tested negative can travel and as a means of removing or relaxing quarantine requirements on arrival. It should be noted however, that air travel can increase exposure to the virus because physical distancing measures may be difficult to achieve. Taking a flight requires spending time in busy areas of airports, such as security and boarding lines, and in the enclosed space of an airplane close to other passengers for several hours, especially during long-haul flights. It may also involve traveling to and from airports using public transport. While testing can help reduce risk, it cannot eliminate it. Testing must therefore be combined with other precautionary measures before, during and after travel, in order to reduce the likelihood that travellers will spread the virus. This also means that the logistics of a reliable testing strategy for air travel can be complex.

So far, most airlines have been asking passengers to present a negative RT-PCR test taken less than 48 hours prior to flying. Countries have also set testing and isolation requirements for passengers entering their territory, including self-isolation or enforced quarantine for a specified period of time upon arrival. Regardless of the type of testing arrangements that could be designed to improve travel safety, a period of strict isolation on arrival in destination countries could remain necessary to limit the spread of the virus, particularly in countries or regions that have managed to reach very low levels of transmission, as illustrated by the experience of Iceland. When the country reopened its borders on 15 June 2020, the authorities exempted travellers from a two‑week quarantine if they tested negative on arrival. However, cases started rising less than a month later. Three months later the authorities revised their policy and now require two tests – one on arrival, and another five days later, with mandatory quarantine in between.

While the switch to rapid antigen tests looks appealing, in particular because the time between taking the test and the results being available is shortened, testing strategies need to remain cautious. As mentioned, increased speed might not remove the importance of some days of self-isolation when reaching the destination country. In addition, a reliable testing strategy contributing to improved travel safety would require repeated tests some days before travel, with confirmatory RT-PCR for positive results. It would also require that all passengers accept getting tested, that they wait for their results before traveling and do not to travel if results turned out to be positive, going into isolation instead. For those people who do travel, another test is necessary some days after arrival to ensure that they did not contract the virus while in transit. The US Centers for Disease Control and Prevention (CDC) published detailed guidance for testing in the context of air travel in November 2020 (CDC, 2020[12]). The European CDC considers that rapid antigen tests are not suited for screening incoming travellers to prevent virus introduction or reintroduction in regions/countries that have achieved zero or very low levels of transmission. In these situations, only RT-PCR should be used to reduce the risk of false negative results (European Centre for Disease Prevention and Control, 2020[11]).

Massive screening campaigns in the general population may appear to be an appealing strategy to guide containment measures, but the related challenges should not be underestimated and effectiveness remains uncertain.

First, testing millions of people every week, with all the pre- and post-analytical work required, is a complex and labour-intensive task. Second, in terms of capacity and cost, rapid antigen tests are the only workable option at this point for testing at a massive scale of millions of people. Their currently poorer performance discussed above, however, raises challenges. Even if the performance of rapid antigen tests improves over time, the issue of low prevalence in the general population and therefore the high number of false positives will remain a problem (see Box 3). In other words, a considerable proportion (quite plausibly more than half) of all “positive” tests will actually be false positives. This risks undermining the acceptance of the test – especially if, as would be necessary for the strategy to be effective, people with a positive test result are expected to isolate themselves. At scale, this is difficult to handle. This means that many people would face restrictions in their daily lives, including on their ability to work, even if they do not carry the virus. Policymakers need to consider whether public support for such a scenario would be sufficient to make the strategy viable. Mass screening is only effective if people are willing to be tested and if those who are identified as positive isolate quickly, and they may resist doing so especially if they doubt the validity of test results.

Some countries are already piloting population-wide screening (see Box 5) but these initiatives have so far delivered uncertain results, and are proving complex and costly to set up. From a technological standpoint, next-generation sequencing (NGS) might potentially constitute a suitable solution in the future. But this technology is still in development. NGS offers a highly sensitive and specific test modality with the possibility of providing extremely high throughput rates. Some companies and laboratories are developing COVID‑19 testing capacity using NGS that can test up to 10 000 samples at a time with a turnaround time to obtain results in 24 to 48 hours (National Academies of Sciences, Engineering and Medicine, 2020[13]).

References

[1] Carter, L. et al. (2020), “Assay Techniques and Test Development for COVID-19 Diagnosis”, ACS Central Science, Vol. 6/5, pp. 591-605, http://dx.doi.org/10.1021/acscentsci.0c00501.

[12] CDC (2020), Testing and International Air Travel, https://www.cdc.gov/coronavirus/2019-ncov/travelers/testing-air-travel.html.

[8] Cochrane COVID-19 Diagnostic Test Accuracy Group (2020), “Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection”, Cochrane Database of Systematic Reviews, http://dx.doi.org/10.1002/14651858.cd013705.

[6] Corman, V. et al. (2020), “Comparison of seven commercial SARS-CoV-2 rapid Point-of-Care Antigen tests”, medRxiv, http://dx.doi.org/10.1101/2020.11.12.20230292.

[3] Dao Thi, V. et al. (2020), “A colorimetric RT-LAMP assay and LAMP-sequencing for detecting SARS-CoV-2 RNA in clinical samples”, Science Translational Medicine, Vol. 12/556, p. eabc7075, http://dx.doi.org/10.1126/scitranslmed.abc7075.

[11] European Centre for Disease Prevention and Control (2020), Options for the use of rapid antigen tests for COVID-19 in the EU/EEA and the UK., https://www.ecdc.europa.eu/sites/default/files/documents/Options-use-of-rapid-antigen-tests-for-COVID-19_0.pdf.

[4] Fozouni, P. et al. (2020), Direct detection of SARS-CoV-2 using CRISPR-Cas13a and a mobile phone, Cold Spring Harbor Laboratory, http://dx.doi.org/10.1101/2020.09.28.20201947.

[14] Gill, M. and M. Gray (2020), “Mass testing for covid-19 in the UK”, BMJ, p. m4436, http://dx.doi.org/10.1136/bmj.m4436.

[9] HAS (2020), Revue rapide sur les tests de détection antigénique du virus SARS-CoV-2, Haute Autorité de Santé, Paris, https://www.has-sante.fr/upload/docs/application/pdf/2020-10/synthese_tests_antigeniques_vd.pdf (accessed on 10 November 2020).

[15] Holt, E. (2020), “Slovakia to test all adults for SARS-CoV-2”, The Lancet, Vol. 396/10260, pp. 1386-1387, http://dx.doi.org/10.1016/s0140-6736(20)32261-3.

[13] National Academies of Sciences, Engineering and Medicine (2020), Rapid Expert Consultation on Critical Issues in Diagnostic Testing for the COVID-19 Pandemic, https://doi.org/10.17226/25984.

[10] OECD (2020), “Testing for COVID-19: A way to lift confinement restrictions”, OECD Policy Responses to Coronavirus (COVID-19), OECD Publishing, Paris, https://www.oecd.org/coronavirus/policy-responses/testing-for-covid-19-a-way-to-lift-confinement-restrictions-89756248/.

[7] Public Health England and University of Oxford (2020), Rapid evaluation of Lateral Flow Viral Antigen detection devices (LFDs) for mass community testing, University of Oxford, Oxford, England, https://www.ox.ac.uk/sites/files/oxford/media_wysiwyg/UK evaluation_PHE Porton Down University of Oxford_final.pdf (accessed on 17 November 2020).

[5] Ramachandran, A. et al. (2020), “Electric field-driven microfluidics for rapid CRISPR-based diagnostics and its application to detection of SARS-CoV-2”, Proceedings of the National Academy of Sciences, p. 202010254, http://dx.doi.org/10.1073/pnas.2010254117.

[2] Thompson, D. and Y. Lei (2020), “Mini review: Recent progress in RT-LAMP enabled COVID-19 detection”, Sensors and Actuators Reports, Vol. 2/1, p. 100017, http://dx.doi.org/10.1016/j.snr.2020.100017.

[16] WHO (2020), Antigen-detection in the diagnosis of SARS-CoV-2 infection using rapid immunoassays, https://www.who.int/publications/i/item/antigen-detection-in-the-diagnosis-of-sars-cov-2infection-using-rapid-immunoassays.

Contact

Stefano SCARPETTA (✉ stefano.scarpetta@oecd.org)

Mark PEARSON (✉ mark.pearson@oecd.org)

Francesca COLOMBO (✉ francesca.colombo@oecd.org)

Frederico GUANAIS (✉ frederico.guanais@oecd.org)

Guillaume DEDET (✉ guillaume.dedet@oecd.org)

Ruth LOPERT (✉ ruth.lopert@oecd.org)

Martin WENZL (✉ martin.wenzl@oecd.org)

Notes

← 1. Short for “Clustered Regularly Interspaced Short Palindromic Repeats”. See below for more details.

← 2. Short for “Loop-mediated Isothermal Amplification”. See below for more details.

← 3. In conventional RT-PCR, various cycles of heating and cooling of the sample are undertaken.

← 5. There are two types of antigen tests: rapid antigen tests that can be used at point-of-care, and enzyme immunoassays (ELISA), which are performed on automated devices in biology laboratories.

← 6. By comparison, costs of RT-PCR tests vary widely but are generally more than USD 50.

← 7. In its interim guidance on the use of antigen tests, WHO recommends a minimum ≥80% sensitivity and ≥97% specificity compared to RT-PCR. See WHO (2020[17]).

Disclaimer

This paper is published under the responsibility of the Secretary-General of the OECD. The opinions expressed and the arguments employed herein do not necessarily reflect the official views of OECD member countries.

This document, as well as any data and map included herein, are without prejudice to the status of or sovereignty over any territory, to the delimitation of international frontiers and boundaries and to the name of any territory, city or area.

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