Firstly, could you share the milestones or developments in COVID-19 serology testing capabilities that you and your colleagues at Siemens Healthineers have achieved over the past year?
Siemens Healthineers launched its laboratory-based total antibody test in May 2020, to detect the presence of SARS-CoV-2 total antibodies (including IgM and IgG antibodies) in the blood. Importantly, the test detects antibodies to the SARS-CoV-2 Spike Protein S1 Receptor-Binding Domain (S1RBD), a key protein on the surface of the virus. The selection of the S1RBD is aligned with multiple vaccines that are either available or in development, with the goal of producing protective antibodies. The test has US FDA EUA authorization. In a study published in July 2020, Public Health England evaluated COVID-19 serology tests from major manufacturers, and concluded that the Siemens test was the only one that met both the sensitivity and specificity requirements set out by the UK Medicines and Healthcare products Regulatory Agency (MHRA).1
In July 2020, we launched our SARS-CoV-2 IgG antibody test (COV2G). It was the first COVID-19 serology test authorised by the US FDA with a semi-quantitative claim.2 A semi-quantitative result enables clinicians to gauge the level of IgG antibodies in a patient’s blood and is necessary to establish a level that may be protective.
In November 2020, Siemens Healthineers was the first leading diagnostics company to offer a quantitative SARS-CoV-2 IgG antibody test to measure neutralising antibodies.3 The detection of neutralising antibodies is critical for potential convalescent donor identification as well as determining vaccine efficacy and monitoring post vaccination antibody titers in the future. Studies have indicated that antibodies that target and bind to the S1RBD show strong correlation to neutralisation activity. Our enhanced SARS-CoV-2 IgG antibody test (sCOVG) demonstrated the ability to measure neutralising antibodies, both in internal studies, as well as in external evaluations. A study published by the University of Innsbruck, demonstrated good correlation of sCOVG index values with virus neutralization titers. The test has received US FDA EUA authorisation.
While we are happy with our current achievements, we know there is still much work to be done. The most important question regarding serology testing today, is whether a serology threshold can be established that would indicate protective immunity against SARS-CoV-2 infection. Siemens Healthineers is collaborating with the US CDC on a study that we hope will answer this question.
In the context of serology testing for measuring vaccine response, would different types of serology tests be needed in different situations, for example, for different types of vaccines? In your opinion, is there a particular serology method that has so far proved to be most effective?
Current commercially available SARS-CoV-2 antibody tests have diverse targets, including nucleocapsid (N) protein, whole spike (both S1 and S2 regions), S1 and S1RBD. Most vaccines in use or development published till date include or are based solely on the spike protein.4 For vaccines that are based solely on the spike protein (i.e. all mRNA, protein and carrier-virus-based vaccines), no antibodies to the SARS-CoV-2 nucleocapsid (N) protein are induced and spike/RBD-based antibody tests would be preferred to monitor the vaccine-induced serological response. Some vaccines are based on inactivated whole SARS-CoV-2 virus and induce antibodies to all the viral proteins. In this case, any SARS-CoV-2 antibody test can be used to monitor vaccine response.
The spike protein is responsible for virus recognition of its target cells and the S1RBD is the specific portion of the spike protein that binds to the ACE2 receptor on the target cell. Hence, neutralising antibodies that prevent the virus from infecting its target cells, mostly target the S1RBD. Therefore, we believe that spike/S1RBD-based antibody tests should be used to assess vaccine responses for all SARS-CoV-2 vaccines, as they will provide a result that is more likely to correlate to neutralisation and protection.
For those who are interested in studying the magnitude of the antibody response and its decay over time, a quantitative serology test is required so that the level of antibody can be determined for each sample.
Serology testing is also used for testing for COVID infection. For that purpose, what are the pros and cons of molecular versus serology testing? What are the factors involved in deciding which test to use?
A molecular test (i.e. RT-PCR) amplifies and detect a portion of virus genetic material, usually from a nasal or throat swab and is considered the gold standard for detecting current infection. These tests are highly accurate but are not without limitations. Handling requirements can be stringent. The accuracy of the test depends on appropriate sample collection process, as well as on the effectiveness of lab personnel in handling the sample and managing technical requirements. Importantly, the viral load starts to decrease starting from Week 2/Week 3 of infection, and this is also the time when more severe symptoms may develop.
Antibodies to SARS-CoV-2 become detectable in many patients starting from Week 1 of symptom onset, and most patients have detectable antibodies from Week 2 onwards. Hence, in cases where patients have symptoms suggestive of COVID-19 but PCR is negative, an antibody test may complement PCR as an aid in diagnosis. Results for an antibody test are often available more quickly than for PCR tests, and some tests can be run in point-of-care settings.
Studies support the value of incorporating antibody testing along with molecular testing in the acute setting (patients presenting with signs and symptoms) to enhance detection and support patient triage, especially for patients who present during later infection.
Complementary roles of molecular and serology
With time, viral loads decrease while antibody titers increase.
Is there a difference between serology tests used for determining vaccine efficacy and COVID infection? How would we know if the antibodies detected are from the vaccine response, or because the individual was previously infected?
For someone that has been infected with COVID-19, they develop antibodies to all the viral proteins. The immune response is similar to those who are vaccinated with inactivated whole SARS-CoV-2 virus vaccines. In this case, no available serology test is able to differentiate antibodies produced by vaccination versus natural infection.
Individuals who are vaccinated with the spike protein-based vaccines (i.e. all mRNA, protein and carrier-virus-based vaccines), antibodies to the spike protein are induced. In this scenario, natural infection can be monitored by testing for antibody to the N protein. A spike/S1RBD based serology tests will not be able to differentiate antibodies produced by vaccination versus natural infection.
Ultimately, it should not matter whether an individual obtained antibodies from natural infection or from vaccination. What matters is whether he/she has a sufficient level of antibodies that can protect him/her from future infection.
What is the highest level of accuracy possible in serology tests currently? How do we ensure that the serology tests themselves are as accurate as possible? What is the next step (or ongoing work being done) in improving the accuracy or effectiveness of serology tests?
Many serology assays that came to market initially were of low quality given the initial interest in facilitating an immediate, even if sub-optimal, testing capability during the outset of the pandemic. Increased regulatory expectations have effectively removed low quality assays from authorized lists. The US CDC suggests use of tests with a specificity ≥99.5% to minimize the potential for false-positive results. Assays with very high specificity will be essential to vaccination campaigns, both to identify vulnerable populations as well as assess for a successful response in large populations.
In your view, what is the role of serology testing in guiding COVID-19 public health strategies?
Because many SARS-CoV-2 infections are likely to go undiagnosed, either due to asymptomatic infection or limited testing availability, many public health institutions are conducting regular sero-surveillance studies of their population. This serves to assess the true extent of the pandemic in different regions, monitor the overall level of potential immunity, and assess the effectiveness of different public health measures. Results may inform future public health policy, such as identifying vulnerable populations and vaccine prioritization.
According to the CDC in the U.S., vaccination should be offered to persons regardless of history of prior symptomatic or asymptomatic SARS-CoV-2 infection. However, in a world of scarce vaccine supply, some countries are using or considering antibody testing as a way to prioritise potential vaccine recipients. One example is Lithuania, which prioritised vaccinations to nursing and care home residents who do not have pre-existing antibodies to SARS-CoV-2.5 Another example is France, which decreed that individuals who recovered from SARS-CoV-2 infection should not be vaccinated until at least 3 months after infection and should only receive one vaccine dose.6
Finally, serology testing for SARS-CoV-2 will be beneficial and potentially even necessary in assessment of vaccine effectiveness. Currently, Siemens Healthineers recommends measuring SARS-CoV-2 antibodies in relation to vaccine use to:
- confirm an initial antibody response (approximately 3–4 weeks after each dose), and
- track antibody levels in months 3, 6, and 9 months and annually following vaccination. This timing may be revised as additional data becomes available.
- potentially establish a threshold for protection or immunity.
An automated and scalable serology assay should include key technical features for effective use: measurement of spike/S1RBD IgG antibodies, very high (≥99.5%) specificity and quantitative results.
What challenges do you foresee in rolling out serology testing in the setting of vaccination? What is/could be done to address these challenges?
For SARS-CoV-2 antibody test results to be clinically meaningful, an antibody-defined threshold remains a key need. In different studies, antibody levels in patient sera were determined using various assays and cut-offs. This limits the ability to confidently compare results across studies. Also, in a real-world setting, clinicians would need to track their patients’ antibody concentrations, regardless of the test method or manufacturer used.
Standardisation of assays is a way to allow comparison of results across the different assays and can be accomplished with reference materials that are well characterised. Siemens Healthineers has investigated a novel approach to define which concentration confers neutralisation for different manufacturers’ antigen targets. Siemens Healthineers is currently working with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) to publish concentrations of antibodies specific to each viral protein that confer neutralisation of the virus. This reference material with assigned concentrations of antibody specific to each viral protein will allow manufacturers to refer to standardized values specific to each type of serology assay.
With an international standard established and adopted by manufacturers, clinicians would be positioned to track their patients’ antibody concentrations, regardless of the test method or manufacturer used. This capability is expected to improve patient care by enabling long-term antibody level comparison—clinical information that is important for verifying natural immunity acquired by patient’s infection with the virus, as well as for determining the effectiveness of vaccines.
- Public Health England & University of Oxford. Evaluation of sensitivity and specificity of four commercially available SARS-CoV-2 antibody immunoassays. 31 (2020).
- Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes First Tests that Estimate a Patient’s Antibodies from Past SARS-CoV-2 Infection. FDA https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-tests-estimate-patients-antibodies-past-sars-cov-2 (2020).
- Siemens Healthineers is the First Leading Diagnostics Company Offering a Quantitative COVID-19 Test to Measure Neutralizing Antibodies. https://www.corporate.siemens-healthineers.com/press/releases/covid-19-igg-quantitative.html.
- Zimmer, C., Corum, J. & Wee, S.-L. Coronavirus Vaccine Tracker. The New York Times https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html.
- Lithuania receives third batch of coronavirus vaccine, new deliveries to arrive weekly – LRT. https://www.lrt.lt/en/news-in-english/19/1312330/lithuania-receives-third-batch-of-coronavirus-vaccine-new-deliveries-to-arrive-weekly.
- Une seule dose de vaccin pour les personnes ayant déjà été infectées par le SARS-CoV-2. Haute Autorité de Santé https://www.has-sante.fr/jcms/p_3237456/en/une-seule-dose-de-vaccin-pour-les-personnes-ayant-deja-ete-infectees-par-le-sars-cov-2.