Biomarker Research and Development for Coronavirus Disease 2019 (COVID-19)
Posted on: 30 December 2020 by chen shanshan
Biomarker Research and Development for Coronavirus Disease 2019 (COVID-19)
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated a fast response from the global scientific community, governmental organizations, the life sciences industry, and healthcare providers. With unprecedented speed, a number of laboratory tests have been developed with the aim to facilitate easy and efficient detection of virus infection, and tests are emerging for the measurements of antibodies for identifying past SARS-CoV-2 infections.
As the pandemic evolves, it is becoming clear that there is a gap between the ambition and the usefulness of these tests. Evidence continues to accumulate on the limitations of the currently available diagnostic and prognostic approaches.
Coronavirus disease 2019 (COVID-19) assays can be distinguished in (1) virus detection assays (nucleic acid and imaging based), (2) immunity assays (serological or immune cell based), and (3) prognostic assays reflecting severity of disease, complications and degree of recovery (miscellaneous biomarker testing).
In particular, serological tests are becoming more relevant as they are able to detect past COVID-19 infections. However, many open questions remain around each test’s specificity and sensitivity, which represents its validity and usefulness in a clinical setting. The value of these tests, as with many other biomarker tests in healthcare and patient management, is one of today’s major challenges.
In addition to SARS-CoV-2 detection and testing of immune response, there is an urgent need to predict which patients will develop specific disease characteristics. Indeed, some individuals develop mild symptoms and others very severe ones for unknown reasons, and patients can differ dramatically in the degree and speed of their response following hospitalization. Recent studies showed how COVID-19 patients with comorbidities, such as hypertension or diabetes mellitus, are more likely to develop a more severe course and progression of the disease. Differences in the immune response or prior coronaviruses infections could also affect the COVID-19 clinical course.
This heterogeneity of manifestations of SARS-CoV-2 infection constitutes one of the greatest challenges in managing the clinical consequences of the pandemic. Biomarker profiles are of vital importance to clinicians when evaluating treatment options, for defining the clinical course, and for close monitoring and support of patients in their disease management and remission trajectory.
Tools should enable population screening and the identification of high-risk patients. Given the large interindividual heterogeneity, this can be achieved using biomarker signatures, composed of multiple analytes. Given their relevance in this context, robust and well-validated biomarkers are crucial to enable effective decision-making.
SARS-COV-2 TESTING: CURRENT SITUATION
SARS-CoV-2 and COVID-19 testing kits are designed to be used in routine laboratories and also at the point-of-care setting, with the ambition of shortening the diagnostic time window and thereby facilitating rapid identification of COVID-19 positive patients and contacts. In order to be effective, these kits must be based on validated biomarkers and biomarker assay formats that yield high sensitivity and specificity results, for instance, to distinguish an infected person from a noninfected one.
SARS-CoV-2 diagnostic tests are based on the detection of the viral genome (eg, reverse transcription polymerase chain reaction (RT-PCR)-based methods, isothermal amplification assays and CRISPR), viral proteins (eg, antigen-based test), or antibodies against the virus (eg, serological test).
Methods based on the viral genome detection, with their large range of applications, high sensitivity, and high sequence specificity, have become a routine and reliable technique for detecting.
To complement the viral genome tests, viral antigen tests have been developed. These tests allow the virus detection early in infection but display limitations on sensitivity and potential cross-reaction with other coronaviruses.
Despite the fact that COVID-19 is a severe pandemic, many governments are leaning toward “mitigation” and “containment” as strategies. The overarching goal is for all countries to control the pandemic by slowing down the transmission and reducing mortality associated with COVID-19. Indeed, in the absence of a vaccine, reaching group immunity is no straightforward path with major ethical considerations as the societal consequences of achieving it are devastating. Mobility and travel restrictions, social distancing, and the use of personal protective equipment have been introduced in order to reduce human-to-human transmission. The use of face masks in particular is enforced widely within the general population, together with hand hygiene.
Stopping the spread of COVID-19 requires finding and testing all suspected cases so that confirmed cases are promptly and effectively isolated and receive appropriate care. It is important that the close contacts of all confirmed cases are rapidly identified, quarantined, and medically monitored for the virus incubation period of up to 14 days.
Next to the need for well-validated and reliable diagnostic tests, this scenario demands high quality and reliable serological tests, measuring the immune responses induced by past and new viral infection, in combination with tests addressing T-cell activity. These assays are important for understanding the prevalence of COVID-19 and whether the development of a humoral immune response to SARS-CoV-2 protects against the disease.
As the World Health Organization (WHO) clearly underlined, “Laboratory tests that detect antibodies to SARS-CoV-2 in people, including rapid immunodiagnostic tests, need further validation to determine their accuracy and reliability” (https://www.who.int/news-room/commentaries/detail/immunity-passports-in-the-context-of-covid-19). Addressing these issues is crucial, as serological assays are critical for the patient care pathway and for the management and surveillance of the virus.
Limitations to the use and development of the tests described above include poor test sensitivity due to sample collection, poorly described reference material, low specificity, and lack of technical validation, and therefore a threat of false disease diagnosis.
Uncertainty in test sensitivity that lead to false-negative cases of COVID-19 likely constitutes a serious threat to the control of the pandemic. Indeed, false negative results are more weighty, because unrecognized infected persons may not be isolated and can infect others . Because of this, some governments require RT-PCR test and quarantine for people who are considered close contacts of positive cases, with additional testing and isolation in case of negative results. Moreover, in presence of a strong epidemiological link to COVID-19 infection, paired serological tests (in the acute and convalescent phase) could support diagnosis.
Testing limitations are likely a result of combining several unknowns such as the lack of understanding of the biology of the disease, in particular its natural history and associated immune response, a relatively low number of samples, and the use of novel laboratory test kits whose quality and accuracy has not been rigorously tested. Furthermore, the lack of rigorous study design and methodology to robustly validate the tests before deployment affects the tests’ reliability and ultimately the correctness of the clinical assessment.
COVID-19 research is still in its early stages, and we need further research worldwide to better face this pandemic. We still need to learn about the biology of the disease and the variable response that patients display in their disease manifestation and recovery. We expect that the process of biomarker discovery and validation will largely guide an accelerated translational strategy to address this global health crisis. A standardized pathway approach toward the biomarker validation process is thus becoming increasingly important. Quality and reproducibility are essential for translating basic findings into concrete clinic interventions and only following this approach is an effective response to the pandemic guaranteed. Significant efforts and resources have been invested in the development of biomarkers for COVID-19 and AMRI urges that research must be of good quality, providing robust, ethical evidence that stands up to scrutiny and can be used to inform policy making. For COVID-19 management, structural use of the relevant research infrastructures is strongly advised, as they play an important role in centralized management of biomarkers R&D pipelines, biobanking, and clinical trials. The collective efforts of AMRI and collaborative actions of the scientific community will create high-quality knowledge that is openly available and will bring a better understanding of SARS-CoV-2, with benefits for all.