Corona Virus Interferon Disruption Test (CVID)
Identification and Companion Diagnostics of High-Risk High Mortality COVID-19 Infections via Corona Virus Interferon Disruption Test (CVID)
IES requests Total RNA isolates or cDNA from confirmed COVID-19 infected patient biofluids to develop a CVID test that could provide confirmation of diagnosis, identify high mortality risk patients and provide immunomodulatory therapeutic insight.
COVID-19 Mortality via “Cytokine Storm Syndrome”
SARS-CoV-2 infection can advance rapidly in certain patients leading to rapid decline and possibly death often due to a profound inflammatory response (i.e. Cytokine Storm Syndrome, CSS) (1). There is currently no defined methods to determine which patients will develop CSS and a lab test that could predict CSS progression would provide clinicians a lab test that can aid in their decision to provide more timely and aggressive treatment and improve patient outcomes. The Coronavirus Interferon Disruption (CVID) test is being developed to address this unmet medical need. Current WHO estimates a 3.7% mortality rate associated with COVID-19 infections, concentrated around patients over the age of 40 and those with preexisting medical conditions such as cardiovascular disease and those with compromised immune systems (2). Increased rates of infection are adversely affected by constraints of medical professionals and life-saving equipment including mechanical ventilators. These pandemic-related limitations due to resource limitations may result in increased mortality rates and therefore further exemplify the rationale for a test that could predict poor outcomes. More effective timely treatments will shorten the treatment times and reduce resource strains most affected by patients spending lengthy periods in the ICU. The proposed CVID test is based upon prior evidence that Coronaviruses produce viral factors that can modify our innate interferon responses that contributes to death in individuals with underlying health conditions. This immune dysregulation has been previously characterized in Coronaviruses by IFN-β, IFN-λ1, and IL-1α, IL-1β, IL-8, which are all regulated by IFNs (3). Hydroxychloroquine has been shown to improve COVID-19 patient outcomes in limited studies(4). The drug is known to reduce excessive interferon production in lupus that indirectly supports the scientific hypothesis that CSS, and in particular the interferons are responsible for severe disease progression (5). The COVID-19 dysregulation is not known and the CVID is intended to define and quantify these SARS-CoV-2 virus-specific changes. The CVID test is anticipated to rapidly provide key metrics to clinicians to provide aggressive treatments to the sickest individuals improving individual survival. Moreover, with limited resources stratifying patients to treatment groups will help conserve strained resources as a result of the expanding pandemic in the US.
The human interferon family direct immune response
The interferons (IFNs) are a complex family of 21 proteins grouped into 3 separate categories based upon their target receptor usage. The largest family is the type I IFNs that include 13 unique IFN-alpha proteins, one beta, one epsilon, one kappa and one omega. The type II IFN is limited to a single IFN-gamma protein while the most recently identified type III IFNs include 3 unique proteins IFN lambda 1, lambda 2 and lambda 3. Expression of the IFN proteins is highly regulated with significant production known to occur following viral infection. Furthermore, IFNs are of the earliest immune responses to infections and are considered the master regulators of cytokines and immunity (6, 7). Genetic studies have indicated that the complex and coordinated patterns of IFN combinations are unique to each viral pathogen with specificity even being observed between two highly similar RSV subtypes (8). IFNs are essential and individuals with impaired IFN may have a dramatic increased frequency for viral infections and increased mortality rates (9, 10). COVID-19 outbreak hospital data from Wuhan, China reveals that high risk mortality patients exhibited “hypercytokine syndrome” distinct from other intensive care unit patients and healthy controls (2, 3, 11).
The Corona Virus Interferon Disruption (CVID) test system for COVID-19 Diagnosis
The CVID test system has been developed in collaboration with FDA scientists to better understand the host immune response to viral infections. The test system is the only complete IFN family quantitative RNA expression test system designed and developed to rapidly detect IFN signatures in clinical sample isolates via previously FDA cleared quantitative polymerase chain reaction (qPCR) platforms, which are currently being used to confirm COVID-19 infections. CVID in parallel to detecting viral RNA provides distinct host response information for earlier and more accurate and definitive diagnosis of viral infection. Additionally, the test can help define the progression of viral response during the natural course of COVID-19 infection from initial, asymptomatic, presentation – progression – recovery or death. Our test provides the only complete look at the interferon controlled host immune response/inflammatory pathways which can contribute to cytokine storm syndrome in non-responding infections like COVID-19.
Proposal for IES collaboration
IES requires clinical collaborators to supply mRNA isolates or downstream synthesized cDNA from confirmed COVID-19 infected patient biofluids in order to quickly develop a CVID test for COVID-19 that could provide confirmation of diagnosis and identify high mortality risk patients. In parallel, we would also recommend the test be conducted with prospective samples as the current diagnosis testing extends to those with mild symptoms, asymptomatic and post-exposure individuals. Both traditional statistical analysis and machine learning methods will be employed to define CVID data providing insight into infectivity, progression, clinical symptoms and survivor CVID patterns over the course of the viral infection and resolution. Our CVID development strategy is comprised of 3 phases spanning a 12-month project period.
Phase 1: Putative CVID Screening Phase 2: CVID Confirmation and Longitudinal Analysis Phase 3: Immunomodulatory interventional guidance
The point of contact and lead scientist for this project is Robert W Figliozzi, Ph.D., IES Life Sciences, Director of Research and Development. Dr. Figliozzi has over eight years of experience in immunology and virology BSL-2 research and development. qPCR design and implementation were a hallmark of his doctoral research in herpes virology. He has been managing collaborative research between IES and UMES/USM for over two years.
Scientific founder Ron Jubin, Ph.D. has 30 years of experience as a virologist developing several drugs and conducting novel research towards the host response to infection. Dr. Jubin will provide key strategic oversight and detailed data review to ensure accurate and timely data-driven decisions are being made to rapidly advance the test to clinical- readiness. Sincerely, Robert W Figliozzi, Ph.D. IES Life Sciences, Inc. Director of Research and Development 410-212-8979 firstname.lastname@example.org
References 1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [published correction appears in Lancet. 2020 Jan 30;:]. Lancet. 2020;395(10223):497–506. doi:10.1016/S0140-6736(20)30183-5 2. WHO, Coronavirus disease 2019 (COVID-19). Situation Report—41.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200301-sitrep-41-covid-19.pdf?sfvrsn=6768306d_2Date: March 1, 2020 3. Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response. Kindler E, Thiel V, Weber F. Adv Virus Res. 2016;96:219-243. doi: 10.1016/bs.aivir.2016.08.006. Epub 2016 Sep 9. Review.PMID: 27712625 4. Gautret, Philippe, et al. "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial." International Journal of Antimicrobial Agents (2020): 105949.Puja Mehta, Daniel F McAuley, Michael Brown, Emilie Sanchez, Rachel S Tattersall, Jessica J Manson, COVID-19: consider cytokine storm syndromes and immunosuppression, The Lancet,2020,ISSN 0140-6736,https://doi.org/10.1016/S0140-6736(20)30628-0. 5. Canadian Hydroxychloroquine Study Group*. "A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus." New England Journal of Medicine 324.3 (1991): 150-154. 6. Karakike E, Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Front Immunol. 2019;10:55. Published 2019 Jan 31. doi:10.3389/fimmu.2019.00055 7. Mesev, E.V., LeDesma, R.A. & Ploss, A. Decoding type I and III interferon signaling during viral infection. Nat Microbiol 4, 914–924 (2019). https://doi.org/10.1038/s41564-019-0421-x 8. Zhao Zha, Felicitas Bucher, Anahita Nejatfard, Tianqing Zheng, Hongkai Zhang, Kyungmoo Yea, Richard A. Lerner. Interferon-γ functions as a master switch. Proceedings of the National Academy of Sciences Aug 2017, 114 (33) E6867-E6874; DOI: 10.1073/pnas.1706915114 9. Hillyer P, et al. 2017. cells. Respiratory syncytial virus infection induces a subset of types I and III interferons in human dendritic cells. Virology. 2017. 504:63-72 10. Dupuis S, et al. 2003. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 33(3):388-91. 11. Ruan, Q., Yang, K., Wang, W. et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-05991-x 12. Sancho-Shimizu V et al. 2011. Inborn errors of anti-viral interferon immunity in humans. CurrOpinVirol. 1(6):487–496.
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