Rapid, Point-of-Care, Host Gene Expression Test for Presymptomatic Viral Infection and to Distinguish Bacterial from Viral Illness

Background: When a new viral pathogen emerges, modern molecular techniques such as sequencing can rapidly identify the putative pathogen. However, developing sensitive and specific tests for the emerging pathogen takes considerably longer, as exemplified by the SARS-CoV-2 pandemic. This dangerous diagnostic void between pathogen discovery and widespread test deployment cripples containment efforts, allowing disease to propagate. Rationale: One way to fill this void is to utilize a pathogen-agnostic test that identifies patients with viral infection either when they are acutely ill or when pre-symptomatic. The most advanced solution to that problem lies in measuring the host response - the immunological response to specific pathogens or pathogen classes. Even when pathogen-specific diagnostic tests have been developed, there is a well-documented discrepancy between test sensitivity in a contrived laboratory environment and real-world clinical sensitivity. Tests that combine pathogen detection with host response improve clinical sensitivity to nearly 100%. Furthermore, host response tests that distinguish viral from bacterial infection fill another key diagnostic void that can mitigate the development of antimicrobial resistance, which disproportionately impacts respiratory health. Objective: This proposal will develop two tests measuring host gene expression signatures for viral infection and to distinguish bacterial from viral disease using a fully automated, sample-to-answer, point-of-care (POC) system. Success will equip clinicians and public health officials with a powerful tool to manage these threats. Specific Aim 1: Develop the Integrated Sample Processing (Franklin-ISP) platform to meet requirements for host gene expression-based tests. Specific Aim 2: Develop and validate a host gene expression test on the Franklin-ISP for the detection of viral infection including pre-symptomatic infection. Specific Aim 3: Develop and validate a host gene expression test on the Franklin-ISP for the discrimination of bacterial and viral infection. Specific Aim 4: Engage with the FDA to define the regulatory path for clearance. Study Design: The development and validation of the proposed novel diagnostics will rely on samples from healthy donors or banked samples from individuals with relevant clinical diagnoses. Impact: The proposed research will deliver a first-in-class, sample-to-answer, POC test measuring the host response to viral infection and separately, a test to discriminate bacterial from viral infection. These tests will detect novel, emerging viral diseases before pathogen-specific tests can be developed and widely deployed. In the long term, these host response tests will have unparalleled ability to improve our management of emerging viral diseases and how we manage the globally ubiquitous challenges of antibiotic stewardship in patients with acute respiratory infection. Built to DARPA (Defense Advanced Research Projects Agency) specifications, the proposed system will seamlessly integrate with current testing paradigms in the U.S. military. It has also been designed to work in any standard U.S.-based health system and laboratory environment to facilitate uptake and utilization. Relevance: The proposed products address FY20 PRMRP Topics Areas Emerging Viral Diseases and Respiratory Health. Our focus on the host rather than the pathogen makes these perfectly suited for emerging viral diseases when pathogen-specific diagnostics are unavailable. The first test (PreV) detects the presence of pre-symptomatic viral infection agnostic to the specific viral pathogen. Rapid identification of viral infection in the pre-symptomatic phase creates opportunities to deliver earlier (and thus more effective) therapy including prophylaxis and can guide public health interventions such as contact tracing, isolation, and quarantine. The second test (B/V) will provide diagnostic information currently unavailable to clinicians resulting in more appropriate use of antimicrobials. Consequently, this test offers an opportunity to mitigate the development of antimicrobial resistance, reduce antibiotic-related adverse events, and improve respiratory health. Less