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Principal Investigator: YOW-PIN LIM
Organization: PROTHERA BIOLOGICS, LLC
Fiscal Year: 2024
Award: $987,396
Funding agency: National Institute of Allergy and Infectious Diseases
The primary goal of this proposed research is to develop a rapid point-of-care (POC) test, based on
Inter-alpha inhibitor Proteins (IAIP) levels in blood, that assesses the risk of neonatal sepsis (NS) and/or
necrotizing enterocolitis (NEC) in infants. NS and NEC are associated with high mortality, serious morbidity,
and adverse neuro-developmental outcomes. The currently available biomarkers are not sensitive and specific
enough for early detection of NS and NEC to reliably guide clinical decisions for continuation of antibiotic
treatment in infants whose conventional test results are uninformative. IAIP are found in human plasma at high
concentrations and are rapidly depleted during acute severe infection/systemic inflammation. In the recently
completed SBIR Phase II study, we successfully developed a prototype for a rapid test (RT) that accurately
measures the IAIP level in blood within 15 minutes, with comparable results to a 6-hour laboratory ELISA.
Using the newly developed RT, we confirmed that IAIP level is a sensitive and specific predictive marker for
NS and NEC using blood samples collected from enrolled infants in two quaternary care NICUs. The AUC of
the ROC analysis comparing infants with positive and negative blood cultures was 0.991 and the sensitivity of
96.3% and specificity of 94.6% (p< 0.001). A similar high predictive value of IAIP was observed in infants with
NEC. Overall, the IAIP test has remarkably high positive and negative predictive values in detecting NS (93%
and 98%, respectively) or when NS and NEC are combined (94% and 95%). In this continuation Phase II-B
project, we will further validate the role and utility of this sensitive host-response biomarker in antibiotic
stewardship and compare head-to-head its performance against Procalcitonin (PCT) and C-Reactive Protein
(CRP). We hypothesize that IAIP levels will be significantly reduced in infants with culture proven NS and/or
NEC (Bell’s Stage >2) and IAIP is more sensitive than PCT and CRP in detecting NS and NEC in suspected
infants that are not confirmed by blood culture or radiographs. The IAIP level will remain normal or not be
significantly altered during non-infectious/non-systemic disturbances that generally do not warrant antibiotic
treatment. The IAIP-RT would be useful in reducing exposure to unnecessary long-term, broad-spectrum
antibiotics to these infants. The specific aims are: 1) Process validation and scale-up manufacturing to produce
clinical-grade IAIP-RT batches for implementation of regulatory strategy; 2) Confirm and validate the ROC
characteristics and cut-off value of the IAIP-RT in larger clinical samples of NS and NEC; 3a) Perform a
comparison study of IAIP test head-to-head with PCT and CRP during clinical evaluation of NS and NEC; 3b)
Assess the potential for antibiotic discontinuation in infants with negative blood culture, negative NEC
symptoms AND normal IAIP level and 4) Compare the Natural History of longitudinally collected IAIP levels
with clinical course and outcome. These studies are designed to obtain a robust and fully developed POC
device to measure IAIP levels in infants that is ready for future clinical studies required for FDA approval.
Terms: <21+ years old><Acute><Adult><Adult Human><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Award><Bedside Testings><Biological Markers><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Body part><C-reactive protein><Characteristics><Clinical><Clinical Evaluation><Clinical Research><Clinical Study><Clinical Testing><Cognitive Discrimination><Consumption><Devices><Discrimination><Disease><Disorder><ELISA><Early Diagnosis><Enrollment><Enzyme-Linked Immunosorbent Assay><Evaluation><Event><Excretory function><Exposure to><Future><Goals><Head><Hour><Human><Immune response><Immune system><Immunoassay><Immunological response><Infant><Infection><Laboratories><Lateral><Life><Light><Logistic Regressions><Measurement><Measures><Meta-Analysis><Miscellaneous Antibiotic><Modern Man><Morbidity><Morbidity - disease rate><Natural History><Necrotizing Enterocolitis><Neonatal><Neonatal Intensive Care><Neonatal Intensive Care Units><Neonatology><Newborn Infant Intensive Care><Newborn Intensive Care Units><Observation research><Observation study><Observational Study><Observational research><Outcome><Outcome Study><Pathologic><Performance><Phase><Photoradiation><Physicians><Plasma><Plasma Serum><Predictive Value><Process><Proteins><Proteins, specific or class, C-reactive><Protocol><Protocols documentation><ROC Analyses><ROC Curve><Reagent><Research><Reticuloendothelial System, Serum, Plasma><Risk Assessment><Role><SBIR><SHAP protein><Sampling><Sepsis><Serine Endopeptidase Inhibitors><Serine Protease Inhibitors><Serine Proteinase Antagonists><Serine Proteinase Inhibitors><Severity of illness><Small Business Innovation Research><Small Business Innovation Research Grant><Specificity><Spontaneous intestinal perforation><Symptoms><Test Result><Testing><VLBW><Validation><Very Low Birth Weight Infant><adulthood><bacterial disease treatment><bacterial infectious disease treatment><bio-markers><biologic marker><biomarker><blood infection><blood-based biomarker><blood-based marker><bloodstream infection><calcitonin precursor polyprotein><clinical decision-making><clinical test><commercial scale manufacturing><design><designing><disease diagnosis><disease severity><early detection><enroll><enzyme linked immunoassay><excretion><heavy chain inter-alpha-trypsin inhibitor><high risk infant><host response><immune system response><immunological status><immunoresponse><inter-alpha-inhibitor><inter-alpha-trypsin inhibitor><inter-α-inhibitor><inter-α-trypsin inhibitor><manufacturing ramp-up><manufacturing scale-up><mortality><neonatal ICU><neonatal sepsis><phase 2 study><phase II study><point of care><point of care testing><portability><predictive biomarkers><predictive marker><predictive molecular biomarker><pro-calcitonin><procalcitonin><prospective><protein pi><prototype><rapid assay><rapid test><rapid tests><receiver operating characteristic analyses><receiver operating characteristic curve><research clinical testing><response biomarker><response markers><scale up batch><scale up production><social role><systemic inflammation><systemic inflammatory response><tool><upscale manufacturing><urinary><user-friendly><validations><very low birth weight><vulnerable infant>