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Principal Investigator: Clifford Lane
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $73,280
Funding agency: National Institute of Allergy and Infectious Diseases
Research in this project is currently focused on six areas. These are: characterization of the survivors of the anthrax attacks of 2001; characterization of emerging respiratory infections including SARS, COVID-19, and influenza; evaluation of experimental vaccines and treatments for Ebola virus; characterizing the long-term sequelae of Ebola virus infection; evaluating experimental therapeutics and biomarkers for COVID-19; characterizing the long-term sequelae of SARS-CoV-2 infection; identifying therapeutic interventions for mpox.
The anthrax study has enrolled a cohort of volunteers who are currently undergoing an extensive diagnostic evaluation.
Despite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID). Clinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Persons with derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation had the highest mortality rate.
A randomized, placebo-controlled trial of aviptadil, a lung-protective neuropeptide, was conducted in 471 hospitalized patients with COVID-19 and hypoxaemic respiratory failure. The median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). Thus, among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes when compared to placebo.
To evaluate the impact of prior Ebola virus infection on subsequent pregnancy outcomes we studied self-reported pregnancy outcomes in two groups: 206 seropositive people who had recovered from Ebola virus disease (seropositive group) and 383 seronegative people who had close contact with people with Ebola (seronegative group). A birth cohort of 105 infants born to 98 mothers in the seropositive group was also followed. There was no evidence of Ebola RNA in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. The odds of an adverse pregnancy outcome were similar between the two groups (OR 1·13, 95% CI 0·71–1·79). Thus, the risks of Ebola virus reactivation in the peripartum and postpartum period and safe pregnancies are entirely possible after recovery from Ebola.
A study of 155 Indonesian children with pneumonias examined the value of a variety of epidemiologic findings, clinical manifestations and laboratory biomarkers to distinguish between bacterial and viral pneumonias. Diarrhea was more frequently reported in bacterial pneumonias while viral infections more frequently occurred during Indonesia’s rainy season (aOR 0.26; 95% CI 0.08–0.90; p = 0.033). Temperature, white blood cell counts, absolute neutrophil count, neutrophil-lymphocyte ratio, C-reactive protein, and procalcitonin were significantly higher in bacterial pneumonias. The combination of CRP and fever had moderate predictive value with sensitivity and specificity of 62.28 and 65.52%, respectively. Thus, combining clinical and laboratory profiles is potentially valuable for discriminating bacterial from viral pediatric community acquired pneumonia and may guide antibiotic use.
Measurements of antibodies to spike and nucleocapsid proteins of SARS-COV-2, plasma levels of nucleocapsid (N) antigen and or viral RNA were made to identify biomarkers predictive of disease progression and/or responses to anti-viral therapy. In a study of 209 individuals enrolled in the ACTIV-2 trials of ambulatory patients with COVID-19, a higher risk of hospitalization/death was seen with unquantifiable versus quantifiable spike Ab (RR= 12.83 [95% CI: 1.76–93.34) and quantifiable vs unquantifiable N Ag (RR, 11.08 [95% CI, 1.52–80.51]). In a separate study, the impact of remdesivir on viral dynamics was determined utilizing stored samples from 642 individuals enrolled in the ACTT-1 randomized placebo-controlled trial of remdesivir in hospitalized patients with COVID-19. Higher baseline plasma RNA levels were associated with poorer clinical outcomes. Decreases in viral RNA and N antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40–2.71) for levels >245 pg/mL vs 1.04 (95% CI, 0.76–1.42) for levels <245 pg/ml. Treatment with remdesivir accelerated the rate of viral RNA and antigen clearance in blood. Thus, absence of spike Ab and presence of plasma N Ag increased the risk of hospitalization/death while reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from remdesivir.
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