Transfusion transmitted infections and pathogen reduction technology. - Project Summary Transfusion transmitted infections (TTIs) from a blood transfusion pose substantilal risk. Preliminary metagenomic sequencing data of Ugandan blood donors demonstrate donors are infected with numerous viruses (e.g., HIV, HBV, HCV, HSV-2, HHV6, pegivirus, JC polyomavirus, EBV, PARV4, PARB19V, SENV, TTMDV, TTV), malaria and bacterial species. In the United States (US), blood donor deferral and screening are insufficient to protect recipients from emerging infections diseases (EID); a proactive system such as pathogen reduction technology (PRT) is needed. Knowledge gap: There are almost no molecular epidemiologic TTI data from Africa or other areas with many EID, few studies have evaluated transfusion- transmission between paired donors and recipients, or assessed whether PRT can eliminate these TTIs. Hypothesis: Blood donor screening for emerging viral, bacterial and parasitic TTIs using highly sensitive targeted metagenomic sequencing will identify a substantial proportion of TTIs. Additionally, Mirasol PRT can prevent transfusion transmission of >80% of TTIs. Aim 1. Evaluate emerging TTI prevalence and associated demographics and risk factors among (1a) blood donors and (1b) people needing transfusion. Aim 2. Quantify the clinical impact and identify demographic risk factors for transfusion-transmission of a broad range of emerging bacterial, viral and parasitic TTIs among recipients transfused with units that have a matched infection. Aim 3. Assess efficacy of whole blood PRT to reduce a wide-range of emerging TTIs. Approach: We will capitalize on the Mirasol Evaluation for Reductions in Infections Trial (MERIT), a large, randomized, double-blinded, controlled trial evaluating the feasibility and efficacy of Mirasol PRT on fresh whole blood (FWB) to reduce TTIs. The donor samples will be used to determine the prevalence and demographic risk factors associated with emerging TTIs among donors. By combining the donor and recipient transfusion pairs, the TTI rate will be determined, and demographic factors associated with transfusion transmission and clinical consequences of the TTI will be assessed. By incorporating both the intervention and control arms, the efficacy of Mirasol PRT at preventing TTIs will also be determined. Our group has also established a state-of-the-art targeted metagenomics technique for sequencing genetically diverse viruses and recently expanded the technique for simultaneous analysis of all known human blood borne viruses, parasites and even emerging infections such as arboviruses. Reconstructed pathogen genomes from the sequence data can be analyzed for genotyping, transmission inference and quantification of pathogen load. Significance & Impact: Combining metagenomic sequceing and samples from a clinical trial will establish baseline efficacy estimates for pathogen reduction. These data will permit the US to improve the understanding of the risks of TTIs and potential mitigation strategies to ensure safe blood transfusions.
