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REDS-III ZIKA Virus Research

1.   US natural history cohort of Zika virus RNA positive blood donors: This study, which is being conducted in collaboration with CDC, will enroll up to 130 blood donors found to be RNA positive for the Zika virus by the Roche and Grifols assays (under an FDA Investigational New Drug [IND]) in a cohort in Puerto Rico and continental US. Participants will be followed at regular intervals over 12 months for viral and serological persistence and clinical outcomes through detailed symptom questionnaires of Zika virus infection. The study will: characterize viral and serological markers of early stages of initially asymptomatic Zika virus infection; identify and store blood components and body fluids that can be further studied to characterize the performance of existing and future assays; provide standards for assay development; study the evolution of viral markers; and establish a biorepository of blood, urine, saliva, and semen samples. This study was launched in June of 2016. The duration of detection of ZIKV RNA in each compartment was determined relative to estimated dates of infection (derived from viral load at index donation and RNA doubling time during ramp-up viremia from macaque infection studies). ZIKV RBC associated RNA was detected well beyond clearance in plasma and previous DENV exposure appears to reduce the duration of RNA persistence. Higher rates of incident ZIKV symptoms were observed than previously reported. The persistence of ZIKV RNA in RBCs has unknown implications for blood screening, which currently relies on plasma testing and RBC infectivity studies are in progress. Whole blood testing may be of value to extend detection of acute infection for diagnostics and monitoring of pregnant women and sexual partners. Update: Based on the lack of zika viremic mini pools (as part of the REDS-III “Zika, Chikungunya, and Dengue incidence in Brazilian blood donors” study) since November 2017 and the lack of any such arbovirus epidemic in Latin America (at a time when peak transmission would be occurring), enrollment into this study will cease and an effort to disseminate results will continue over the next year.

2.   Zika, Chikungunya, and Dengue incidence in Brazilian blood donors: This study will calculate the rates of Chikungunya, Dengue, and Zika viremic blood donations in Brazil between April 2016 and June 2018 at the four large, geographically dispersed REDS-III Brazil blood centers using a research-use only assay that is available in the US. This project monitors the rates of viremia in donors which are a reasonable proxy of the rates of viremia in the general population for arbovirus infections. Results from this study will allow transfusion medicine experts and government officials (Brazil and US) to better evaluate which strategies to implement to enhance the safety of the blood supply vis-à-vis these three viruses.

3.   Impact of Zika and Chikungunya viruses acquisition through blood transfusion: This study was initiated in April 2016 as a pilot study, and formally started in February 2017, but discontinued as a result of limited arbovirus activity in Brazil in 2017. The objectives of the study are 1) establish whether Zika virus is transmitted by blood in this Dengue endemic setting; 2) collect data on the relationship between viral burden and the frequency of transfusion-transmitted infection and duration of viral persistence without symptoms; and, 3) assess the frequency and manifestations of clinically apparent disease in infected recipients (which may be less common than in mosquito¬ acquired infections in healthy individuals). Pre- and post-transfusion blood samples will be collected from all transfusion recipients who agree to participate; these samples are tested for the direct presence of Zika, Chikungunya, or Dengue viruses. This information will allow us to identify patients who did not have Zika virus before the transfusion but appear to have acquired the infection after transfusion. For these patients, samples of the blood products they received will be retrieved and tested for the presence of Zika virus. Additionally, their clinical symptoms will be ascertained. The presence of Zika virus in the blood product that was transfused will provide evidence of a possible transfusion transmission and will trigger additional follow-up and ascertainment. Such data are critically needed to help guide donor testing and deferral strategies in endemic and non-endemic settings. Update: Based on the lack of significant arbovirus viremia detected from the mini pool samples collected in November 2017 to January 2018 as part of the “Zika, Chikungunya, and Dengue incidence in Brazilian blood donors” protocol, this study will not restart in 2018.

4.   Zika virus research study in chronically transfused Brazilian patients with sickle cell disease: The purpose of this study is to evaluate the rate of transfusion-transmission and the clinical consequences of Chikungunya, Dengue, and Zika virus infection in this chronically-transfused population. The consequences of Zika and Chikungunya virus infections in patients with sickle cell disease are unknown at this time. Patient enrollment was started but then discontinued in early 2017. Given limited arbovirus activity in Brazil in 2017, it is anticipated that this study will be re-launched in early 2018. Update: In 2017, 135 post-transfusion samples with sufficient volume for ZIKV/CHIKV/DENV testing were sent to the US for testing. Of these, no patients were identified as having any of these infections. Based on the lack of significant arbovirus viremia detected from the mini pool samples collected in November 2017 to January 2018 as part of the “Zika, Chikungunya, and Dengue incidence in Brazilian blood donors” protocol, this study will not restart in 2018.

5.   Characterization of blood transfusion-transmission of Zika virus in macaques: The purpose of this study is to support non-human primate studies designed to understand the transfusion-transmissibility of various blood components and stages of acute infection, as well as the efficacy of pathogen-inactivation technologies to reduce transfusion-transmissibility of Zika virus. Existing data demonstrates that macaques are an excellent surrogate for modeling Zika virus transmission in humans and initial studies have been conducted using serial dilutions of plasma from ZIKV RNA reactive blood donors, in order to determine the minimal infectious dose (MID). We have currently performed dose escalation studies in a total of five animals using two individual human plasma samples and one macaque plasma sample from one of the initial experimentally infected animals. All plasmas were ZIKV RNA reactive and anti-Zika seronegative. For the first human plasma we found the MID equaled an average of 6,000 RNA copies using a total of two animals. The second human plasma was more infectious, with just 200 RNA copies sufficient for infection. The macaque plasma was also more infectious, with 1,000 RNA copies leading to infection.



National Institutes of Health    Department of Health and Human Services