Additional Information

This page describes the REDS III-US Zika study for the purpose of biospecimen requests. Interested parties should contact the Parent Study Contact listed above. Data from the study are separately available from the BioLINCC study page.

Objectives

This study (REDS-III US Zika Natural History Study) used donor NAT screening to identify and enroll asymptomatic ZIKV infected blood donors into a one-year follow-up study. The study design enabled identification of donors early in acute infection (i.e., before or shortly after development of ZIKV-specific immune responses), representing a highly informative population for characterization of laboratory parameters and incidence of clinical findings. We sought to investigate the dynamics of viral and serological markers and clinical symptomatology following acute ZIKV infection in NAT-positive blood donors, and collect comprehensive data on viral persistence in blood compartments and body fluids in DENV-exposed and -naïve donors to estimate time from infection to earliest detection of Zika; time to loss of detectable virus from plasma, red cells and other compartments; and time to emergence and loss of immune response to infection.

Background

Zika virus (ZIKV) is a mosquito-borne arbovirus that can also be transmitted congenitally and through transfusion and sexual contact. It was first identified in the Zika forest in Uganda in the 1950’s. More recently, it spread to Malaysia and Indonesia, then to Micronesia, French Polynesia and, in 2014 to Brazil. Although asymptomatic or mildly symptomatic in most cases, ZIKV can cause Guillain-Barré syndrome and infection during pregnancy has been associated with intrauterine fetal death and congenital Zika syndrome. The goal of this study was to characterize viral persistence and immune responses to Zika infection following acute infection. This information is needed to inform blood donor and diagnostic testing policies and understand the natural history of ZIKV infection. The study was designed to enable development of a comprehensive repository of well-characterized samples to support 1) validation of screening and diagnostic ZIKV assays, 2) studies of host immune responses to ZIKV to inform vaccine development and novel therapeutic approaches, 3) analyses of mechanisms of clearance or persistence and 4) analyses of predictive markers of symptom development

Participants

53 initially asymptomatic blood donors recruited into follow-up study were eligible for enrollment if donating at blood centers participating in our follow-up study (Banco de Sangre de Servicios Mutuos, OneBlood, Vitalant, New York Blood Center or American Red Cross) from April through December 2016, coinciding with a large ZIKV virus epidemic in PR and small autochthonous outbreak in South Florida. Blood donor index donation plasma samples were screened using either the RMS cobas® Zika or Grifols Procleix Zika Virus NAT assays. ZIKV infection in NAT-reactive donors was confirmed by repeat-reactivity on the screening NAT assay, reactivity on a confirmatory RT-PCR assay on index plasma, or ZIKV IgM seroconversion in index or follow-up serum samples; this supplemental testing was conducted as part of the manufacturers’ INDs. ZIKV quantitative viral load (VL) testing (qRT-PCR) was performed on plasma and residual RBC when available, and serological testing for ZIKV (IgM and IgG) and DENV (IgG) were performed on index and follow-up serum at VRI. Eligible participants were consented for follow-up study through a protocol approved by the UCSF Committee for Human Research. Follow-up visits were requested at weeks 1, 3, 6 and months 3, 6, 9, 12 following index NAT-reactive donations.

Design

Fifty-three ZIKV-infected blood donors identified through ZIKV nucleic acid amplification technology (NAT) screening were enrolled into a one year follow-up study, with blood and body fluid samples and detailed symptom data collected at up to seven visits over 1 year after study entry. All sample types were tested for ZIKV RNA by quantitative RT-PCR (qRT-PCR); follow-up plasma, whole blood (WB) and urine were also tested by replicate qualitative TMA NAT testing. Plasma was tested for flavivirus-specific IgM and IgG. Twenty-four were recruited before a detectable immune response (i.e. they were IgM-negative), 26 were positive for zika IgM, 2 had equivocal tests for IgM and 1 had an inconclusive test. Subjects were also tested for dengue IgG at baseline index donation; 38 were positive and 15 were negative. Statistical models were developed of time to emergence and disappearance of zika from the various compartments. Models of time to detection and time to loss of an immune response were developed. ZIKV RNA persistence for each assay/sample type and serum antibody persistence from estimated date of plasma NAT-detectable infection were calculated from follow-up data using survival statistical methods. Further details of study design are provided in the documentation of the public use dataset for this study on the BioLINCC website.

Conclusions

Determinations of viral marker persistence are enhanced by follow-up of pre- and asymptomatic RNA+/Ab- blood donors. We found higher rates of post-donation symptomatic infection than in most previous reports. RBC-associated ZIKV RNA persists for several months following clearance from plasma and body fluids, and replicate highly sensitive NAT testing extends RNA detection in all compartments. WB testing can extend detection of acute infection for diagnostics and monitoring of pregnant women, sexual partners and travellers.

Publications

Stone M, Bakkour S, Lanteri MC, Brambilla D, Simmons G, Bruhn R, Kaidarova Z, Lee TH, Orlando Alsina J, Williamson PC, Galel SA, Pate LL, Linnen JM, Kleinman S, Busch MP; NHLBI Recipient Epidemiology Donor Evaluation Study REDS-III Program. Zika virus RNA and IgM persistence in blood compartments and body fluids: a prospective observational study. Lancet Infect Dis. 2020 Dec;20(12):1446-1456. doi: 10.1016/S1473-3099(19)30708-X. PMID: 32673593; PMCID: PMC10029720.