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  1. Science & Research (Biologics)

Reducing Threats to the Blood Supply from West Nile Virus, Dengue Virus, and Chikungunya Virus Through Development of Detection Tools and Studies of Genetic Evolution and Pathogenesis

Principal Investigator: Maria Rios, PhD
Office / Division / Lab: OBRR / DETTD / LEP


General Overview

The mission of our research program is to reduce the risk of transmission of West Nile Virus (WNV), dengue virus (DENV), chikungunya virus (CHIKV), and the newly recognized threat Zika virus (ZIKV), through donated blood. This work is important because these viruses together have a substantial public health impact. ZIKV has caused large outbreaks in the Pacific region and the Americas since 2013, causes the Guillain-Barre syndrome and, when infecting pregnant women, birth defects such as microcephaly. Outbreaks of WNV in the U.S. have caused illness in tens of thousands of people, including ~20,000 cases of neurological disease, and >1,800 deaths through 2015. DENV causes 50-100 million cases of disease and tens of thousands of deaths annually worldwide. The first CHIKV outbreak in the Americas began in late 2013 in the Caribbean and quickly spread to South, Central and North American countries, causing >2 million cases by mid-2016. No effective therapies or FDA-licensed vaccines exist for these human infections. ZIKV, CHIKV and DENV are not yet established in the U.S., although small outbreaks have been caused by DENV in Hawaii, Texas and New York, both DENV and CHIKV in Florida, and all three have affected U.S. territories. Infected travelers and inadvertent importation of infected mosquitoes pose a risk, since the transmitting vectors (Aedes mosquitoes) are present in the contiguous U.S.

These viruses frequently cause asymptomatic (silent) infections, during which affected individuals feel well enough to donate blood. Transfusion-transmitted (TT) WNV, DENV and ZIKV have been reported, and TT-CHIKV is suspected to have occurred. Symptomatic infections may include headache, rash, conjunctivitis, joint and muscle pain and fever, and are often mistaken for the common cold; however, they may evolve into serious, fatal diseases.

To address the potential for WNV transmission through transplants and transfusions, FDA collaborated with industry and blood banks to develop new donor screening tests, which were in use by summer 2003 under an FDA-approved research protocol.

In response to the threat of these viruses, our laboratory is 1) preparing standardized virus stocks for evaluation of the accuracy of commercially-developed tests designed to identify these viruses in blood prior to their release for marketing and quality control by FDA; 2) studying the genetic variability of these viruses in order to identify mutants that could escape detection by these tests or interfere with vaccine development; 3) developing and evaluating technologies that enhance the ability of tests to identify the genetic variability of these pathogens in small volumes of specimen; 4) studying how the viruses interact with cellular components of blood, including red blood cells (RBCs) and 5) studying how the viruses cause disease, which might produce new information that could help in the search for new approaches for pathogen inactivation and therapies.

Our regulatory research also includes the development of renewable DNA reference panels to evaluate the accuracy of commercially developed blood donor molecular genotyping kits. These kits are used to enhance matching of RBC units for patients who need frequent transfusions, such as Sickle Cell Disease patients.


Scientific Overview

Our research focuses on understanding human infection with arthropod-borne viruses (arboviruses) relevant to transfusion safety, such as Zika virus (ZIKV), chikungunya virus (CHIKV), Dengue virus (DENV), and West Nile virus (WNV). These viruses present a challenge to the scientific community because these diseases can be fatal but there are no specific therapies or FDA-licensed vaccines available. These viruses are commonly transmitted by mosquitoes; ZIKV, CHIKV and DENV by Aedes sp., and WNV by Culex sp. ZIKV can also be sexually transmitted, and transfusion-transmission has been reported for all but CHIKV, which can be potentially transmitted by that route. Most infections with ZIKV, DENV and WNV, and many with CHIKV, are asymptomatic, despite the presence of viremia.

WNV is endemic in the contiguous U.S. where the blood supply is screened by WNV-NAT. Additionally, local transmissions of CHIKV in Florida, and DENV in Florida, South Texas and New York have occurred. A DENV outbreak occurred in Hawaii in 2015-16, and DENV is endemic to Puerto Rico and other U.S. territories. No locally-transmitted mosquito-borne cases of ZIKV have been reported in the U.S. There is also evidence that arbovirus mutations (CHIKV in Italy and WNV in the U.S.), enabled new variants to spread more efficiently.

Travel and U.S. troop deployment to areas where arboviruses are endemic, have raised concerns that these diseases could be inadvertently imported and spread by mosquitoes already established in the U.S. This threat has prompted development of new blood-screening assays designed to keep the U.S. blood supply safe for transfusions. Reference reagents for those agents assist development and validation of new assays; aid the determination of sensitivity and specificity to meet FDA regulatory requirements for licensure, and ensure consistency of new lots prior to market. A major roadblock is the lack of large volumes of well-characterized viral stocks, which cannot be obtained by direct human sampling.

This research program aims to: 1) produce reference panels needed to promote transfusion safety and update existing standard reagents as needed for FDA testing proficiency and lot-release panels; 2) identify the potential impact of genetic mutations of viruses on the performance of diagnostic and screening assays, and the efficacy of vaccines and therapies under development; 3) investigate the relevance of genetic variation to virus fitness and virulence using in vitro culture systems with human and animal cells; 4) assess potential ways to increase the sensitivity of current assays to improve blood safety; 5) investigate the biological properties and significance of viral association with blood cells (primarily RBCs) and their significance for infection by transfusion; 6) develop technology to enhance detection of arboviruses and predict infection outcomes.

These studies will cover unmet needs such as reference materials to assist the development and licensure of assays, and data to assess the efficacy of blood screening by estimation of residual risks after their implementation, and support decision-making on issues for which clinical evidence is not available, including blood safety, transplantation and vaccines.


Publications

  1. J Mol Diagn 2024 Mar 16 [Epub ahead of print]
    DNA reference reagents for genotyping RH variants.
    Sippert E, Volkova E, Rippee-Brooks M, Denomme GA, Flegel WA, Lee C, Araojo R, Illoh O, Liu Z, Rios M, Collaborative Study Group
  2. Viruses 2023 Oct 31;15(11):2190
    Nanoluciferase reporter Zika viruses as tools for assessing infection kinetics and antibody potency.
    Xu Y, Vertrees D, He Y, Momben-Abolfath S, Li X, Brewah YA, Scott DE, Konduru K, Rios M, Struble EB
  3. Cytokine 2023 Sep;169:156306
    Serotype-associated immune response and network immunoclusters in children and adults during acute Dengue virus infection.
    Henrique Ferreira Sucupira P, Silveira Ferreira M, Santos Coutinho-da-Silva M, Alves Bicalho K, Carolina Campi-Azevedo A, Pedro Brito-de-Sousa J, Peruhype-Magalhães V, Rios M, Konduru K, Teixeira-Carvalho A, Grazziela Alves Coelho-Dos-Reis J, Ribeiro do Valle Antonelli L, Bortolo de Rezende V, Ludolf Ribeiro de Melo F, Couto Garcia C, Carla Silva-Andrade J, Artur da Costa-Rocha I, Alves da Rocha L, Aprigio Silva V, Damasceno Pinto S, Araújo de Melo S, Guimarães Costa A, de Souza Gomes M, Rodrigues Amaral L, Luiz Lima Bertarini P, Cristina da Silva Furtado E, Vieira Pinto da Silva E, Alves Ramos B, Barros Dos Santos É, Nazaré Oliveira Freitas M, Maria Caetano Faria A, Fernando da Costa Vasconcelos P, de Souza Bastos M, Carício Martins L, Assis Martins-Filho O, Sobreira Silva Araújo M
  4. Lett Appl Microbiol 2022 Nov;75(5):1330-5
    A risk assessment model for transfusion transmission of dengue.
    Huang Y, Forshee RA, Fares-Gusmao R, Chancey C, Rios M, Anderson SA, Yang H
  5. Front Immunol 2022 May 31;13:892990
    Serum soluble mediator profiles and networks during acute infection with distinct DENV serotypes.
    Coutinho-da-Silva MS, Sucupira PHF, Bicalho KA, Campi-Azevedo AC, Brito-de-Sousa JP, Peruhype-Magalhães V, Rios M, Teixeira-Carvalho A, Coelho-Dos-Reis JGA, Antonelli LRDV, de Rezende VB, de Melo FLR, Garcia CC, Silva-Andrade JC, da Costa-Rocha IA, Bastos MS, da Rocha LA, Silva VA, Ferreira EDS, Marinho EPM, Costa AG, Gomes MS, Amaral LR, Furtado ECDS, da Silva EVP, Ramos BA, Dos Santos EB, Freitas MNO, Vasconcelos PFDC, Martins-Filho OA, Araujo MSS, Ferreira MS, Martins LC
  6. J Mol Diagn 2020 Oct;22(10):1272-9
    ACKR1 alleles at 5.6 kb in a well-characterized renewable FDA reference panel for standardization of blood group genotyping.
    Srivastava K, Khil PP, Sippert E, Volkova E, Dekker JP, Rios M, Flegel WA
  7. Am J Trop Med Hyg 2020 Apr;102(4):880-3
    Genomic and phylogenetic analysis of Zika virus isolates from asymptomatic blood donors in 2016.
    Assis F, Sippert E, Rocha B, Volkova E, Fares-Gusmao R, Ok S, Chancey C, Rios M
  8. Antiviral Res 2020 Feb;174:104670
    GloPID-R report on chikungunya, o'nyong-nyong and Mayaro virus, part 5: entomological aspects.
    Pezzi L, Diallo M, Rosa-Freitas MG, Vega-Rua A, Ng LFP, Boyer S, Drexler JF, Vasilakis N, Lourenco-de-Oliveira R, Weaver SC, Kohl A, de Lamballerie X, Failloux AB, GloPID-R chikungunya, o'nyong-nyong and Mayaro virus Working Group
  9. Viruses 2020 Jan 3;12(1):61
    Novel approach for insertion of heterologous sequences into full-length ZIKV genome results in superior level of gene expression and insert stability.
    Volkova E, Tsetsarkin KA, Sippert E, Assis F, Liu G, Rios M, Pletnev AG
  10. Antiviral Res 2019 Dec;172:104611
    GloPID-R report on chikungunya, o'nyong-nyong and Mayaro virus, part 2: epidemiological distribution of o'nyong-nyong virus.
    Pezzi L, LaBeaud AD, Reusken CB, Drexler JF, Vasilakis N, Diallo M, Simon F, Jaenisch T, Gallian P, Sall A, Failloux AB, Weaver SC, de Lamballerie X, GloPID-R chikungunya, o'nyong-nyong and Mayaro virus Working Group
  11. J Mol Diagn 2019 Nov;21(6):1025-33
    A Zika reference panel for molecular-based diagnostic devices as a US Food and Drug Administration response tool to a public health emergency.
    Garcia M, Fares-Gusmao R, Sapsford K, Chancey C, Grinev A, Lovell S, Scherf U, Rios M
  12. Viruses 2019 Nov 14;11(11):1058
    Use of monocyte-derived macrophage culture increases Zika virus isolation rate from human plasma.
    Sippert E, Rocha BC, Assis FL, Ok S, Rios M
  13. Sci Rep 2019 Nov 20;9(1):17172
    Differential pattern of soluble immune markers in asymptomatic Dengue, West Nile and Zika virus infections.
    Fares-Gusmao R, Rocha BC, Sippert E, Lanteri MC, Anez G, Rios M
  14. Transfusion 2019 Sep;59(9):3039-40
    New RHCE*ce variant allele in African descent holds 105C > T (silent) in cis to 48C in Exon 1 and 733G in Exon 5.
    Sippert E, Volkova E, Denomme GA, Liu M, Liu Z, Rios M
  15. Antiviral Res 2019 Jun;166:66-81
    GloPID-R report on Chikungunya, O'nyong-nyong and Mayaro virus, part I: biological diagnostics.
    Pezzi L, Reusken CB, Weaver SC, Drexler JF, Busch M, LaBeaud AD, Diamond MS, Vasilakis N, Drebot MA, Siqueira AM, Ribeiro GS, Kohl A, Lecuit M, Ng LFP, Gallian P, de Lamballerie X, Boyer S, Brasil P, Diallo M, Failloux AB, Jaenisch T, Lourenco-de-Oliveira R, Neyts J, Rios M, Rodriguez-Morales AJ, Rosa-Freitas MG, Sall A, Simmons G, Simon F, Vega Rua A
  16. J Mol Diagn 2019 May;21(3):525-37
    Validated reference panel from renewable source of genomic DNA available for standardization of blood group genotyping.
    Volkova E, Sippert E, Liu M, Mercado T, Denomme GA, Illoh O, Liu Z, Rios M, Collaborative Study Group
  17. Transfusion 2018 Sep;58(9):2171-4
    Production and characterization of Zika virus RNA reference reagents as a response to a public health emergency.
    Fares-Gusmao R, Chancey C, Volkova E, Grinev A, Sippert E, Jiang Z, Rios M
  18. Genome Announc 2018 Jul 5;6(27):e00572-18
    Complete genome sequences of Zika virus strains used for the formulation of CBER/FDA RNA reference reagents and lot release panels for nucleic acid technology testing.
    Volkova E, Grinev A, Fares-Gusmao R, Chancey C, Rios M
  19. PLoS Negl Trop Dis 2018 Jun 7;12(6):e0006462
    Multi-parameter approach to evaluate the timing of memory status after 17DD-YF primary vaccination.
    Costa-Pereira C, Campi-Azevedo AC, Coelho-Dos-Reis JG, Peruhype-Magalhaes V, Araujo MSS, do Vale Antonelli LR, Fonseca CT, Lemos JA, Malaquias LCC, de Souza Gomes M, Rodrigues Amaral L, Rios M, Chancey C, Persi HR, Pereira JM, de Sousa Maia ML, Freire MDS, Martins RM, Homma A, Simoes M, Yamamura AY, Farias RHG, Romano APM, Domingues CM, Tauil PL, Vasconcelos PFC, Caldas IR, Camacho LA, Teixeira-Carvalho A, Martins-Filho OA
  20. J Immunol Methods 2017 Sep;448:9-20
    Heparin removal by ecteola-cellulose pre-treatment enables the use of plasma samples for accurate measurement of anti-Yellow fever virus neutralizing antibodies.
    Campi-Azevedo AC, Peruhype-Magalhães V, Coelho-Dos-Reis JG, Costa-Pereira C, Yamamura AY, de Lima SMB, Simões M, Nunes FFC, de Castro Zacche Tonini A, Lemos EM, Brum RC, de Noronha TG, da Silva Freire M, de Lourdes Sousa Maia M, Camacho LAB, Rios M, Chancey C, Romano A, Domingues CM, Teixeira-Carvalho A, Martins-Filho OA, Collaborative Group for Studies of Yellow Fever Vaccine
  21. Transfusion 2017 Aug;57(8):1977-87
    Collaborative study to establish World Health Organization international reference reagents for dengue virus types 1 to 4 RNA for use in nucleic acid testing.
    Anez G, Volkova E, Jiang Z, Heisey DAR, Chancey C, Fares RCG, Rios M, Collaborative Study Group
  22. J Mol Diagn 2017 Jul;19(4):549-60
    Highly multiplex real-time PCR-based screening for blood-borne pathogens on an OpenArray platform.
    Grigorenko E, Fisher C, Patel S, Winkelman V, Williamson P, Chancey C, Anez G, Rios M, Majam V, Kumar S, Duncan R
  23. Antiviral Res 2017 May;141:19-28
    Strategies for serum chemokine/cytokine assessment as biomarkers of therapeutic response in HCV patients as a prototype to monitor immunotherapy of infectious diseases.
    Menezes EG, Coelho-Dos-Reis JG, Cardoso LM, Lopes-Ribeiro A, Jonathan-Goncalves J, Porto Goncalves MT, Cambraia RD, Soares EB, Silva LD, Peruhype-Magalhaes V, Rios M, Chancey C, Teixeira-Carvalho A, Martins-Filho OA, Teixeira R
  24. Transfusion 2017 Mar;57(3pt2):734-47
    Relative analytical sensitivity of donor nucleic acid amplification technology screening and diagnostic real-time polymerase chain reaction assays for detection of Zika virus RNA.
    Stone M, Lanteri MC, Bakkour S, Deng X, Galel SA, Linnen JM, Munoz-Jordán JL, Lanciotti RS, Rios M, Gallian P, Musso D, Levi JE, Sabino EC, Coffey LL, Busch MP
  25. Transfusion 2017 Mar;57(3pt2):748-61
    Harmonization of nucleic acid testing for Zika virus: development of the 1st World Health Organization International Standard.
    Baylis SA, Hanschmann KO, Schnierle BS, Trosemeier JH, Blumel J, Zika Virus Collaborative Study Group
  26. Emerg Infect Dis 2017 Jan;23(1):115-8
    Meningitis associated with simultaneous infection by multiple dengue virus serotypes in children, Brazil.
    Marinho PE, Bretas de Oliveira D, Candiani TM, Crispim AP, Alvarenga PP, Castro FC, Abrahão JS, Rios M, Coimbra RS, Kroon EG
  27. J Virol Methods 2017 Jan;239:17-25
    Development of a microarray-based assay for rapid detection and monitoring of genetic variants of West Nile virus circulating in the United States.
    Grinev A, Chancey C, Volkova E, Chizhikov v, Rios M
  28. PLoS Negl Trop Dis 2016 May 16;10(5):e0004717
    Genetic variability of West Nile virus in U.S. blood donors from the 2012 epidemic season.
    Grinev A, Chancey C, Volkova E, Anez G, Heisey DA, Winkelman V, Foster GA, Williamson P, Stramer SL, Rios M
  29. J Appl Microbiol 2016 Apr;120(4):1119-29
    Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens.
    Dong M, Fisher C, Anez G, Rios M, Nakhasi HL, Hobson JP, Beanan M, Hockman D, Grigorenko E, Duncan R
  30. J Womens Health 2016 Mar;25(3):222-34
    The Food and Drug Administration Office of Women's Health: impact of science on regulatory policy: an update.
    Elahi M, Eshera N, Bambata N, Barr H, Lyn-Cook B, Beitz J, Rios M, Taylor DR, Lightfoote M, Hanafi N, DeJager L, Wiesenfeld P, Scott PE, Fadiran EO, Henderson MB
  31. PLoS Negl Trop Dis 2016 Feb 12;10(2):e0004445
    Distribution of dengue virus types 1 and 4 in blood components from infected blood donors from Puerto Rico.
    Anez G, Heisey DA, Chancey C, Fares RC, Espina LM, Souza KP, Teixeira-Carvalho A, Krysztof DE, Foster GA, Stramer SL, Rios M
  32. Hum Vaccin Immunother 2016 Feb;12(2):491-502
    Booster dose after 10 years is recommended following 17DD-YF primary vaccination.
    Campi-Azevedo AC, Costa-Pereira C, Antonelli LR, Fonseca CT, Teixeira-Carvalho A, Villela-Rezende G, Santos RA, Batista MA, Campos FM, Pacheco-Porto L, Junior OA, Hossell DM, Coelho-Dos-Reis JG, Peruhype-Magalhaes V, Costa-Silva MF, de Oliveira JG, Farias RH, Noronha TN, Lemos JA, von Doellinger VD, Simoes M, de Souza MM, Malaquias LC, Persi HR, Pereira JM, Martins JA, Dornelas-Ribeiro M, Vinhas AA, Alves TR, Maia ML, Freire MD, Martins RM, Homma A, Romano AP, Domingues CM, Tauil PL, Vasconcelos PF, Rios M, Caldas IR, Camacho LA, Martins-Filho OA
  33. Genome Announc 2016 Feb 11;4(1):e01583-15
    Complete genome sequences of dengue virus type 1 to 4 strains used for the development of CBER/FDA RNA reference reagents and WHO international standard candidates for nucleic acid testing.
    Anez G, Heisey DA, Volkova E, Rios M
  34. Vox Sang 2015 Nov;109(4):312-8
    Collaborative study for the characterization of a chikungunya virus RNA reference reagent for use in nucleic acid testing.
    Anez G, Jiang Z, Heisey DA, Kerby S, Rios M, Chikungunya virus Collaborative Study Group
  35. Biomed Res Int 2015;2015:321873
    Epidemiological scenario of Dengue in Brazil.
    Fares RC, Souza KP, Anez G, Rios M
  36. Biomed Res Int 2015;2015:376230
    The global ecology and epidemiology of West Nile virus.
    Chancey C, Grinev A, Volkova E, Rios M
 
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