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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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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

Mosquito-borne diseases, such as dengue fever, yellow fever, Japanese encephalitis, West Nile encephalitis, and chikungunya fever, kill more than 1 million people worldwide every year.

The outbreaks of West Nile encephalitis in the U.S. highlight the potential threat of viruses spread by mosquitoes, ticks, and certain other insects, and the need for assays to screen, diagnose and differentiate them from each other. In the U.S., public health officials first recognized West Nile virus (WNV) in 1999, and the disease has since become established in this country. Outbreaks of WNV infections have occurred for 12 consecutive years, infecting two to four million people, and causing illness in tens of thousands of people, including ~13,000 cases of neurological disease, and over 1,200 deaths between 1999 and 2010.

In 2002 the potential for human-to-human transmission of WNV through organ transplants and blood transfusion raised concerns among public health officials about the safety of the blood supply. In response, FDA collaborated with industry and blood collection facilities to develop new donor screening tests. In the summer of 2003, the FDA approved the use of these tests by scientists studying this problem, and blood testing laboratories began using them to screen the blood supply for this virus under a research protocol.

While not yet established in the Continental U.S., Dengue virus (DENV) and chikungunya virus (ChikV) could reach the U.S. through travel by infected individuals or through inadvertent transportation of infected mosquitoes. Certain mosquitoes already common in the U.S. could then spread these viruses and thus cause a public health crisis.

DENV, which causes dengue fever, hemorrhagic fever (headache, fever, bleeding in the body), and shock syndrome (collapse of the circulatory system), is the most significant mosquito-borne disease in the world, with an estimated 2.5 billion people at risk for infection in subtropical and tropical regions. Globally, DenV causes 50-100 million cases of disease and tens of thousands of deaths per year. DENV has also reached epidemic proportions in the U.S. territories of Puerto Rico and Samoa, and local transmission has occurred in the U.S.-Mexico border.

ChikV outbreaks causing debilitating diseases have been reported in Europe, Africa, the Middle East, India, and Southeast Asia. Epidemics can be explosive, with large numbers of human cases and rapid spread of the virus. In fact, the virus can adapt to new areas of the world through genetic mutation, as reported when circulating viruses being commonly transmitted by Aedes aegypti adapted to Aedes albopictus through a single mutation in codon 226 of the envelope protein and caused multiple outbreaks in other areas, including Italy and Singapore. Indeed, ChikV has been recognized in 35 travelers returning to the U.S. from affected areas. Such adaptation could enable this virus to spread within the U.S. through mosquitoes already existing in various areas of the country.

Symptoms of illnesses caused by WNV, DENV and ChikV include headaches, joint and muscle pain and fever, and can be mistaken for the common cold. These infections can evolve to extremely serious disease and death. There are no specific therapies or effective vaccines for these infections, laboratory diagnosis can be very time-consuming, and tests that differentiate among these agents are laborious to run.

Of special concern is the fact that these viruses frequently cause asymptomatic infections during which the virus circulates in the blood. Individuals with such "silent" infections feel well enough to donate blood and pose the threat of transmission of these viruses through blood donations because they are not identified as being infected. In fact, WNV and DENV transmission by transfusion have been documented, and ChikV transmission by transfusion is suspected.

Our research addresses, 1) preparation of standardized virus stocks that can be used to evaluate the accuracy of tests designed to identify these viruses in blood before the FDA approves such tests for marketing and quality control; 2) study of the genetic variability of viruses in order to identify mutants that could escape detection by these tests and interfere with vaccine development; 3) development and evaluation of technologies that enhance the ability of tests to identify the genetic variability of several different pathogens, while requiring only small volumes of specimen; and 4) studies of how the viruses cause disease, which might produce new information that could help in the search for new approaches for pathogen inactivation and therapies.

In sum, this research program aims to use the latest technologies to further reduce the risk of blood transfusion and prevent the emergence of new potential public health risks.


Scientific Overview

Arthropod-borne viruses (arboviruses) cause human diseases such as dengue fever, yellow fever, Japanese encephalitis, West Nile encephalitis, and chikungunya fever. Causing billions of infections worldwide, arboviruses present a challenge to the scientific community because there are no specific therapies available to treat these diseases, or vaccines to prevent some of them.

Most of the infections are acquired through mosquito bites and are asymptomatic despite the presence of viremia. West Nile virus (WNV) and Dengue (DENV) have been transmitted by transfusion, while Chikungunya (ChikV) and Japanese Encephalitis (JEV) are considered to be potentially transmissible this way.

WNV is endemic in the continental U.S. and the entire blood supply is currently screened for this virus. Small outbreaks of DENV reported in South Texas and Florida were probably initiated in the continental U.S. by imported cases, and DENV is endemic in Puerto Rico. Only imported cases of ChikV and JEV have been reported in the U.S.

The mosquitoes that transmit these viruses (Aedes aegypti and Aedes albopictus) are present in the U.S. There is evidence that both, mutations in the viral genome of ChikV found in Italy and WNV mutations found in the U.S., produced fit variants that spread very efficiently and caused human disease.

The deployment of U.S. troops to areas of the world where mosquito-borne diseases are endemic, and increased travel to and from those areas, has raised concern that these diseases could inadvertently be brought to the U.S. and spread through transmitting mosquitoes already existing in this country. Thus, these viruses pose a potential threat to the nation's blood supply.

These observations are encouraging the development of new assays, which in turn will require development of appropriate reference reagents to define analytical sensitivity and specificity in order to fulfill regulatory pathways for licensure and lot-release-panels. A major roadblock to the development of these reagents is the requirement for well-characterized viral stocks in large volumes to be used over many years with a fair degree of reproducibility that could not be obtained by direct human sampling.

This research program aims to: 1) produce reference panels for DENV 1-4 and ChikV; 2) study genetic variation in WNV and evaluate the impact of naturally occurring mutations in the performance of diagnostic and screening assays, work that will also facilitate evaluation of the efficacy of vaccines and therapies under development; 3) investigate the relevance of genetic variation to virus fitness and virulence of WNV using in vitro culture systems with human and animal cells; 4) assess potential approaches to increase sensitivity of current assays to improve blood safety; 5) update the standard reagents with new WNV strains for FDA proficiency and lot release panels; 6) investigate the properties and significance of the association of WNV virions with blood cells, primarily RBCs, and its significance for infection by transfusion; and 7) develop a nanotechnology-based microarray assay to detect DENV 1-4 and genetic variability of WNV without the need for viral isolation.

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


Publications

Transfusion 2012 Sep;52(9):1949-56
Polymerase chain reaction-based tests for pan-species and species-specific detection of human Plasmodium parasites.
Mahajan B, Zheng H, Pham PT, Sedegah MY, Majam VF, Akolkar N, Rios M, Ankrah I, Madjitey P, Amoah G, Addison E, Quakyi IA, Kumar S

Am J Trop Med Hyg 2012 Sep;87(3):548-53
Phylogenetic analysis of dengue virus types 1 and 4 circulating in Puerto Rico and Key West, Florida, during 2010 epidemics.
Añez G, Heisey DA, Espina LM, Stramer SL, Rios M

J Virol Methods 2012 Aug;183(2):219-23
Application of a full-genome microarray-based assay for the study of genetic variability of West Nile virus.
Grinev A, Lu Z, Chizhikov V, Rios M

Vox Sang 2012 Aug;103(2):99-106
Distribution of hepatitis C virus in circulating blood components from blood donors.
Chancey C, Winkelman V, Foley JB, Silberstein E, Teixeira-Carvalho A, Taylor DR, Rios M

Vox Sang 2012 Jul;103(Suppl. S1):62-3
Dengue virus and other arboviruses: a global view of risks.
Rios M, Anez G, Chancey C, Grinev A

PLoS One 2011;6(11):e27459
Circulation of different lineages of dengue virus type 2 in central america, their evolutionary time-scale and selection pressure analysis.
Anez G, Morales-Betoulle ME, Rios M

BMC Immunol 2010 Jan 20;11:3
Anti-West Nile virus activity of in vitro expanded human primary natural killer cells.
Zhang M, Daniel S, Huang Y, Chancey C, Huang Q, Lei YF, Grinev A, Mostowski H, Rios M, Dayton A

ISBT Sci Ser 2009;4(1):87-94
Climate change and vector-borne viral diseases potentially transmitted by transfusion
Rios M

J Virol Methods 2008 Dec;154(1-2):27-40
Microarray-based assay for the detection of genetic variations of structural genes of West Nile virus.
Grinev A, Daniel S, Laassri M, Chumakov K, Chizhikov V, Rios M

J Infect Dis 2008 Nov 1;198(9):1300-8
In Vitro Evaluation of the Protective Role of Human Antibodies to West Nile Virus (WNV) Produced during Natural WNV Infection.
Rios M, Daniel S, Dayton AI, Wood O, Hewlett IK, Epstein JS, Caglioti S, Stramer SL

Emerg Infect Dis 2008 Mar;14(3):436-44
Genetic Variability of West Nile Virus in US Blood Donors, 2002-2005.
Grinev A, Daniel S, Stramer S, Rossmann S, Caglioti S, Rios M

Clin Infect Dis 2007 Jul 15;45(2):181-6
West nile virus adheres to human red blood cells in whole blood.
Rios M, Daniel S, Chancey C, Hewlett IK, Stramer SL

Neurology 2007 Jan 16;68(3):206-13
Differentiation of HAM/TSP from patients with multiple sclerosis infected with HTLV-I.
Puccioni-Sohler M, Yamano Y, Rios M, Carvalho SM, Vasconcelos CC, Papais-Alvarenga R, Jacobson S

Vox Sang 2006 Jul;91(1):81-7
Dombrock gene analysis in Brazilian people reveals novel alleles.
Baleotti W Jr, Rios M, Reid ME, Hashmi G, Fabron A Jr, Pellegrino J Jr, Castilho L

Transfusion 2006 Apr;46(4):659-67
Monocytes-macrophages are a potential target in human infection with West Nile virus through blood transfusion.
Rios M, Zhang MJ, Grinev A, Srinivasan K, Daniel S, Wood O, Hewlett IK, Dayton AI

J Med Virol 2006 Apr 18;78(S1):S22-S23
Evaluation of FDA licensed HIV assays using plasma from Cameroonian blood donors.
Lee S, Hu J, Tang S, Wood O, Francis K, Machuca A, Rios M, Daniel S, Vockley C, Awazi B, Zekeng L, Hewlett I

J Infect Dis 2006 Feb 1;193(3):427-37
Human T Lymphotropic Virus Types I and II Western Blot Seroindeterminate Status and Its Association with Exposure to Prototype HTLV-I.
Yao K, Hisada M, Maloney E, Yamano Y, Hanchard B, Wilks R, Rios M, Jacobson S

Clin Infect Dis 2005 Jun 1;40(11):1673-6
Seroprevalence of human T cell leukemia virus in HIV antibody-negative populations in rural Cameroon.
Machuca A, Wood O, Lee S, Daniel S, Rios M, Wolfe ND, Carr JK, Eitel MN, Tamoufe U, Torimiro JN, Burke D, Hewlett IK

Transfus Med 2005 Feb;15(1):49-55.
High frequency of partial DIIIa and DAR alleles found in sickle cell disease patients suggests increased risk of alloimmunization to RhD.
Castilho L, Rios M, Rodrigues A, Pellegrino J Jr, Saad ST, Costa FF

Vox Sang 2004 Oct;87(3):190-5
A novel FY allele in Brazilians.
Castilho L, Rios M, Pellegrino J Jr, Saad ST, Costa FF, Reid ME

Transfusion 2004 Feb;44(2):170-2
Evidence that Hy- RBCs express weak Joa antigen.
Scofield TL, Miller JP, Storry JR, Rios M, Reid ME

Vox Sang 2004 Feb;86(2):136-40
Weakened expression of 'e' owing to concomitant occurrence of Cys16 and Val245 (VS antigen).
Rodrigues A, Rios M, Costa FF, Saad ST, Pellegrino J Jr, Castilho L

 

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