Keeping Blood and Blood Products Safe by Developing Tests for Malaria and Other Parasites and Helping to Develop Malaria Vaccine
Principal Investigator: Sanjai Kumar, PhD
Office / Division / Lab: OBRR / DETTD / LEP
Malaria is transmitted in more than 100 countries, causing approximately 250 million infections and about 550,000 deaths annually. In addition, each year more than 28 million Americans travel to areas of the world where malaria is transmitted. Returning travelers and immigrants from these countries account for about 1500 clinical cases of malaria and present a potential risk to the United States blood supply that sometimes results in transfusion-transmitted malaria (TTM).
There is no FDA-licensed vaccine against malaria or a test to detect the presence of malaria parasites in blood donors. Therefore, the FDA strategy for reducing the risk of TTM is to defer potential blood donors based on their travel or residence history in endemic areas in countries where malaria is transmitted. Consequently, an estimated 100,000 blood donors are deferred each year due to a potential risk of malaria exposure.
The major objective of this research program is to develop novel, highly sensitive technologies to detect malaria parasites in blood donors. Such tests could further reduce both TTM and the unnecessary deferral of otherwise suitable donors, thus increasing the supply of safe blood. The program also strives to develop laboratory tests that could help to evaluate the safety and efficacy of malaria vaccines under development and detect malaria parasites in mosquitoes. In addition, we are also working to identify the correlates of malaria immunity and pathogenesis. Knowledge on biomarkers that are predictive of malaria immunity and severe disease would facilitate the preclinical development and regulatory review of candidate malaria vaccine submissions.
Babesiosis, transmitted by a tick-vector, is caused by infection of humans with intraerythrocytic protozoa of the genus Babesia. Babesiosis can also be transmitted by transfusion of blood and blood products collected from an infected donor. Tick-borne B. microti transmission is endemic to certain Northeastern, mid-Atlantic and upper Midwestern states. In addition, because of travel from non-endemic states to endemic states, babesiosis cases are routinely reported from non-endemic states. Currently, B. microti is the highest-ranking pathogen that is transmitted by blood transfusion in the U.S. for which no donor screening is available. Since 1980 when the first U.S. case of transfusion-transmitted babesiosis (TTB) was reported, more than 225 cases of TTB have been reported in 22 states, with approximately 28 fatalities.
Our laboratory is engaged in research to identify novel B. microti antigens for vaccine and diagnostic use and developing technologies for detection of B. microti nucleic acid and antibody in blood donors. Our laboratory is also conducting studies on B. microti biology and pathogenesis to identify the window period (time from infection to detection), minimum infectious doses, duration of chronicity and persistence of antibodies in experimental models and in individuals living in endemic areas.
Transmission transmitted malaria (TTM) remains a serious public health concern in the United States. An effective donor screening test could improve blood safety, prevent the sporadic cases of TTM that still occur, while reducing the number of unnecessary deferrals of more than 100,000 uninfected donors each year.
Therefore, we are developing novel nucleic acid-based (NAT) and antibody assays to identify blood donors who may have been exposed to malaria. Our approach also employs discovery of novel molecules to develop higher sensitivity NAT, antigen detection test and antibody assays for detection of the four major Plasmodium species (P. falciparum, P. vivax, P. malariae and P. ovale) that cause infection in humans. We are also evaluating novel multiplex platforms for simultaneous detection of Plasmodium and Babesia parasites and other closely related pathogens in blood.
Our laboratory is also pursuing the following studies in support of the development and regulatory review of candidate malaria vaccines: 1) use of in vitro assays and animal models to identify biomarkers that could be used to predict the safety and virulence profile of irradiation-attenuated or genetically-attenuated P. falciparum parasite vaccines under development; 2) identification of novel vaccine antigens against liver stage and sexual stages of P. falciparum; 3) determination of immunological correlates of protective immunity induced by recombinant malaria vaccine candidates and by natural immunity; and 4) host mechanisms that mediate the pathogenesis of severe malaria (cerebral malaria and severe anemia).
We believe that these state-of-the art malaria research projects will help the FDA scientists to fill the gaps in the public health needs in blood safety and malaria vaccine development, and maintain the necessary expertise for review of donor screening devices against infectious agents and investigational malaria vaccine submissions.
Transfusion-transmitted babesiosis (TTB) is caused by transfusions of blood and blood components collected from donors with unrecognized asymptomatic babesia infections. Since 1980, more than 225 cases of TTB have been documented in the United States, while the actual number is thought to be much higher because of under-diagnosis and under-reporting. While under-reported, B. microti is the most frequently reported transfusion-transmitted infectious agent in the United States. Also, in recent years, B. microti accounted for about half of all transfusion-related fatalities due to microbial agents (comparable to bacterial infections).
There is no FDA-approved vaccine or a laboratory test to detect Babesia infections in blood donors. We are developing both NAT and antibody tests that can distinguish between prospective blood donors with a current infection and those who have had previous exposure to Babesia parasites.
Our current projects include 1) genome-wide search to identify novel B. microti antigens for diagnostics and vaccine use; 2) application of newly discovered antigens to develop novel NAT and antibody-based tests to detect Babesia infections in blood donors; and 3) immunological studies to understand the biology, mechanism of immunity and pathogenesis of B. microti.
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
PLoS One 2017 Apr 21;12(4):e0174229
A no film slot blot for the detection of developing P. falciparum oocysts in mosquitoes.
Grabias B, Verma N, Zheng H, Tripathi AK, Mlambo G, Morin MJ, Locke E, Kumar S
J Microbiol Methods 2017 Jan;132:76-82
Comparison of multiplex PCR hybridization-based and singleplex real-time PCR-based assays for detection of low prevalence pathogens in spiked samples.
Hockman D, Dong M, Zheng H, Kumar S, Huff MD, Grigorenko E, Beanan M, Duncan R
PLoS One 2016 Dec 2;11(12):e0166814
Molecular markers of radiation induced attenuation in intrahepatic Plasmodium falciparum parasites.
Oakley MS, Verma N, Zheng H, Anantharaman V, Takeda K, Gao Y, Myers TG, Pham PT, Mahajan B, Kumar N, Sangweme D, Tripathi AK, Mlambo G, Aravind L, Kumar S
Expert Opin Drug Saf 2016 Jul;15(7):903-10
Adverse neuropsychiatric effects of antimalarial drugs.
Grabias B, Kumar S
Malar J 2015 Nov 14;14(1):451
A comparison of Plasmodium falciparum circumsporozoite protein-based slot blot and ELISA immuno-assays for oocyst detection in mosquito homogenates.
Stone W, Grabias B, Lanke K, Zheng H, Locke E, Diallo D, Birkett A, Morin M, Bousema T, Kumar S
Infect Immun 2015 Oct;83(10):3890-901
Expression, purification and biological characterization of Babesia microti apical membrane antigen 1.
Moitra P, Zheng H, Anantharaman V, Banerjee R, Takeda K, Kozakai Y, Lepore T, Krause PJ, Aravind L, Kumar S
PLoS One 2015 Oct 27;10(10):e0141141
Co-expression of Interleukin-15 enhances the protective immune responses induced by immunization with a murine malaria MVA-based vaccine encoding the circumsporozoite protein.
Parra M, Liu X, Derrick SC, Yang A, Molina-Cruz A, Barillas-Mury C, McGavern DB, Zheng H, Thao Pham P, Sedegah M, Belmonte A, Litilit DD, Waldmann TA, Kumar S, Morris SL, Perera LP
PLoS One 2015 Oct 15;10(10):e0140332
Babesiosis occurrence among the elderly in the United States, as recorded in large Medicare databases during 2006-2013.
Menis M, Forshee RA, Kumar S, McKean S, Warnock R, Izurieta HS, Gondalia R, Johnson C, Mintz PD, Walderhaug MO, Worrall CM, Kelman JA, Anderson SA
J Microbiol Methods 2015 Jan;108:19-24
A sensitive enhanced chemiluminescent-ELISA for the detection of Plasmodium falciparum circumsporozoite antigen in midguts of Anopheles stephensi mosquitoes.
Grabias B, Zheng H, Mlambo G, Tripathi AK, Kumar S
PLoS One 2014 Dec 22;9(12):e115807
A slot blot immunoassay for quantitative detection of Plasmodium falciparum circumsporozoite protein in mosquito midgut oocyst.
Kumar S, Zheng H, Deng B, Mahajan B, Grabias B, Kozakai Y, Morin MJ, Locke E, Birkett A, Miura K, Long C
Eur J Immunol 2014 Sep;44(9):2680-91
T-bet modulates the antibody response and immune protection during murine malaria.
Oakley MS, Sahu BR, Lotspeich-Cole L, Majam V, Pham PT, SenguptaBanerjee A, Kozakai Y, Morris SL, Kumar S
Curr Protoc Microbiol 2014 May 1;33:18.4.1-11
Western blot assay for quantitative and qualitative antigen detection in vaccine development.
Kumar S, Zheng H, Mahajan B, Kozakai Y, Morin M, Locke E
J Immunol 2013 Nov 1;191(9):4699-708
The transcription factor T-bet regulates parasitemia and promotes pathogenesis during Plasmodium berghei ANKA murine malaria.
Oakley MS, Sahu BR, Lotspeich-Cole L, Solanki NR, Majam V, Pham PT, Banerjee R, Kozakai Y, Derrick SC, Kumar S, Morris SL
Transfusion 2013 Jul;53(7):1429-41
Investigating the prevalence of transfusion transmission of Plasmodium within a hyperendemic blood donation system.
Freimanis G, Sedegah M, Owusu-Ofori S, Kumar S, Allain JP
PLoS One 2013 Jul 4;8(7):e66115
Molecular Analysis of Non-Specific Protection against Murine Malaria Induced by BCG Vaccination.
Parra M, Liu X, Derrick SC, Yang A, Tian J, Kolibab K, Kumar S, Morris SL
J Immunol Methods 2013 Apr 30;390(1-2):99-105
A chemiluminescent-western blot assay for quantitative detection of Plasmodium falciparum circumsporozoite protein.
Kumar S, Zheng H, Sangweme DT, Mahajan B, Kozakai Y, Pham PT, Morin MJ, Locke E, Kumar N
J Infect Dis 2013 Jan 1;207(1):164-74
Radiation-induced cellular and molecular alterations in asexual intraerythrocytic Plasmodium falciparum.
Oakley MS, Gerald N, Anantharaman V, Gao Y, Majam V, Mahajan B, Pham PT, Lotspeich-Cole L, Myers TG, McCutchan TF, Morris SL, Aravind L, Kumar S
Hum Vaccin Immunother 2012 Nov 1;8(11):1564-84
Clinical trial in healthy malaria-naive adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA.
Richie TL, Charoenvit Y, Wang R, Epstein JE, Hedstrom RC, Kumar S, Luke TC, Freilich DA, Aguiar JC, Sacci JB Jr, Sedegah M, Nosek RA Jr, De La Vega P, Berzins MP, Majam VF, Abot EN, Ganeshan H, Richie NO, Banania JG, Baraceros MF, Geter TG, Mere R, Bebris L, Limbach K, Hickey BW, Lanar DE, Ng J, Shi M, Hobart PM, Norman JA, Soisson LA, Hollingdale MR, Rogers WO, Doolan DL, Hoffman SL
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
Emerg Infect Dis 2012 Jan;18(1):128-31
Babesiosis among Elderly Medicare Beneficiaries, United States, 2006-2008.
Menis M, Anderson SA, Izurieta HS, Kumar S, Burwen DR, Gibbs J, Kropp G, Erten T, Macurdy TE, Worrall CM, Kelman JA, Walderhaug MO
PLoS One 2011;6(12):e28164
Malaria infections do not compromise vaccine-induced immunity against tuberculosis in mice.
Parra M, Derrick SC, Yang A, Tian J, Kolibab K, Oakley M, Perera LP, Jacobs WR, Kumar S, Morris SL
Trends Parasitol 2011 Oct;27(10):442-9
Clinical and molecular aspects of malaria fever.
Oakley MS, Gerald N, McCutchan TF, Aravind L, Kumar S
PLoS One 2011 Sep;6(9):e24398
Protection from experimental cerebral malaria with a single dose of radiation-attenuated, blood-stage Plasmodium berghei parasites.
Gerald NJ, Majam V, Mahajan B, Kozakai Y, Kumar S
Malar J 2011 Jun 20;10:168
Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults.
Dodoo D, Hollingdale MR, Anum D, Koram KA, Gyan B, Akanmori BD, Ocran J, Adu-Amankwah S, Geneshan H, Abot E, Legano J, Banania G, Sayo R, Brambilla D, Kumar S, Doolan DL, Rogers WO, Epstein J, Richie TL, Sedegah M
Eukaryot Cell 2011 Apr;10(4):474-82
Mitosis in the human malaria parasite Plasmodium falciparum.
Gerald N, Mahajan B, Kumar S
Transfusion 2011 Mar;51(3):630-5
Survival of Plasmodium falciparum in human blood during refrigeration.
Chattopadhyay R, Majam VF, Kumar S
Infect Immun 2011 Mar;79(3):1244-53
Molecular correlates of experimental cerebral malaria detectable in whole blood.
Oakley MS, Anantharaman V, Venancio TM, Zheng H, Mahajan B, Majam V, McCutchan TF, Myers TG, Aravind L, Kumar S
Exp Parasitol 2011 Jan;127(1):1-8
Plasmodium falciparum: nitric oxide modulates heme speciation in isolated food vacuoles.
Ostera G, Tokumasu F, Teixeira C, Collin N, Sa J, Hume J, Kumar S, Ribeiro J, Lukat-Rodgers GS, Rodgers KR
Infect Immun 2010 Nov;78(11):4613-24
Multiple antigen peptide vaccines against Plasmodium falciparum malaria.
Mahajan B, Berzofsky JA, Boykins RA, Majam V, Zheng H, Chattopadhyay R, de la Vega P, Moch JK, Haynes JD, Belyakov IM, Nakhasi HL, Kumar S
Transfusion 2009 Dec;49(12):2759-71
Transfusion-transmitted babesiosis in the United States: summary of a workshop.
Gubernot DM, Nakhasi HL, Mied PA, Asher DM, Epstein JS, Kumar S
Vaccine 2009 Sep 25;27(42):5719-25
Report of a consultation on the optimization of clinical challenge trials for evaluation of candidate blood stage malaria vaccines, 18-19 March 2009, Bethesda, MD, USA.
Moorthy VS, Diggs C, Ferro S, Good MF, Herrera S, Hill AV, Imoukhuede EB, Kumar S, Loucq C, Marsh K, Ockenhouse CF, Richie TL, Sauerwein RW
PLoS One 2009 Aug 27;4(8):e6793
Pathogenic roles of CD14, galectin-3, and OX40 during experimental cerebral malaria in mice.
Oakley MS, Majam V, Mahajan B, Gerald N, Anantharaman V, Ward JM, Faucette LJ, McCutchan TF, Zheng H, Terabe M, Berzofsky JA, Aravind L, Kumar S
Indian J Exp Biol 2009 Jul;47(7):527-36
Malaria vaccine: latest update and challenges ahead.
Chattopadhyay R, Kumar S
Exp Parasitol 2009 Jun;122(2):112-23
Plasmodium: mammalian codon optimization of malaria plasmid DNA vaccines enhances antibody responses but not T cell responses nor protective immunity.
Dobano C, Sedegah M, Rogers WO, Kumar S, Zheng H, Hoffman SL, Doolan DL
J Biol Chem 2008 Nov 14;283(46):31871-83
Centrins, cell cycle regulation proteins in human malaria parasite plasmodium falciparum.
Mahajan B, Selvapandiyan A, Gerald NJ, Majam V, Zheng H, Wickramarachchi T, Tiwari J, Fujioka H, Moch JK, Kumar N, Aravind L, Nakhasi HL, Kumar S
Infect Immun 2008 Oct;76(10):4518-29
Host Biomarkers and Biological Pathways that are Associated with the Expression of Experimental Cerebral Malaria in Mice.
Oakley MS, McCutchan TF, Anantharaman V, Ward JM, Faucette L, Erexson C, Mahajan B, Zheng H, Majam V, Aravind L, Kumar S
PLoS Pathog 2008 Apr 25;4(4):e1000053
HDP-a novel heme detoxification protein from the malaria parasite.
Jani D, Nagarkatti R, Beatty W, Angel R, Slebodnick C, Andersen J, Kumar S, Rathore D
Expert Opin Drug Saf 2007 Sep;6(5):505-21
Assessment of safety of the major antimalarial drugs.
Chattopadhyay R, Mahajan B, Kumar S
Infect Immun 2007 Apr;75(4):2012-25
Molecular Factors and Biochemical Pathways Induced by Febrile Temperature in Plasmodium falciparum Parasites.
Oakley MS, Kumar S, Anantharaman V, Zheng H, Mahajan B, Haynes JD, Moch JK, Fairhurst R, McCutchan TF, Aravind L
Infect Immun 2007 Mar;75(3):1177-85
A novel chimeric Plasmodium vivax Circumsporozoite protein induces biologically functional antibodies that recognize both VK210 and VK247 sporozoites.
Yadava A, Sattabongkot J, Washington MA, Ware LA, Majam V, Zheng H, Kumar S, Ockenhouse CF
Int J Parasitol 2006 Aug;36(9):1037-48
Protein disulfide isomerase assisted protein folding in malaria parasites.
Mahajan B, Noiva R, Yadava A, Zheng H, Majam V, Mohan KV, Moch JK, Haynes JD, Nakhasi H, Kumar S
Infect Immun 2005 Sep;73(9):5402-9
Identification, Cloning, Expression, and Characterization of the Gene for Plasmodium knowlesi Surface Protein Containing an Altered Thrombospondin Repeat Domain.
Mahajan B, Jani D, Chattopadhyay R, Nagarkatti R, Zheng H, Majam V, Weiss W, Kumar S, Rathore D
Infect Immun 2005 Sep;73(9):6091-100
Genome-wide expression profiling in malaria infection reveals transcriptional changes associated with lethal and nonlethal outcomes.
Schaecher K, Kumar S, Yadava A, Vahey M, Ockenhouse CF
Expert Opin Investig Drugs 2005 Jul;14(7):871-83
Antimalarial drugs: current status and new developments.
Rathore D, McCutchan TF, Sullivan M, Kumar S
J Biol Chem 2005 May 27;280(21):20524-9
An immunologically cryptic epitope of Plasmodium falciparum circumsporozoite protein facilitates liver cell recognition and induces protective antibodies that block liver cell invasion.
Rathore D, Nagarkatti R, Jani D, Chattopadhyay R, de la Vega P, Kumar S, McCutchan TF