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 occurs in more than 100 countries, causing a total of approximately 250 million infections and one million deaths annually, and each year more than 28 million Americans travel to areas of the world where malaria is transmitted. Returning travelers and immigrants from these countries represent a potential risk to the US blood supply that sometimes results in transfusion-transmitted malaria (TTM); during the last decade five cases of TTM were reported.
Currently there is no FDA-licensed test in the US 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 areas where malaria is common. Consequently, an estimated 150,000 potential donors are deferred each year due to a potential risk of malaria exposure.
The major objective of this research program is to develop laboratory tests to detect malaria parasites in blood donors. Such tests could 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.
Our laboratory has also recently begun to develop laboratory tests to identify potential blood donors infected with Babesia parasites, the pathogens that cause babesiosis, a disease with malaria-like symptoms. Babesiosis is locally prevalent in various regions of the United States. Transfusion of blood and blood products collected from donors infected with Babesia can cause transfusion-transmitted babesiosis (TTB) that could be potentially fatal. Importantly, even though the highest number of reported cases of both babesia and TTB cases are reported in the U.S., this important parasitic infection has not been well studied.
TTM remains a serious public health concern in the US, with the latest recognized case of TTM occurring in July 2009. An effective donor screening test could improve blood safety, prevent the few cases of TTM that still occur, while reducing the number of unnecessary deferrals of thousands of uninfected donors.
Therefore, we are developing the following tests to ensure the safety of the nation's blood supply: 1) enzyme-linked immunosorbent assays to detect antibodies against malaria in the blood of prospective donors; and 2) DNA-based tests to detect malaria parasites in blood donors.
Our laboratory is also pursuing the following studies in support of the development of candidate malaria vaccines: 1) use of in vitro assays and animal models to identify genetic markers based on global gene expression analysis of irradiation-attenuated or genetic-mutant Plasmodium falciparum parasites to predict the safety and virulence of live attenuated malaria vaccines; 2) determining immunological correlates of protection induced by recombinant malaria vaccine candidates in the murine P. yoelii model; and 3) identifying host factors associated with pathogenesis of cerebral malaria in a P. berghei mouse model using microarray studies and biological assays.
We believe that these state-of-the art malaria research projects will help prepare FDA scientists to review the latest generation of malaria vaccines now being developed.
Transfusion-transmitted babesiosis (TTB) is caused by transfusions of blood or blood components collected from donors with unrecognized asymptomatic babesia infections. Since 1979, more than 80 cases of TTB have been documented in the United States, while the actual number is thought to be much higher. While under-reported, B. microti is the most frequently reported transfusion-transmitted infectious agent in the United States. Furthermore, between 2006-2008, FDA received 10 reports of TTB-related fatalities in which babesiosis was listed as the primary or contributing cause of death. In fact, 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 laboratory test to detect Babesia infections in blood donors, although some at-risk donors can be identified by asking them if they have had babesiosis.
Babesia species cause a wide spectrum of clinical manifestations, ranging from asymptomatic to severe acute or even fatal illness. Asymptomatic carriers are especially difficult to recognize and probably cause most cases of TTB.
We are developing both DNA tests 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) using mini-genome-wide gene sequencing to identify novel Babesia microti antigens for diagnostics and vaccine use; 2) developing DNA- and antibody-based tests to detect Babesia infections in blood donors; and 3) identifying biomarkers of Babesia pathogenesis in humans by microarray- and immunological-based studies.
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
J Microbiol Methods 2014 Oct 22;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
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;33:18.4.1-18.4.11
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
Infect Immun 2004 Apr;72(4):2248-53
Measuring the effects of an ever-changing environment on malaria control.
McCutchan TF, Grim KC, Li J, Weiss W, Rathore D, Sullivan M, Graczyk TK, Kumar S, Cranfield MR
Hybrid Hybridomics 2004 Apr;23(2):133-6
Production of monoclonal antibodies against a 19-kD recombinant Plasmodium vivax MSP1 for detection of P. vivax malaria in Turkey.
Ak M, Babaoglu A, Dagci H, Turk M, Bayram S, Ertabaklar H, Ozcel MA, Uner A, Charoenvit Y, Kumar S, Hoffman SL
Gene Ther 2004 Mar;11(5):448-56
Reduced immunogenicity of DNA vaccine plasmids in mixtures.
Sedegah M, Charoenvit Y, Minh L, Belmonte M, Majam VF, Abot S, Ganeshan H, Kumar S, Bacon DJ, Stowers A, Narum DL, Carucci DJ, Rogers WO