Safety of Blood and Blood Products from Contamination with Malaria Parasites and Studies on Malaria Immunity and Pathogenesis

Principal Investigator: Sanjai Kumar, PhD
Office / Division / Lab: OBRR / DETTD / LBPUA

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Overview

Public Health Issue: Each year, more than 28 million Americans travel to or live in countries where malaria is transmitted. Returning travelers and immigrants from malaria-endemic countries pose a potential risk of passing the infection to others through blood transfusion. A primary objective of this research program is to protect the nation's blood supply from transfusion-transmitted malaria (TTM). A secondary objective is to develop laboratory tests (based on genetic markers) that could set a standard for pre-clinical evaluation of the safety and efficacy of malaria vaccines. In addition, we have also started a research program to develop laboratory tests to detect Babesia infections in blood donors. Babesiosis, a malaria-like illness, is caused by infection of erythrocytes with protozoan parasites belonging to the genus Babesia. In the U.S., the highest prevalence of babesiosis occurs in the Northeastern states, some Midwestern states and in California and Washington State. Transfusion-transmitted babesiosis (TTB) has been reported in the US caused by transfusion of blood collected from donors infected with Babesia parasites, including reports to the FDA of fatal TTB (primary or contributory cause of death.

Regulatory Contribution: Currently, in the US, there is no FDA licensed blood screening test to detect the presence of malaria parasites and FDA issued donor deferral policies based on the travel or residence history (i.e., theoretical risk of exposure) is the only method to minimize the incidences of TTM. It is estimated that approximately 120,000 donors are deferred each year due to a potential risk of exposure to malaria parasites. This laboratory program seeks to further improve the safety and availability of the blood supply and reduce both TTM and malaria-risk related donor deferrals. Similarly, availability of a laboratory test to detect Babesia infections in blood donors would allow identification and deferral of donors who are either infected with Babesia parasites or present the risk of TTB, thus ensuring the blood supply from the risk of TTB. Our research program to develop laboratory tests of vaccine safety and efficacy will facilitate identification of the regulatory criteria for malaria vaccine submissions to CBER.

Research Approach: (a) Development of an enzyme-linked immunosorbent assay to detect malarial antibodies as a blood test that might augment current donor deferral policy for reducing malaria risk; (b) Development of DNA based tests to detect infections with malaria parasites in blood donors; (c) Identification of genetic markers (based on global gene expression analysis) in the Plasmodium yoelii-mouse model and in P. falciparum (human malaria) using recombinant protein-based vaccines and irradiation-attenuated or genetic-mutant (targeted gene deletions) malaria parasites; (d) Identification of biomarkers markers that could predict the safety and virulence of live attenuated malaria vaccines; (e) Identification of the host factors associated with the pathogenesis of cerebral malaria in the berghei-mouse model.

Mission Relevance & Outcomes: TTM remains a serious public health concern in the US. The latest recognized case of TTM occurred in 2005. During the last 20 years (for which accurate data are available), the occurrence of TTM remained relatively stable at rates of approximately 0.25 case per 1 million blood units collected; however, in most recent years, possibly as a result of FDA's persistent efforts to encourage the rigorous implementation of donor deferral policies, the rate of TTM declined to approximately 0.027 cases per million units collected. The greatest burden of a deferral policy based on donor history is the loss of otherwise suitable donors; approximately 150, 000 individuals are deferred each year due to a perceived risk of malaria exposure. We believe that an effective donor screening test would improve blood safety, preventing the few cases of TTM that still occur, while reducing the number of unintended deferrals of thousands of uninfected donors. Therefore, we are working to develop and validate a DNA-based malaria detection test (for universal donor screening) and an antibody-based test (to screen selected donor populations with a perceived risk of malaria exposure). We are simultaneously conducting research to understand the underlying mechanisms of naturally acquired and vaccine-induced immunity to malaria, molecular factors associated with cerebral malaria, and identifying the biomarkers of vaccines (both recombinant-based and live-attenuated candidate vaccines) that might predict their safety and efficacy before clinical trials begin. We believe that these state-of-the art malaria research projects are necessary to help prepare FDA scientists to review the newest generation of malaria vaccines now being developed with sophisticated technologies.

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Publications

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