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  1. Science & Research (Biologics)

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


General Overview

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.


Scientific Overview

Malaria

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.

Babesiosis

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.


Publications

  1. PLoS Negl Trop Dis 2024 Mar 14 [Epub ahead of print]
    Absence of anti-Babesia microti antibody in commercial intravenous immunoglobulin (IVIG).
    Kostka J, Maharjan AS, Kumar S, Hackenyos D, Krause PJ, Dieckhaus K
  2. Open Forum Infect Dis 2024 Jan;11(1):ofad568
    Immune control in repeated Babesia microti infection in a patient with B-cell deficiency.
    Little JS, Oakley MS, Thorner AR, Johnston D, Majam V, Liakos AD, Novack LA, Zheng H, Meredith S, Chou CK, Newton BR, Soiffer RJ, Krause PJ, Baden LR, Kumar S
  3. Clin Infect Dis 2024 Jan 15;78(1):228-30
    Reduced risk of transfusion-transmitted babesiosis with blood donor testing.
    Eder AF, O'Callaghan S, Kumar S
  4. Infect Immun 2023 Oct;91(10):e0016223
    Protective efficacy and correlates of immunity of immunodominant recombinant Babesia microti antigens.
    Meredith S, Majam V, Zheng H, Verma N, Puri A, Akue A, KuKuruga M, Oakley M, Kumar S
  5. Trends Parasitol 2022 Oct;38(10):904-18
    A vaccine for human babesiosis: prospects and feasibility.
    Al-Nazal H, Low L, Kumar S, Good MF, Stanisic DI
  6. Clin Infect Dis 2022 Mar 23 [Epub ahead of print]
    Frequency and geographic distribution of Borrelia miyamotoi, Borrelia burgdorferi, and Babesia microti infections in New England residents.
    Johnston D, Kelly JR, Ledizet M, Lavoie N, Smith RP, Parsonnet J, Schwab J, Stratidis J, Espich S, Lee G, Maciejewski KR, Deng Y, Majam V, Zheng H, Bonkoungou SN, Stevens J, Kumar S, Krause PJ
  7. Biochem Biophys Res Commun 2021 Nov 5;577:58-63
    Live attenuated rubella vectors expressing Plasmodium falciparum circumsporozoite protein (Pf-CSP) provide a novel malaria vaccine platform in the rhesus macaque.
    Virnik K, Zhou W, Medvedev A, Walsh G, Perry-Anderson J, Majam V, Felber BK, Kumar S, Berkower I
  8. Pathogens 2021 Nov 30;10(12):1563
    Technologies for detection of Babesia microti: advances and challenges.
    Meredith S, Oakley M, Kumar S
  9. Front Microbiol 2021 Sep 3;12:697669
    Babesia microti: pathogen genomics, genetic variability, immunodominant antigens, and pathogenesis.
    Puri A, Bajpai S, Meredith S, Aravind L, Krause PJ, Kumar S
  10. Sci Transl Med 2021 Jun 9;13(597):eabg2112
    Plasmodium falciparum Pf77 and male development gene 1 as vaccine antigens that induce potent transmission-reducing antibodies.
    Tripathi AK, Oakley MS, Verma N, Mlambo G, Zheng H, Meredith SM, Essuman E, Puri A, Skelton RA, Takeda K, Majam V, Quakyi IA, Locke E, Morin M, Miura K, Long CA, Kumar S
  11. Cell Host Microbe 2021 Jun 9;29(6):894-903.e5
    Pre-clinical evaluation of a whole-parasite vaccine to control human babesiosis.
    Al-Nazal HA, Cooper E, Ho MF, Eskandari S, Majam V, Giddam AK, Hussein WM, Islam MT, Skwarczynski M, Toth I, Kumar S, Zaid A, Batzloff M, Stanisic DI, Good MF
  12. Proc Natl Acad Sci U S A 2021 Mar 16;118(11):e1907653118
    CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with Plasmodium infection.
    Torrez Dulgeroff LB, Oakley MS, Tal MC, Yiu YY, He JQ, Shoham M, Majam V, Okoth WA, Malla P, Kumar S, Weissman IL
  13. Open Forum Infect Dis 2020 Dec 15;8(2):ofaa608
    Babesiosis occurrence among United States Medicare beneficiaries, ages 65 and older, during 2006-2017: overall and by state and county of residence.
    Menis M, Whitaker BI, Wernecke M, Jiao Y, Eder A, Kumar S, Xu W, Liao J, Wei Y, MaCurdy TE, Kelman JA, Anderson SA, Forshee RA
  14. Sci Rep 2020 Jun 12;10(1):9598
    Antigen discovery, bioinformatics and biological characterization of novel immunodominant Babesia microti antigens.
    Verma N, Puri A, Essuman E, Skelton R, Anantharaman V, Zheng H, White S, Gunalan K, Takeda K, Bajpai S, Lepore TJ, Krause PJ, Aravind L, Kumar S
  15. Infect Immun 2019 Oct;87(10):e00236-19
    Antibody-dependent IFN-gamma-independent sterilizing immunity, induced by a subunit malaria vaccine.
    Chawla B, Mahajan B, Oakley M, Majam VF, Belmonte A, Sedegah M, Shimp RL Jr, Kaslow DC, Kumar S
  16. NPJ Vaccines 2019 Oct 14;4:42
    Harmonization of Zika neutralization assays by using the WHO International Standard for anti-Zika virus antibody.
    Mattiuzzo G, Knezevic I, Hassall M, Ashall J, Myhill S, Faulkner V, Hockley J, Rigsby P, Wilkinson DE, Page M, collaborative study participants
  17. Pathogens 2019 Jul 17;8(3):102
    Persistence of Babesia microti Infection in Humans.
    Bloch EM, Kumar S, Krause PJ
  18. Malar J 2019 Apr 2;18(1):116
    Sensitive real-time PCR detection of Plasmodium falciparum parasites in whole blood by erythrocyte membrane protein 1 gene amplification.
    Grabias B, Essuman E, Quakyi IA, Kumar S
  19. Sci Rep 2018 Aug 1;8(1):11568
    Transcriptome analysis based detection of Plasmodium falciparum development in Anopheles stephensi mosquitoes.
    Oakley MS, Verma N, Myers TG, Zheng H, Locke E, Morin MJ, Tripathi AK, Mlambo G, Kumar S
  20. Transfusion 2018 Aug;58(8):1924-32
    Superior real-time polymerase chain reaction detection of Babesia microti parasites in whole blood utilizing high-copy BMN antigens as amplification targets.
    Grabias B, Clement J, Krause P, Lepore T, Kumar S
  21. Infect Immun 2018 Jul;86(7):e00899-17
    TCRbeta combinatorial immunoreceptor expression by neutrophils correlates with parasite burden and enhanced phagocytosis during a Plasmodium berghei ANKA malaria infection.
    Chorazeczewski JK, Aleshnick M, Majam V, Okoth WA, Kurapova R, Akue A, KuKuruga M, Kumar S, Oakley MS
  22. PLoS One 2018 Jul 25;13(7):e0201043
    TCRbeta-expressing macrophages induced by a pathogenic murine malaria correlate with parasite burden and enhanced phagocytic activity.
    Oakley MS, Chorazeczewski JK, Aleshnick M, Anantharaman V, Majam V, Chawla B, Myers TG, Su Q, Okoth WA, Takeda K, Akue A, KuKuruga M, Aravind L, Kumar S
  23. J Infect Dis 2018 Mar 15;217(6):1012-3
    Response to Lisette et al.
    Grabias B, Essuman E, Oakley M, Kumar S
  24. Transfusion 2018 Mar;58(3):617-9
    Community-acquired and transfusion-transmitted babesiosis are increasing: why and what to do?
    Kumar S, Fish D, Krause PJ
  25. J Infect Dis 2017 Nov 15;216(10):1264-72
    A novel gametocyte biomarker for superior molecular detection of the Plasmodium falciparum infectious reservoirs.
    Essuman E, Grabias B, Verma N, Chorazeczewski JK, Tripathi AK, Mlambo G, Addison EA, Amoah AGB, Quakyi I, Oakley MS, Kumar S
  26. 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
  27. 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
  28. 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
  29. 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
  30. Expert Opin Drug Saf 2016 Jul;15(7):903-10
    Adverse neuropsychiatric effects of antimalarial drugs.
    Grabias B, Kumar S
  31. 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
  32. 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
  33. 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
  34. 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
  35. Proc Natl Acad Sci U S A 2015 Mar 10;112(10):3062-7
    CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite.
    Banerjee R, Khandelwal S, Kozakai Y, Sahu B, Kumar S
  36. 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
 
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