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  1. Biologics Research Projects

Improving the Safety of Blood and Blood Related Products by Reducing the Risk of Transfusion-Transmission of Leishmania Parasites

Hira Nakhasi, PhD., FASTMH

Office of Blood Research and Review
Division of Emerging and Transfusion Transmitted Diseases
Laboratory of Emerging Pathogens

[email protected]

Biosketch

I am the Director of the Division of Emerging and Transfusion Transmitted Diseases in the Office of Blood Research and Review (OBRR) at the Center for Biologics Evaluation and Research (CBER) of FDA.  I received my Masters and Ph.D. in biochemistry from the M.S. University in Baroda, India and post-doctoral training at the National Institutes of Health in Bethesda, MD, USA and Columbia University in NY.   Before my current position, I was also the acting associate director for Research in OBRR/CBER and Chief of Laboratory of Parasitic Biology and Biochemistry in the Division of Allergenic and Parasitic Products, in the Office of Vaccines Research and Review at CBER.

My main research focus is on the development of Leishmania donovani vaccine and diagnosis. My laboratory is also developing diagnostic reagents for blood-borne parasitic pathogens to ensure the safety of our nation’s blood supply.

My scientific expertise in molecular virology, parasitology, immunology and vaccinology is reflected in over 130 publications, including reviews and book chapters and membership of the review committees of several high impact journals, reviewer of grants, and invited talks at national and international forums. My research on Leishmania vaccine is partially funded by research grants from various sources.  I am also a member of several scientific organizations, including the American Association of Immunologists, American Society of Microbiologists, American Society of Tropical Medicine and Hygiene, and a Fellow of the American Society of Tropical Medicine and Hygiene (FASTMH). I have also received numerous awards, including the US Department of Human and Health Services Distinguished Service Award.

General Overview

Leishmaniasis is a vector-borne disease caused by Leishmania parasites transmitted by the bite of certain species of sand fly in parts of South America, Africa, Southeast Asia, the Middle East, and Southern and Eastern Europe. It has been designated by the World Health Organization as one of the top 10 neglected tropical diseases. Environmental changes such as global warming or human migrations have affected the vector-reservoir-host triad and led an expansion of the leishmaniasis geographical range. Co-infection of HIV and visceral leishmaniasis has led to the reemergence of visceral leishmaniasis in Leishmania non-endemic countries.

United States military personnel or civilians stationed in areas of the world where leishmaniasis occurs are at risk of infection. This threat has increased in recent years because of extensive travel to these areas by US citizens and migration of people from endemic areas. Recently, it has been reported that local cases of Leishmania infection are occurring in the southern states of US.

Depending on the specific type of the disease, a person with leishmaniasis can develop disfiguring ulcers in the skin, nose, mouth, or throat; or suffer potentially fatal spleen or liver damage. Transfusions of blood from infected donors can also spread the parasite.

Approximately 12 million people are infected worldwide, > 350 million people at risk, with more than half a million new clinical cases reported annually and ~50,000 deaths annually. There are no vaccines or donor screening assays for Leishmania parasites. In addition, immigration from Latin American, Asian, African and Middle Eastern countries where incidence of Leishmaniasis is increasing because of the failure of health care system, non-compliance to drug treatment and political unrest in some of these countries poses a serious risk of spread of the disease in the US. 90% of human visceral leishmaniasis infections are asymptomatic and can transmit Leishmania parasite through blood transfusion. Industry is currently developing vaccines and diagnostic tests for Leishmania infection for evaluation by FDA.

One of the major obstacles to detecting the parasites in blood is that they occur in very low numbers. Therefore, we are developing methods using state-of-art technologies to solve that problem.

My laboratory is evaluating the safety and efficacy of various vaccine candidates, including genetically modified live attenuated parasites. We are also developing biomarkers of safety and immunity that can be used by the manufacturers to test the safety and effectiveness of such vaccines before submitting them to FDA for evaluation.

Scientific Overview

In addition, we have developed genetically modified Leishmania donovani parasites and performing preclinical evaluation of their immunogenicity and safety in animal models, such as mice, hamsters and dogs. We also are evaluating their immunogenicity in peripheral blood mononuclear cells form normal and infected individuals from the endemic regions of Leishmania.

Following are the specific regulatory challenges that my laboratory is trying to address regarding Leishmania vaccines.

  1. What are the differences in immune and non-immune biomarkers of immunogenicity among various Leishmania vaccine candidates (recombinant vs. genetically modified vaccines) and can some of the biomarkers predict protection in the clinical setting?
  2. Will Leishmania vaccines protect both lethal and non-lethal Leishmania infections?
  3. Will Leishmania vaccines protect in the presence of other co-parasitic infections, such as malaria and Chagas, which are common in the Leishmania endemic regions?
  4. Approximately 90% of the individuals who are infected with Leishmania do not show any symptoms. These individuals can transmit infections to non-infected individuals, either through blood transfusion or through the sand fly vector. Therefore, will Leishmania vaccine be effective in asymptomatic individuals?
  5. Natural infection in endemic areas occurs through the bite of an infected sand fly, which is the vector for Leishmania. Can Leishmania vaccines be effective against infection via sand fly bite in preclinical studies? 

To address the above-mentioned questions, we have accomplished some of the goals and are pursuing the others. These studies are being conducted in collaboration with scientists from with National Institute of Allergy and Infectious Diseases (NIH), Ohio State University, McGill University (Montreal, Canada) and the Institute of Tropical Medicine (Nagasaki University, Japan).

Publications

  1. PLoS Negl Trop Dis 2019 Nov 18;13(11):e0007865
    Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner.
    Musa MA, Nakamura R, Hena A, Varikuti S, Nakhasi HL, Goto Y, Satoskar AR, Hamano S
  2. PLoS Negl Trop Dis 2019 Sep 19;13(9):e0007616
    Innovations for the elimination and control of visceral leishmaniasis.
    Selvapandiyan A, Croft SL, Rijal S, Nakhasi HL, Ganguly NK
  3. Front Immunol 2019 Sep 24;10:2273
    miR-21 expression determines the early vaccine immunity induced by LdCen(-/-) immunization.
    Gannavaram S, Bhattacharya P, Siddiqui A, Ismail N, Madhavan S, Nakhasi HL
  4. Vox Sang 2019 Jan;114(1):17-27
    International survey on the impact of parasitic infections: frequency of transmission and current mitigation strategies.
    Leiby DA, O'Brien SF, Wendel S, Nguyen ML, Delage G, Devare SG, Hardiman A, Nakhasi HL, Sauleda S, Bloch EM
  5. Front Immunol 2018 Nov 26;9:2741
    Leptin functions in infectious diseases.
    Maurya R, Bhattacharya P, Dey R, Nakhasi HL
  6. Parasitol Res 2018 Oct;117(10):3215-28
    A Leishmania-specific gene upregulated at the amastigote stage is crucial for parasite survival.
    Avishek K, Ahuja K, Pradhan D, Gannavaram S, Selvapandiyan A, Nakhasi HL, Salotra P
  7. Biochim Biophys Acta 2018 Aug;1865(8):1148-59
    A novel signal sequence negative multimeric glycosomal protein required for cell cycle progression of Leishmania donovani parasites.
    Ahuja K, Beg MA, Sharma R, Saxena A, Naqvi N, Puri N, Rai PK, Chaudhury A, Duncan R, Salotra P, Nakhasi H, Selvapandiyan A
  8. Front Immunol 2018 Jun 4;9:1176
    Centrin-deleted Leishmania donovani parasites help CD4+ T cells to acquire Th1 phenotype and multi-functionality through downregulation of CD200-CD200R immune inhibitory axis.
    Singh RK, Gannavaram S, Ismail N, Kaul A, Gedda MR, Nakhasi HL
  9. Parasitology 2018 Apr;145(4):443-52
    Dermotropic Leishmania donovani in Sri Lanka: visceralizing potential in clinical and preclinical studies.
    Kariyawasam KKGDUL, Selvapandiyan A, Siriwardana HVYD, Dube A, Karunanayake P, Senanayake SASC, Dey R, Gannavaram S, Nakhasi HL, Karunaweera ND
  10. Front Immunol 2017 Dec;8:1788
    Immunization with live attenuated Leishmania donovani Centrin(-/-) parasites is efficacious in asymptomatic infection.
    Ismail N, Kaul A, Bhattacharya P, Gannavaram S, Nakhasi HL
  11. Cell Host Microbe 2018 Jan 10;23(1):134-43
    Gut microbes egested during bites of infected sand flies augment severity of leishmaniasis via inflammasome-derived IL-1beta.
    Dey R, Joshi AB, Oliveira F, Pereira L, Guimarães-Costa AB, Serafim TD, de Castro W, Coutinho-Abreu IV, Bhattacharya P, Townsend S, Aslan H, Perkins A, Karmakar S, Ismail N, Karetnick M, Meneses C, Duncan R, Nakhasi HL, Valenzuela JG, Kamhawi S
  12. J Immunol 2018 Jan 1;200(1):163-76
    Live attenuated Leishmania donovani centrin gene-deleted parasites induce IL-23-dependent IL-17-protective immune response against visceral leishmaniasis in a murine model.
    Banerjee A, Bhattacharya P, Dagur PK, Karmakar S, Ismail N, Joshi AB, Akue AD, KuKuruga M, McCoy JP Jr, Dey R, Nakhasi HL
  13. BMC Infect Dis 2017 Dec 22;17(1):791
    Genetic diversity of Leishmania donovani that causes cutaneous leishmaniasis in Sri Lanka: a cross sectional study with regional comparisons.
    Kariyawasam UL, Selvapandiyan A, Rai K, Wani TH, Ahuja K, Beg MA, Premathilake HU, Bhattarai NR, Siriwardena YD, Zhong D, Zhou G, Rijal S, Nakhasi H, Karunaweera ND
  14. Sci Rep 2017 Oct 16;7(1):13240
    Role of mast cells in clearance of Leishmania through extracellular trap formation.
    Naqvi N, Ahuja K, Selvapandiyan A, Dey R, Nakhasi H, Puri N
  15. Sci Rep 2017 Oct 31;7(1):14693
    Ly6Chi inflammatory monocytes promote susceptibility to Leishmania donovani infection.
    Terrazas C, Varikuti S, Oghumu S, Steinkamp HM, Ardic N, Kimble J, Nakhasi H, Satoskar AR
  16. Sci Rep 2017 Jul 5;7(1):4718
    Whole genome sequencing of live attenuated Leishmania donovani parasites reveals novel biomarkers of attenuation and enables product characterization.
    Gannavaram S, Torcivia J, Gasparyan L, Kaul A, Ismail N, Simonyan V, Nakhasi HL
  17. Cell Immunol 2016 Nov;309:37-41
    Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines.
    Banerjee A, Bhattacharya P, Joshi AB, Ismail N, Dey R, Nakhasi HL
  18. Sci Rep 2016 Sep 14;6:33059
    Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs.
    Avishek K, Kaushal H, Gannavaram S, Dey R, Selvapandiyan A, Ramesh V, Negi NS, Dubey US, Nakhasi HL, Salotra P
  19. PLoS Negl Trop Dis 2016 Aug 31;10(8):e0004963
    Live attenuated Leishmania donovani centrin knock out parasites generate non-inferior protective immune response in aged mice against visceral leishmaniasis.
    Bhattacharya P, Dey R, Dagur PK, Joshi AB, Ismail N, Gannavaram S, Debrabant A, Akue AD, KuKuruga MA, Selvapandiyan A, McCoy JP Jr, Nakhasi HL
  20. Am J Trop Med Hyg 2016 Jul 6;95(1):109-19
    Differential Role of Leptin as an Immunomodulator in Controlling Visceral Leishmaniasis in Normal and Leptin-Deficient Mice.
    Maurya R, Bhattacharya P, Ismail N, Dagur PK, Joshi AB, Razdan K, McCoy JP Jr, Jill A, Dey R, Nakhasi HL
  21. Transfusion 2016 Jun;56(6 Pt 2):1537-47
    Multiplex detection and identification of viral, bacterial, and protozoan pathogens in human blood and plasma using a high-density resequencing pathogen microarray platform.
    Kourout M, Fisher C, Purkayastha A, Tibbetts C, Winkelman V, Williamson P, Nakhasi HL, Duncan R
  22. Front Immunol 2016 May 13;7:187
    Modulation of innate immune mechanisms to enhance Leishmania vaccine-induced immunity: role of coinhibitory molecules.
    Gannavaram S, Bhattacharya P, Ismail N, Kaul A, Singh R, Nakhasi HL
  23. J Appl Microbiol 2016 Apr;120(4):1119-29
    Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens.
    Dong M, Fisher C, Anez G, Rios M, Nakhasi HL, Hobson JP, Beanan M, Hockman D, Grigorenko E, Duncan R
  24. Parasit Vectors 2016 Apr 30;9(1):250
    Application of rapid in vitro co-culture system of macrophages and T-cell subsets to assess the immunogenicity of dogs vaccinated with live attenuated Leishmania donovani centrin deleted parasites (LdCen-/-).
    Viana KF, Fiuza JA, Gannavaram S, Dey R, Selvapandiyan A, Bartholomeu DC, Silveira-Lemos DD, Bueno LL, Dutra WO, Fujiwara RT, Nakhasi HL, Giunchetti RC
  25. Methods Mol Biol 2016;1403:623-38
    Methods to evaluate the preclinical safety and immunogenicity of genetically modified live-attenuated Leishmania parasite vaccines.
    Gannavaram S, Bhattacharya P, Dey R, Ismail N, Avishek K, Salotra P, Selvapandiyan A, Satoskar A, Nakhasi HL
  26. PLoS Negl Trop Dis 2016 Jan 11;10(1):e0004322
    Intradermal immunization of Leishmania donovani centrin knock-out parasites in combination with salivary protein LJM19 from sand fly vector induces a durable protective immune response in hamsters.
    Fiuza JA, Dey R, Davenport D, Abdeladhim M, Meneses C, Oliveira F, Kamhawi S, Valenzuela JG, Gannavaram S, Nakhasi HL
  27. Infect Immun 2015 Oct;83(10):3800-15
    Genetically modified live attenuated L.donovani parasites induce innate immunity through classical activation of macrophages that direct Th1 response in mice.
    Bhattacharya P, Dey R, Dagur PK, Kruhlak M, Ismail N, Debrabant A, Joshi AB, Akue A, Kukuruga M, Takeda K, Selvapandiyan A, McCoy JP Jr, Nakhasi HL
  28. Proc Natl Acad Sci U S A 2015 Jul 28;112(30):E4094-103
    TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.
    Allman WR, Dey R, Liu L, Siddiqui S, Coleman AS, Bhattacharya P, Yano M, Uslu K, Takeda K, Nakhasi HL, Akkoyunlu M
  29. Vaccine 2015 Jan 3;33(2):280-8
    Vaccination using live attenuated Leishmania donovani centrin deleted parasites induces protection in dogs against Leishmania infantum.
    Fiuza JA, Gannavaram S, Santiago HD, Selvapandiyan A, Souza DM, Passos LS, Mendonca LZ, Lemos-Giunchetti DD, Ricci ND, Bartholomeu DC, Giunchetti RC, Bueno LL, Correa-Oliveira R, Nakhasi HL, Fujiwara RT

 

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